Feature Article

Dodging New Potholes on the Research Superhighway - April, 2006 Issue

Mary A. Banks, RN, BS, BSN
Director, Office of the Institutional Review Board

Author has nothing to disclose with regards to commercial support.

Educational Objectives:

• List the major types of incidents that OHRP categorizes as reportable.
• Explain acceptable plans of action that the institution can take to address unanticipated problems.
• Describe an incident that OHRP has designated as "serious non-compliance."
• Explain the procedures that you should take if you identify a situation during the conduct of your research that was not IRB-compliant.

PRINT | CLOSE WINDOW

• Introduction
• OHRP Reporting - What do they want?
• Unanticipated Problems Involving Risks to Subjects or Others
• Serious or Continuing Noncompliance
• Suspension or Termination
• Conclusion
• Quiz

Introduction

The scars of others should teach us caution. Saint Jerome (374 AD - 419 AD)

While dodging and swerving to avoid numerous potholes on the Southeast Expressway, it occurred to me that it would be useful to caution investigators about the potential regulatory “potholes” lurking along their research superhighways. A warning such as this might prove beneficial, since certain regulatory potholes are deep. The good news is that most can be avoided with some awareness and skilled maneuvering.

All investigators should be aware of the IRB’s regulatory responsibility for reviewing and approving or disapproving research, conducting ongoing review of research, and approving modifications to research (45 CFR 46.109). Less well known are the IRB’s regulatory requirements for reporting to the Office of Human Research Protections (OHRP) investigator noncompliance and unanticipated problems involving risks to subjects and others. The new direction of these OHRP reporting requirements is the topic of this article.

OHRP Reporting – What do they want?

Certain incidents must be reported to OHRP based on requirements in 45 CFR 46.103(b)(5). Historically IRBs have had difficulty complying with this regulation because OHRP was unclear about how it wanted this information reported. On May 27, 2005 OHRP published the Guidance on Reporting Incidents to OHRP. In this guidance OHRP clarified its expectations with regards to “incident reporting”.

In this guidance OHRP categorizes reportable incidents into three major types:

A. unanticipated problems involving risks to subjects or others;
B. serious or continuing noncompliance with HHS regulations at 45 CFR part 46 or the requirements or determinations of the institutional review board (IRB);
C. suspension or termination of IRB approval.

 

Unanticipated Problems Involving Risks to Subjects or Others

[Editor’s Note: Please see the October, 2007 Clinical Research Times article for an updated guidance and policy on reporting unanticipated problems (rather than adverse events) to the IRB.]

While the May 27, 2005 OHRP guidance provides little detail as to the definition of “unanticipated problems”, there is an OHRP DRAFT Guidance on Reporting and Reviewing Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others, which provides significant detail about these unanticipated problems.

This DRAFT guidance explains that the vast majority of adverse events (AE and SAEs) occurring in research are expected in light of the known toxicities or the subjects’ underlying conditions. Thus these do NOT represent unanticipated problems and do not need to be reported to OHRP. Conversely, a small proportion of research related adverse events do represent unanticipated problems and so these must be reported to OHRP.

Numerous examples of unanticipated problems that require reporting to OHRP are provided within this guidance document, including:

• A subject enrolled in a new drug clinical trial develops severe hepatic failure. The risk profile for the drug included mild elevation in liver enzymes in 10% of subjects but no history of subjects developing clinically significant liver disease. The consent form identified mild liver injury as a potential risk. The investigators could identify no other etiology, and thus attributed the liver failure to the study drug. This is a reportable unanticipated problem because although the risk of mild liver injury was foreseen, severe liver injury resulting in hepatic failure was unforeseen, and the protocol and consent form required modification.
• A behavioral study requires that subjects complete a detailed survey about early childhood. The study was reviewed as no more than minimal risk by the IRB. After completing the survey, one subject had a severe psychological reaction manifested by depression and suicidal ideation. The PI determined the reaction was the result of the survey questions triggering repressed memories of child abuse. The protocol and consent did not describe these risks. This SAE represents an unanticipated problem because the risk of the negative reaction was not foreseen.
• Due to a processing error by a pharmacy technician, a subject in a clinical trial received a dose of study drug that was ten times higher than the dose in the approved IRB protocol. The dosing error increased the risk of toxic manifestations but the subject experienced no detectable harm or adverse effect. Nevertheless, this constitutes a reportable unanticipated problem.

The IRB’s report to OHRP of these unanticipated problems must include a detailed description of the problem, and the corrective action the institution is taking or plans to take to address the problem (e.g., revise the protocol, suspend subject enrollment, terminate the research, revise the informed consent document, inform enrolled subjects, increase monitoring of subjects). When reviewing a report of an unanticipated problem, OHRP assesses most closely the adequacy of the actions taken by the institution to address the problem.

As of April, 2006, the OHRP guidance document referenced in this section is still in DRAFT form. The BUMC IRB policies for reporting of unanticipated problems will be modified as soon as the final guidance is published.

Serious or Continuing Noncompliance

This category specifically addresses investigator noncompliance. This may be noncompliance with regulatory requirements or with IRB policies and procedures. Noncompliance in this category must be reported to OHRP if it is serious OR continuing; it need not be both.

While OHRP has left room for interpretation by individual IRBs as to which “incidents” are SERIOUS, there are certain incidents which OHRP has designated as serious noncompliance. All incidents that involve the conduct of non-exempt human subjects research activities without IRB approval or without appropriate informed consent are serious and are, therefore, reportable to OHRP. Here are some examples of non-exempt human subjects research conducted without IRB approval:

Initiation of research-related activities without full IRB approval. Conditional approval does NOT constitute full IRB approval. Full IRB approval is not granted until all conditions have been met and the IRB has generated an approval letter in INSPIR.
Research conducted without IRB review. Both failure by investigators to submit human subjects research studies to the IRB for review; OR failure to include all human subjects research activities in the IRB submission, fall into this category.
No IRB approval by an institution engaged in research. Although a protocol may be approved by another IRB, if BUMC is engaged in research, then the BUMC IRB must also grant approval before the research can begin (unless an authorization agreement is in place between the two institutions). Note: if BUMC is the recipient of the grant, then BUMC is engaged in research.
Modifications to an approved IRB protocol without IRB approval. All changes or modifications to approved research must be approved by the IRB before they can be instituted. An exception can be made if the safety of subjects is at risk. In such instances the IRB must be contacted immediately and a protocol exception submitted in INSPIR.
Research conducted after the expiration date of a research protocol. The regulations make no allowances for granting extensions to the study approval period. If the IRB has not granted FULL approval by the expiration date, then all research-related activities must cease, including subject recruitment, data analysis and follow-up activities (unless the IRB finds that it is in the best interests of individual subjects to continue participating in the research interventions. In such situations the PI must immediately submit an EXCEPTION REQUEST and arrange with the IRB for prompt review of the protocol.)
Enrolling subjects who do NOT meet the inclusion / exclusion criteria specified in the IRB protocol. If the PI wishes to enroll subjects who do not meet the enrollment criteria, an EXCEPTION REQUEST must first be approved by the IRB. It is not sufficient to only receive approval from the study sponsor.

The IRB will make determinations as to whether incidents represent continuing noncompliance on a case-by-case basis. Possible examples of continuing noncompliance include (but are not be limited to)

Multiple reports of an investigator failing to follow IRB procedures
Investigator frequently allowing studies to lapse
Multiple instances of investigator using invalid or unapproved forms
Investigator failing to follow his or her own corrective action plan as submitted to the IRB

Reports of investigator noncompliance made to OHRP by the IRB must include a detailed description of the noncompliance and the corrective action the institution is taking or plans to take to address the noncompliance (e.g., educate the investigator, educate all research staff, suspend the protocol, suspend the investigator from performing research, conduct random audits of the investigator or all investigators). In such instances OHRP is most concerned with the corrective action plan to prevent recurrence.

Suspension or Termination

45 CFR 46.113 states that “An IRB shall have authority to suspend or terminate approval of research that is not being conducted in accordance with the IRB's requirements or that has been associated with unexpected serious harm to subjects. Any suspension or termination of approval shall include a statement of the reasons for the IRB's action and shall be reported promptly to the investigator, appropriate institutional officials, and the department or agency head. ”

Disapproval by the IRB at the time of continuing review of previously approved research, and disapproval/non-approval by the IRB of multi-site research which has been approved by other sites must also be reported in this category. Studies where IRB approval has lapsed are considered to be expired studies rather than terminated or suspended studies, so they do not have to be reported to OHRP. (But, as indicated above, research conducted after a study has lapsed is reportable as serious noncompliance; and research that is repeatedly allowed to lapse is reportable as continuing noncompliance.)

For incidents in this category, the IRB must submit to OHRP a detailed description of the reason for the suspension or termination, and the actions the institution is taking or plans to take to address the suspension or termination (e.g., investigate alleged noncompliance, educate the investigator, educate all research staff, require monitoring of the investigator or the research project).

Conclusion

Investigators are reminded that the reporting requirements for the IRB discussed in this article are not optional. The IRB must comply with these regulations and cannot opt to deal with issues of noncompliance by an alternative method (such as an internal memo). Investigators who wish to see these regulations put into action may view OHRP determination letters sent to other institutions. These letters are publicly available and can be accessed by clicking on OHRP determination letters.

Investigators may also consult the BUMC IRB policies and procedures for details about who is copied on reports made to OHRP. In most instances a copy of the OHRP report will also be sent to the PI’s Department Chair or Chief, the BUMC Institutional Official, the study sponsor, the FDA (if appropriate) and the IRB Panel Chair. In certain instances, other IRBs involved in the research may also be notified.

Top

Click here and close window if you are a BUMC researcher
and would like to take the quiz now.

Close Window