On July 19 Hopkins received notice that the Office of Human Research Protection was suspending all federally supported medical research projects involving human research at almost all Hopkins institutions.The action was taken three days after the School of Medicine issued a report in which it took full responsibility for the death on June 2 of a research volunteer. A story on the report follows; the university's response to the OHRP decision appears online here.

A School of Medicine review committee investigating the death of a research volunteer has concluded that although the precise cause of death is "likely to remain uncertain," it believes her death resulted from exposure to inhaled hexamethonium. Committee members based their conclusion on "the timing between hexamethonium inhalation and the development of pulmonary symptoms" and other factors.

The committee report, submitted July 16 to the federal Office of Human Research Protection, said the autopsy on the volunteer, Ellen Roche, showed widespread lung damage but "provided no specific etiologic diagnosis." Nevertheless, the committee report said, "the death was as the result of participation in the hexamethonium phase of the experiment."

"Regardless of the fact that we are unlikely ever to know precisely how or why this happened, Hopkins takes full responsibility for what did happen," said Edward D. Miller, dean and CEO of Johns Hopkins Medicine, commenting on the committee's findings. "We can only imagine the family's grief, and as the institution conducting the research, we want the family and the public to know that we acknowledge our responsibility. Our goal from the start," he added, "has been to find out the facts, identify any factors that would have predicted or prevented such an event, to correct any deficiencies in our institutional review processes, as well as in faculty compliance, and to inform the public fully when the facts were in."

Roche became ill within days of her participation as the third subject in the inhalation study and died June 2 after many weeks of intense efforts to save her life.

Beyond consideration of the timing between hexamethonium inhalation and the development of lung symptoms, the committee based its overall opinion on cause of death on the lack of any other identifiable cause, including a wide variety of infectious agents; the development of pulmonary symptoms, although less severe ones, after hexamethonium inhalation by the first research volunteer in the study; and on previous reports of a link between prolonged use of intravenous hexamethonium administration and lung problems in a few very sick patients.

The report from the committee, chaired by Lewis Becker, professor of medicine-cardiology at Hopkins, a faculty member with long experience with institutional review boards and human research protocols and newly appointed director of the Hopkins Joint Committee on Clinical Investigation-1, one of Hopkins' IRBs, also noted it had divided opinion for some of its conclusions. The report thus "represents the opinion of the majority rather than a total consensus. In addition," the report continued, "it should be emphasized that although the facts in this case were relatively easily established, deciding what actions should or should not have been taken by the IRB or the principal investigator at the time events were transpiring was often very difficult, and engages several unsettled, but important issues..."

The report also stated that:

Roche received state-of-the-art medical care, including "liberal use" of expert consultants and all treatments known to be effective.

There was no coercion involved in her recruitment as a volunteer.

The research in question "had solid scientific rationale and was well designed,"... "required human subjects and could not have been adequately done in experimental animals" and "was of particular importance given the increasingly high prevalence of asthma in urban populations."

The IRB at the Johns Hopkins Bayview Medical Center followed published standard procedures in reviewing and approving the proposed research submitted by principal investigator Alkis Togias, but the majority of the committee believed the IRB should have required more evidence of safety in the use of hexamethonium.

Both outside expert consultants to the committee thought the need for an Investigational New Drug (IND) opinion or exemption from the U.S. Food and Drug Administration to use hexamethonium, which is no longer on the FDA's approved list of drugs, was far from clear and that there was "adequate precedent" for IRB approval of the study without one. The committee also noted that other inhaled drugs for lung studies have been considered exempt from IND by the FDA in the past. But the committee also said that in this case, where the inhalation of hexamethonium had been performed previously in a small sample of volunteers, it believed the IRB should have asked the principal investigator to get a written opinion from the FDA about the need for an IND.

The consent form signed by the research volunteer "accurately outlined the purpose of the study, the procedures, the benefits and the alternatives." Moreover, the principal investigator "made a good faith effort to discover potential toxicities through current standard medical literature searches and textbook reviews." But the committee also said it believes that the consent form was "inadequate in the description of the research risks." It was "divided" on whether the principal investigator should have known about the published case reports linking prolonged intravenous hexamethonium use with lung disease and therefore whether this information should have been included in the consent form.

Specifically, the committee said the consent form should have indicated that hexamethonium was not FDA approved and was no longer used clinically; that hexamethonium as an inhalant was used only experimentally, never clinically; that the safety of inhaled hexamethonium was unknown with certainty since it was based on published reports involving a total of only 20 people; and that there was a possibility of serious adverse event or death related to study participation.

The report also noted procedural departures from the approved protocol by the principal investigator, which were further spelled out in a letter sent on July 13 by Hopkins' vice dean for research, Chi Dang. In the letter, Dang noted that "as a result of the investigation committee's findings, we have determined that Dr. Togias' protocol was not conducted in compliance with the stated Johns Hopkins University School of Medicine policies and federal regulations for requiring review of amendments to a research protocol."

The committee report said, however, that it was likely that the departures would have been approved by the IRB had they been reported as required. The committee also found that the principal investigator should have promptly reported to the IRB the cough of the first volunteer.

"Johns Hopkins has a robust system and high standards for doing human research, with many studies involving many subjects reviewed each year by our institutional review boards, whose volunteer members are expert and dedicated," according to Dang. "They and we are committed to our research mission to advance human health and equally committed to ensuring the safety of human subjects. In light of this event, which has given us all pause, we have scrutinized our processes and procedures and are raising the bar higher to ensure the safety of all those who participate in research at Hopkins."

Dang said steps to be taken include:

Creation of a third institutional review board to handle the review of the large number of studies and increase expertise available for analysis of submitted protocols. (This already is in place.)

Initiation by the IRB of a hold on all of Togias' research and on 16 other investigator-initiated projects that involve agents not covered by an FDA-approved IND number, pending the outcome of ongoing reviews and further consultations with the FDA on the need for an approved IND in such cases. (This already has been done.)

An increase in the number of random quality control checks of ongoing research protocols to see how well they ensure safety and adhere to best practices.

Continued cooperation with the FDA and OHRP in their ongoing investigations.

Initiation of an intensive review of the IRB processes by an external audit firm.

Development of an action plan to address any deficiencies identified in the Hopkins system for protection of human research subjects.

Hopkins earlier delivered a strong reminder to all research faculty that policies and rules of procedure governing human research and protection must be strictly adhered to and that they must inform the IRB of any changes in approved protocols. All Hopkins investigators listed on a human subjects research application must pass an examination regarding research using human subjects before the IRB will issue final approval of a protocol.

In the July 13 letter to OHRP's director of compliance oversight, Dang responded to several questions also answered in the full committee report, including some related to whether the IRB or Togias was aware of hexamethonium's implication in some cases of lung damage prior to approval of the research. "The investigation committee [which included members with expertise in pulmonary medicine and in use of investigational drugs] probed this question extensively," the letter said.

Committee members "during the investigation ... themselves conducted searches to determine how easily one could find information about the pulmonary side effects ... ," Dang wrote. "Some members -- were unable to find the specific, old references -- until several search engines were employed, review articles identified and detailed analysis of 1950s material 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 -- we intend to develop and articulate a standard at Hopkins that will be applied for all investigator-initiated research projects."

The letter also noted that "the IRB did not conduct an independent search of the literature as it relied on the information submitted by the investigator who was known to them as an experienced researcher. The application from Togias included four references to similar studies of inhaled drugs in human subjects, and the IRB neither requested nor searched for additional safety data beyond that provided..."

Commenting further on the changes already made and those that may come, Miller said that "medicine is the one profession that routinely investigates its own mistakes, sometimes in brutally harsh ways and even when its practitioners make multiple, reasonable decisions in their care of people. Mistakes sometimes seem obvious only in hindsight, but they still need correcting. And that is what we are doing."

An external review committee, headed by Samuel Hellman, dean emeritus of the University of Chicago School of Medicine, is reviewing the work of the internal committee. This committee will submit a report to Hopkins leadership and trustees, probably by late summer.

Twenty-four-year-old Ellen Roche was a School of Medicine employee working at the Johns Hopkins Asthma and Allergy Center and a frequent volunteer in research designed to understand fundamental lung mechanisms involved in asthma. Specifically, the study in question was designed to shed light on how normal people's lungs maintain good function when exposed to factors that constrict them, and what role is played in this process by bronchial nerves.

A technician in the Asthma and Allergy Center, although not in the laboratory conducting the research for which she volunteered, Roche on May 4 received as part of the study approximately one gram of hexamethonium by inhalation to produce a blockade of certain bronchial nerve ganglia. On May 5, she developed a dry cough and other symptoms and subsequently flu-like symptoms (May 7) and fever (May 9) along with shortness of breath. She was admitted to the Johns Hopkins Bayview Medical Center on May 9, and her symptoms worsened over the next days and weeks and, despite all efforts, she died on June 2 with symptoms of adult respiratory distress syndrome.

"The research for which Ellen volunteered was vastly important to the advancement of human health," Miller said. "Without her help and the help of others like her, we cannot hope to treat, prevent or cure a disease that afflicts more than 10 million Americans and kills many. Hers was a truly noble act. We will do whatever it takes to protect those who generously volunteer to help advance medical knowledge and care."

The committee's report is available at http://www.hopkinsmedicine.org. Membership lists of both the internal investigative committee and the external advisory committee can also be found on that site.