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Johns Hopkins Medical Institutions’ response to the U.S. Food and Drug Administration’s observations concerning the death of a research volunteer:
1. Failure by the sponsor/clinical investigator to submit an investigational new drug (IND) to the U.S. Food and Drug Administration (FDA) prior to conducting this clinical investigation, which involved the administration of hexamethonium bromide by inhalation to three human subjects.
Both the investigator and the IRB believed an IND was not needed for two reasons: a) the study was not meant to test the therapeutic value of hexamethonium, but was a basic physiological study; b) hexamethonium was long used as an approved drug and was taken off the FDA registry in 1997 at the request of the manufacturer, presumably not because of adverse effects, but because other, better agents were available for treatment of high blood pressure.
While the IRB reached its conclusion in a thoughtful manner, since the event, the IRB placed a hold on investigations involving agents for which there is not an IND number until it consults with the FDA on the IND issue.
2. Failure to report a unanticipated adverse event to the IRB (a persistent cough in the first subject, from April 25 to May 3, 2001).
Dr. Alkis Togias informed the FDA inspectors that it was his opinion that the cough was due to an upper respiratory ailment going around the campus at that time. We are reiterating to faculty that all unanticipated adverse events must be reported to the IRB.
3. and 4. Failure to follow protocol and to report changes to the protocol, specifically by adding sodium bicarbonate to the hexamethonium to be administered by inhalation to the second and third subjects, thus altering the saline solution listed in the protocol.
As previously reported, for the comfort of the volunteers the investigator made alterations in the administered substance in accordance with preparations previously used and reported in the literature. Nonetheless, these should have been reported to the IRB. We have reminded faculty of the necessity to obtain approval for all changes to approved protocols.
5. Failure to obtain effective informed consents from subjects by failing to disclose that inhalation administration of hexamethonium was an experimental use of the drug.
After review and consideration, our IRB believed the lengthy consent form was adequate in addressing known risks. This issue is being addressed by the internal review committee, and we are awaiting its findings.
These preliminary observations may have had nothing to do with the death of the research volunteer, but we agree that they raise issues that we are addressing. We will do whatever it takes to protect those people who generously volunteer to help advance medical knowledge and care.
Source: Johns Hopkins Medical Institutions, Baltimore.