Ellen Roche was a vibrant 24-year-old laboratory technician at the Johns Hopkins Asthma and Allergy Center who lost her life on June 2, 2001, while participating in what seemed like a normal asthma study.
Her death raised critical questions about research ethics, informed consent, and the safety protocols designed to protect healthy volunteers.
Ellen Roche was a healthy young woman who worked as a laboratory technician at the Johns Hopkins Bayview Medical Center's Asthma and Allergy Center in Baltimore, Maryland. 4 When she volunteered for the asthma study, she had nothing to gain except an experience in research and a modest honorarium of $365.1, 2
She participated in a research protocol involving the administration of hexamethonium bromide by inhalation and methacholine challenge.
According to National Library of Medicine, Hexamethonium Bromide acts as Antihypertensive agent, ganglionic blocker, and nicotinic antagonists.
The study Roche volunteered for was designed to test a controversial theory about asthma. Researchers wanted to understand why healthy people could protect themselves against asthma-like reactions while those with asthma could not. 4
The hypothesis was fascinating: both people with asthma and those without experienced similar reactions when exposed to inhaled irritants, experiencing bronchiolar vasoconstriction. However, people without asthma can overcome the reaction through deep breathing, while asthmatics cannot. 4
The study aimed to provoke a mild asthma attack in healthy volunteers to help doctors discover the reflex mechanism that protects normal lungs. 1
Led by Dr. Alkis Togias, an associate professor and clinical immunologist at Johns Hopkins, the research was funded by the National Institutes of Health in Bethesda, Maryland. It built upon Togias's previous work demonstrating that healthy individuals could resist the bronchoconstrictive effects of inhaled methacholine through deep breathing, while asthmatics could not. 4
The researchers sought to elucidate the neural mechanisms underlying these protective reactions.
Their approach involved blocking the ganglionic nerve transmission in normal lungs using hexamethonium. 2
Hexamethonium is a ganglion blocker that affects both the sympathetic and parasympathetic nervous systems. It was used as an antihypertensive medication in the 1940s and 1950s but was withdrawn by the Food and Drug Administration in the early 1970s after superior blood pressure medications emerged. 4
The drug works by disabling the protective mechanism of lung relaxation induced by deep breathing, exactly what the researchers wanted to study. 2
Roche signed an informed consent form before participating. However, this document warned only about wheezing, chest tightness, and temporary difficulty in breathing. 2 Critically, the consent form failed to indicate that hexamethonium was not an approved drug for clinical use and had never been approved for delivery by inhalation in the United States. 3
This omission would later become a central point of criticism in the investigation following her death.
Roche was the third volunteer in the clinical trial.
The day after inhaling hexamethonium, she experienced a cough and shortness of breath, followed by flu-like symptoms. 3, 4 She reported these symptoms including dry cough, wheezing, and muscle aches within 36 hours but she managed to until her sixth visit. 4
Her condition deteriorated rapidly. She developed:
A persistent cough and progressive breathing difficulty
Fever and flu-like symptoms
A 35% reduction in lung function
Acute respiratory distress syndrome
Renal failure 2,4
Within a week of her initial symptoms, Roche was placed on a ventilator. Her lung tissue began breaking down, her blood pressure fell, and her kidneys started to fail.
Despite aggressive medical intervention, nothing could save her. Ellen Roche died on June 2, 2001, approximately one month after entering the study. 1
An autopsy revealed no specific cause for the catastrophic lung damage. 3 The study was then subsequently suspended. 4
The investigation into Roche's death uncovered numerous safety lapses that, in hindsight, might have prevented the tragedy:
The hexamethonium solution was not prepared by a pharmacist, and the protocol for its preparation and delivery by nebulization was altered during the course of evaluating the first two volunteers.
This lack of pharmaceutical oversight potentially compromised both sterility and proper drug delivery. 3
2. Ignored Warning Signs from Previous Volunteer
The first volunteer in the study experienced a cough, shortness of breath with deep breathing and exertion, and reductions in measured lung function for one week following hexamethonium inhalation.
Rather than thoroughly investigating these concerning symptoms, consulting with the Research Ethics Board, or reaching out to other researchers experienced with hexamethonium, the lead researcher concluded the episode was probably due to a concurrent viral infection.
Note: This assumption would later prove tragically wrong.
In hindsight, proper discussions and evaluation might have delayed or prevented administration of the drug to the third volunteer, Ellen Roche. 3
The researchers used a sitting rather than standing position to measure hemodynamic changes.
This could have resulted in greater ganglionic blockade than achieved in previous reports. The only reliable way to assess the completeness of ganglionic blockade is by measuring orthostatic changes in blood pressure and heart rate when moving from lying to standing.
Using the lying-to-sitting position may have blunted this response, potentially giving the false impression that insufficient hexamethonium had been administered. 3
Perhaps most troubling was the inadequate review of existing medical literature. A handful of adverse pulmonary reactions to hexamethonium had been reported in medical journals in the 1950s, including cases of bronchiolitis obliterans organizing pneumonia (BOOP) and acute respiratory distress syndrome (ARDS). 4
Following Roche's death, Johns Hopkins investigators found additional reports of pulmonary toxicity published between 1953 and 1962, including an article in the Canadian Medical Association Journal from 1955, and a 1972 review article, none of these were included in the protocol submitted to the Research Ethics Board. 3
Even more damning, discussions within the medical community after the tragedy uncovered an unpublished report of a possible pulmonary complication experienced by a healthy volunteer in a 1978 San Francisco study after receiving hexamethonium by inhalation. 3
The association with pulmonary toxicity was not considered until Roche was already hospitalized, when researchers discovered the website pneumotox.com, which suggested a relation to longer-term use of ganglionic blockade for treating hypertension. 3
Following Ellen Roche's death, the tragedy was formally reported to the University's Institutional Review Board and to the Office of Human Research Protections, the division of the US Department of Health and Human Services responsible for enforcing the ethical treatment of research subjects and investigating deaths and adverse reactions in federally funded studies. 4
The Office for Human Research Protections conducted a thorough investigation into the circumstances of Ellen Roche's death. Their findings were damning: they accused the Johns Hopkins Institutional Review Board of failing to take proper precautions and evaluated the entire human subject protection system at the institution. 1
After Roche's death, Dr. Solbert Permutt, a pulmonologist at Johns Hopkins University and one of the investigators, issued an advisory letter to fellow researchers warning them to avoid hexamethonium in human experiments. 4
While neither of the review panels felt that the historical information about pulmonary toxicity would have necessarily stopped the trial, the collective failures in safety protocols, literature review, and adverse event monitoring painted a picture of systemic problems in research oversight. 3
The tragedy of Ellen Roche's death became a catalyst for significant changes in clinical research oversight:
In January 2000, Health Canada had published clinical trial regulations clarifying the conduct of clinical trials and the roles and responsibilities of Research Ethics Boards. Roche's case underscored the urgent need for such frameworks worldwide. 3
The National Council on Ethics in Human Research, which had been working to improve ethical review of clinical research since 1989, actively promoted voluntary accreditation of Research Ethics Boards with increased resources and training. 3
Research institutions, hospitals, and universities reviewed their policies and procedures to ensure the safety of all clinical trial participants, whether healthy volunteers or patients, and the proper disclosure of all risks before obtaining consent. 3
Savulescu, J. (2002). The hexamethonium asthma study and the death of a normal volunteer in research. Journal of Medical Ethics 28 (1):3-4.
Sibbald, Barbara. “Asthma Research Claims Life of Test Participant.” CMAJ 165, no. 4 (August 21, 2001): 464.
Ogilvie RI. The death of a volunteer research subject: lessons to be learned. CMAJ. 2001;165(10):1335-1337.
Josefson D. Healthy woman dies in research experiment. BMJ. 2001;322(7302):1565.
