FDA Warning Letter Re: Fatal Experiment: Hexamethonium Inhalation_Johns Hopkins
Tue, 22 Apr 2003
An FDA Warning Letter was sent to Dr. Alkis Togias of the Johns Hopkins University Asthma & Allergy Center (March 31, 2003). The letter lists specific federal safety requirements and their violation in the hexamethonium inhalation experiment that he conducted. Participation in that nontherapeutic experiment killed Ellen Roche, a healthy volunteer who was an employee of Johns Hopkins.
While the letter is addressed to Dr. Togias, it articulates FDA rules and policies applicable to all clinical drug experiments. The letter affirms personal responsibility as the benchmark for all investigators who conduct human drug experiments: “all clinical investigators are responsible for knowing and complying with applicable FDA regulations.”
The letter affirms FDA’s rule requiring investigators to file an investigational new drug application (IND) for the use of any drug (chemical compound): “any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects…except for the use of a marketed drug in the course of medical practice.” (21 CFR 312.3) Any human use of hexamethonium bromide–a chemical compound (drug) not approved for marketing–constitutes a clinical investigation.
Among the federal violations listed is “causing the introduction or delivery of an unapproved new drug in interstate commerce.” Other violations include:
“failure to submit an IND (investigational new drug application);
failure to provide adequate animal toxicity data;
failure to provide a summary of previous human studies with hexamethonium;
failure to provide dosing rationale; failure to describe procedures for identifying, collecting, and reporting adverse events;
failure to notify and obtain IRB approval for changes in protocol– such as, dosing conditions, formulation, and delivery system;
failure to promptly report unanticipated problems–such as persistent cough and shortness of breath.”
The letter notes that “essential elements” of informed consent were also violated in the Johns Hopkins hexamethonium experiment. The following risks were not disclosed to the subjects:
a. “Inhalation of hexamethonium bromide was an experimental use of the drug.” Instead, the consent form referred to hexamethonium as “a medication.”
b. The chemical grade used was labeled “for laboratory use only and not for drug use.”
c. Risk of lung toxicity and death.
d. Inhaled hexamethonium bromide “could result in a wide range of adverse events resulting from ganglionic blockade.”
e. Unexpected adverse events experienced by previous subjects.
Finally, in its Warning Letter, FDA affirms a universal research requirement:
“any clinical investigation involving human subjects should include basic elements designed to maximize human safety.”
FDA criticizes Dr. Togias for failing to to take the necessary steps to maximize the safety of human subjects: “We believe that your failure to provide FDA with all of the information that is required in an IND submission, including chemistry, manufacturing, and control information; pharmacology and toxicology information; detailed information of prior human experience with hexamethonium bromide; and explicit procedures for drug administration and clinical monitoring, may have contributed to your failure to identify risks associated with participation in this study.”
FDA “suggests” that Dr. Togias enter into a “restricted agreement with the agency regarding [ ] future use of investigational new drugs.” See: http://www.fda.gov/cder/warn/2003/02-hfd-45-0303.pdf
FDA’s letter to Dr. Togias spells out federal safety requirements for the protection of human research subjects that apply to all drug related human experiments. However, FDA’s pattern of issuing slaps on the wrist to those who violate essential research protection requirements–even when these violations lead to preventable deaths– will do little to deter others from violating the rules, or from interpreting them for their own convenience.
Another recent example of FDA’s slap on the wrist, involved Dr. David Faxon, immediate past president of the American Heart Association–who was found to have committed multiple medical ethics violations. Among the violations cited by the FDA: falsification of data, falsification of medical records to facilitate inclusion of patients that should have been excluded. But the only penalty issued on June 19, 2002, was to restrict Dr. Faxon for 3 years as principal investigator for no more than “two (2) FDA regulated clinical investigations at any one time” and that he “shall not be principal clinical investigator for study that enrolls more than 25 subjects at the site where he is the principal investigator.” http://www.fda.gov/ora/compliance_ref/bimo/restlist.htm
Such slaps on the wrist are hardly commensurate with the nature of the violations, nor are they likely to deter anyone from violating research safeguards. For some, even a slap on the wrist is too much and an undeserved insult. Assistant Vice Chancellor of Vanderbilt University, Alastair Wood, is quoted in The Baltimore Sun (below), questioning FDA’s authority. He claims that “it is still unclear when researchers who aren’t developing drugs need FDA clearance for human tests.”
Wood even argues that symptom provoking, “challenge” experiments, should be outside of FDA’s oversight jurisdiction. [These are controversial nontherapeutic experiments, possibly posing the greatest risk for human subjects–as when severe symptoms of disabling conditions are deliberately exacerbated. See: http://www.ahrp.org/testimonypresentations/InducedPsychosisBiblio.php ]
Safety violations and deaths have recently been documented at Veterans Affairs medical centers. See: http://www.ahrp.org/infomail/0403/13.php Even the watchdogs–FDA investigators–have violated research safety rules. See: http://www.ahrp.org/infomail/0403/16.php
The Alliance for Human Research Protection (AHRP) believes that uninterrupted evidence of the system’s failure to protect human subjects, demonstrates the need for both ongoing monitoring and oversight by independent agents. Additionally, those who want to be granted the privilege of conducting research on human subjects should be required to undergo rigorous training in research methods, research ethics, and regulatory requirements. They should have to pass a qualifying proficiency examination.
Currently there are no restrictions and no qualifying licensure requirements: Anyone who obtains a grant can shop around to gain institutional review board approval to experiment on humans.
Perhaps the greatest need for deterring research abuses is enforcement of existing regulations with meaningful penalties imposed on violators.
AHRP Board of Directors:
Vera Hassner Sharav, President
David Cohen, Ph.D. Secretary
John H. Noble, Jr., Ph.D. Treasurer
Loren Mosher, MD
Meryl Nass, MD
Sally Rogow, Ed.D.
THE BALTIMORE SUN
JHU researcher found to have violated rules
FDA proposes restrictions; study resulted in death
By Julie Bell
April 18, 2003
Nearly two years after the death of a research volunteer at the Johns Hopkins School of Medicine, the Food and Drug Administration has concluded that the physician conducting the experiment violated federal regulations and asked that he restrict his research.
Dr. Alkis Togias has given a copy of the FDA’s March 31 warning letter to the school. Togias is negotiating with the FDA over terms of a settlement, and his once-suspended research has been restarted, according to a statement from the school.
“Dr. Togias has cooperated fully in all aspects of this matter and anticipates reaching an appropriate agreement with the FDA regarding research activities falling within that agency’s jurisdiction,” the statement said. It described the restrictions the FDA has proposed on Togias’ research as “limited.”
Hopkins spokesman Trent Stockton said neither the school nor Togias would have additional comment. Togias’ lawyer, Daniel A. Kracov, also declined to comment.
The federal government briefly shut down all human experiments at Hopkins seven weeks after the death of Ellen Roche in June 2001, citing widespread safety lapses. Roche had inhaled the chemical hexamethonium bromide in an experiment designed to help scientists understand how the lungs of healthy people protect against asthma attacks.
Within six months after the shutdown, the university had reapproved almost all the 2,600 halted experiments except those led by Togias. It was unclear yesterday when his research began again or how many people it involved. The warning letter cited Togias for failing to apply to the FDA before using hexamethonium bromide, failing to get the approval of a university oversight board before changing aspects of the experiment and failing to properly warn volunteers who participated in the study of its risks.
Vanderbilt University Assistant Vice Chancellor Alastair Wood, a member of an external committee Hopkins appointed to review its human experiments after Roche’s death, said yesterday that it is still unclear when researchers who aren’t developing drugs need FDA clearance for human tests.
For years, he said, many researchers have used substances already present in the human body to trigger reactions such as the raising or lowering of blood pressure without seeking FDA approval. The studies, known as “challenge” studies, are the precursors to later, FDA-approved studies in which drugs are tested in people to see if they counter those reactions. Hexamethonium bromide is not naturally present the body.
Wood said, “I think clarity would be useful.”
Copyright © 2003, The Baltimore Sun
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