On July 2, Johns Hopkins Medicine released the following statement:
The death last month of the young woman participating in a Johns Hopkins research study is a terrible tragedy. Since her death, we have been cooperating fully with the FDA and with the Office of Human Research Protection, as well as conducting our own internal review, which will be supplemented by an external review. Our efforts are meant not just to determine what happened in this specific case but to try to find ways to prevent any such occurrence in the future.
The FDA inspectors provided their preliminary observations to the study's principal investigator, Alkis Togias, on June 28, with a suggestion that his written response be submitted in time to accompany the inspectors' report, which may not be complete for two weeks. He intends to comply, and we believe that he should have the opportunity to respond. The university also will promptly make available to the FDA and OHRP the report of an internal review committee which has been actively examining all aspects of the research and events leading up to the death of this volunteer.
Nonetheless, because the FDA has chosen to make its preliminary observations public, we will discuss some of the FDA's observations and steps we already have taken to address them:
1. Failure by the sponsor/clinical investigator to submit an IND to the 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 several reasons:
* The study was not meant to test the therapeutic value of hexamethonium but was a basic physiological study.
* 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 our IRB reached its conclusion in a thoughtful manner, since the event the IRB has placed a hold on investigations involving agents for which there is not an IND number until we consult with the FDA on the IND issue.
2. Failure to report an unanticipated adverse event to the IRB (a persistent cough in the first subject, from April 25 to May 3).
Dr. 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.