We are responding to the second request contained in your letter of 6/15/2001. Since the original response to you dated 6/22/2001, the internal investigation committee has worked diligently to review the facts associated with the conduct of the research protocol, and the circumstances surrounding the death of the subject enrolled in the protocol. As we discussed by phone, a copy of their report will be provided to you on Monday, 7/16/2001, at the time of OHRP’s site visit. It provides additional details to support the responses to questions (1)(f) of your 6/15/2001 letter. We have considered the report of the investigation committee, and offer the following response to your specific questions as noted below.

"(2) By Friday, July 13, 2001, please provide OHRP with a report of your investigation into OHRP’s concerns and the circumstances surrounding the death of the subject enrolled in the above referenced research. A response to the following additional questions:

(c) (i) In his May 9, 2001 letter to Dr. Briefel, Dr. Togias reported that hexamethonium had been implicated in some cases of bronchiolitis obliterans organizing pneumonia (BOOP). Was Dr. Togias or the IRB aware of this information prior to the approval of the research? If not, why not."

During the investigation process, the committee members themselves conducted searches to determine how easily one could find information about the pulmonary side effects of hexamethonium. This effort is described in detail in the committee report. Some members of the investigation committee were unable to find the specific, old references to hexamethonium side effects until several search engines were employed, review articles identified, and detailed analysis of 1950’s material was reviewed. The committee was divided on the issue of what constitutes a sufficient search of the literature in support of a human subjects research application. Nonetheless, we recognize that the standard applied to material used in support of safety of a research protocol should be high. Since there is no accepted or agreed upon standard in the medical research community with regard to how extensively one should search for safety information, we intend to develop and articulate a standard at Hopkins that will be applied for all investigator-initiated research projects.

(ii) On what basis did the IRB determine that the hexamethonium used in this research was safe to administer via inhalation to human subjects? Did the IRB receive and review information related to the source, manufacture, quality, and safety of the hexamethonium used in this research?

The committee was aware of the 4 published papers, which did not mention pulmonary toxicity in a total of 20 human subjects. Nevertheless, after initial review of Dr. Togias’ RPN by the IRB members, Dr. Gary Briefel, the IRB Chair, wrote to the principal investigator with questions raised in the review. One question was: " If the hexamethonium is not an FDA approved product, the protocol should describe the source of the hexamethonium and how it will be made safe for human use." Dr. Briefel confirmed to the investigation committee that he and other members of the IRB were aware that hexamethonium was not a marketed drug.

In his response to the IRB, the principal investigator did not specify the FDA status of hexamethonium, but he indicated that the drug would be provided from the manufacturer, Fluka. He provided a certificate of analysis from Fluka verifying that the substance was 99.6% pure by argentometry (although Dr. Togias had indicated in his correspondence that purity was established by thin layer chromatography). The contaminants were said by the investigator to be inorganic salts. A limulus test was to be done to exclude endotoxin contamination. The principal investigator did not have the product in hand at the time of his response to the IRB, and so was unable to describe the labeling on Fluka’s hexamethonium bromide product ("For laboratory use only. Not for drug, household, or other use."). The IRB was apparently satisfied with these responses. Approval for the study was granted at the convened IRB meeting on 9/18/00.

"(I) If your investigation reveals noncompliance, a description of any corrective actions that have been or will be taken by your institution to prevent such noncompliance from recurring.

As indicated in my letter dated June 22, 2001, the IRB took action to suspend approval of any investigator-initiated project involving a drug, device, or biologic which is not covered by an FDA approved IND number. As the result of the investigation committee’s findings, we have determined that Dr. Togias’ protocol was not conducted in full compliance with the approved protocol and the stated JHUSOM policies and federal regulations for requiring review of amendments to a research protocol. We have also administratively suspended approval of all of Dr. Togias’ other approved studies while the review process is ongoing.

As the result of the finding that the protocol was revised without informing the IRB of the protocol changes, we have also reminded all investigators of their responsibility to have any changes in a protocol approved before they are implemented. A broadcast e-mail to all members of the JHMI community was sent out as follows:

Dr. William Brody – President, JHU
Dr. Edward D. Miller – CEO JHMI and Dean of the Medical Faculty
Dr. Gary Briefel - Chairman, JHBMC IRB
Dr. Solbert Permutt – Grant Principal Investigator
Dr. Alkis Togias – Protocol Principal Investigator
General Counsel’s Office – JHHS and JHU