Lehigh Valley Hospital & Health Network.

Allentown, PA, May 1 (OHRP)

It was alleged that the Lehigh Valley Hospital (LVH) IRB did not review and approve protocol changes and enrolled a complainant's husband into a research project even though he was ineligible due to treatment with the anti-arrhythmic medication digoxin.

OHRP determined that there was no proven violation of HHS regulations regarding this allegation because, as the hospital's report stated, "digoxin does not possess any of accepted classes of Vaughan-Williams antiarrhythmic properties and as such is not traditionally classified as an anti-arrhythmic."

Further, the report noted, "The specific purpose of this exclusion criterion was to avoid enrollment of patients taking medications that possess intrinsic beta blocking properties ... which could potentially affect the pharmacodynamic effects of the intervention under study (i.e., perioperative beta blockade). Such exclusion criteria have been used in prior studies of the effect of perioperative beta-blockade for the same reason."

Based on this explanation, OHRP concluded the use of the drug digoxin was not and did not need to be within the scope of the stated exclusion criteria for the protocol.

The complaint also charged the hospital with failing to have a cardiologist assess the subject's eligibility for the study, as required by the protocol. The agency reviewed the hospital's IRB-approved protocol and noted that the protocol did not require that the assessment/screening be conducted by a cardiologist; instead, the protocol stated that "Patients will be screened for cardiac risk factors prior to surgery." Notwithstanding the protocol requirements, the agency acknowledged LVH's statement that the principal investigator confirmed with the subject's primary cardiologist that the subject was a candidate for the study.

It was alleged that the hospital's review board approved the research even though it had failed to ensure that risks to subjects are minimized. In specific, the complaint alleged that the exclusion criteria of a resting heart rate less than 55 beats per minute or systolic blood pressure less than 90, unless the subject is already being treated with a beta-blocker, did not adequately minimize risks to subjects. It was also alleged that even in the presence of treatment with beta-blocker, such low heart rate or blood pressure should have been an exclusion criterion.

OHRP concluded that the hospital did not violate HHS regulations because:

* The exclusion criteria only applied when determining whether a patient was a potential study candidate; these criteria were not the parameters by which beta-blocker dosing decisions were made during the study;

* The hemodynamic parameters by which dosing decisions were made were consistent with the American College of Cardiology/American Heart Association 2006 Focused Update on Perioperative Beta-Blocker Therapy and typical clinical practice with LVH;

* Literature supports the practice of targeting a heart rate of 60 bpm or below in the perioperative period to achieve maximum cardioprotection with the use of perioperative beta-blocking agents; and

* Dosing parameters set by the study team are supported by the lack of adverse events related to hypotension or bradycardia for the entire study.

Based on the information submitted, the agency made some recommendations regarding the hospital's review board Polices and Procedures. Al though various policies within the Polices and Procedures Document distinguish between voting IRB members and non-voting IRB members, no such entity as a non-voting review board member exists under HHS regulations, OHRP noted, and recommended revising these policies accordingly.

The policy on IRB Meeting Administration does not reflect that meeting minutes will include the basis for disapproving research. Lehigh Valley equates "tabling of the research" with deferral, not disapproval. The agency recommended revising this policy to reflect that the hospital IRB meeting minutes will include, among other things, the basis for disapproving research as required by regulations.

The policy on Criteria for IRB Approval provides that "All research proposals that intend to enroll human subjects must meet certain criteria before study related procedures can be initiated." OHRP noted that reference to "study related procedures" in this policy may be too narrow.

Regulations provided that an IRB must review and approve all research activities covered by this policy, including all research interventions or interactions with a living individual that result in the collection of data about the individual. According to the definition of 'human subject' in federal regulations, an intervention "includes both physical procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subject's environment that are performed for research purposes."

An interaction includes "communication or interpersonal contact between investigator and subject;" e.g., collecting eligibility information from potential subjects prior to initiating study-related procedures. Thus, an IRB must review and approve all research activities, including all recruitment interactions with a living individual, before study related activities can occur given that these activities result in the collection of data about living individuals for research purposes. Based on this explanation, OHRP recommended that Lehigh Valley consider revising this policy to more clearly define the scope of "study related procedures."

The hospital's Categories of Action policy states that the hospital IRB calculates the approval date studies in which approval is withheld pending minor clarifications based on the date that the review board approves required information or materials. HHS regulations require that except when an expedited review procedure is used, each board must review proposed research at convened meetings at which a majority of the members of the IRB are present, including at least one member whose primary concerns are in nonscientific areas; and an IRB must conduct continuing review of research at intervals appropriate to the degree of risk, but not less frequently than once per year.

According to the OHRP Continuing Review Guidance document, review boards should focus on the date of the convened meeting at which the IRB conditional approval occurred when determining the date for continuing review, and not the date that the required information or materials are approved by the IRB. BiM0