Johns Hopkins Admits Fault in Fatal Experiment
July 17, 2001
The experiment that killed Ellen Roche, a healthy 24 year old volunteer–who was clearly not informed about the risks she was incurring by breathing hexamethonium–demonstrates that there are no protections that ordinary people can rely on, when they become research subjects.
The disagreement among members of Johns Hopkins internal committee and FDA “interpretation” demonstrate that there are currently no clear mandatory safety requirements to protect research subjects. Johns Hopkins Vice-Dean for Research and the President wrote to the Federal Office of Human Research Protection (below) stating:
“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.”
The fact is, there are no reliable enforcement mechanisms, and no mandatory requirement to share information about prior adverse consequences. The New York Times reports that FDA “often has information from drug company studies that can address safety questions.” But FDA has been exempting academic research centers from obtaining FDA permission to conduct human experiments with unapproved drugs–no matter how serious the potential adverse reactions. And the reason is to save money!
Ellen Roche and Jesse Gelsinger were the victims of the current self-regulating “research protection system” which has been revealed as nothing more than an elaborate institutionalized self-defense mechanism. As ethicist George Annas, has often stated, the system protects the institution, not the subjects.
THE NEW YORK TIMES
JUL 17, 2001
Johns Hopkins Admits Fault in Fatal Experiment
By GINA KOLATA
BALTIMORE, July 16 — Johns Hopkins University said today that it accepted full responsibility for the recent death of a volunteer in an experiment. In a report on its investigation into the death, the university said the researcher who conducted the experiment and the ethics committee that approved it had failed to take adequate precautions to protect research subjects.
"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 Dr. Edward B. Miller, the dean and chief executive of Johns Hopkins Medicine.
The volunteer, Ellen Roche, died from lung failure on June 2. Ms. Roche, a 24-year-old technician at the university's asthma and allergy center, had been ill since May 5, one day after she inhaled an experimental compound as part of a study to understand the cause of asthma.
Ms. Roche spent several weeks in an intensive care unit. Her air sacs collapsed, her lungs became stiff, air began to leak out of them, her organs began to fail, and, finally, her family decided to remove her life supports.
The fatal illness probably was precipitated, university officials said, when Ms. Roche took a drug in the study. The study was conducted at the center where she worked, but not by the researcher she worked for. She was healthy, and the study was not intended to help her personally. Volunteers were paid up to $365 for their time and effort.
While stressing that they might never know why Ms. Roche became so ill and died, the medical center's internal committee wrote in its report that they believed the drug she took "was either solely responsible for the subject's illness or played an important contributory role."
The report is being submitted to the federal Office of Human Research Protection.
"This was a horrible tragedy," said Dr. Miller at a solemn news conference today to release the medical center's report. Dr. Miller said another committee, of experts from outside the university, was also investigating and would issue its report by late summer. The Food and Drug Administration and the Department of Health and Human Services are investigating as well.
The university has suspended all of the 10 studies being conducted by the principal investigator, Dr. Alkis Togias, an associate professor of clinical immunology.
Joann Rodgers, a university spokeswoman, said the university was "having discussions with the family." But she did not know whether a lawsuit had been filed.
The report issued today depicted a study that went horribly awry. And it raises questions of what is required to assure the utmost safety for volunteers in research. The study was investigating why healthy people and people with asthma responded so differently to substances that constricted their airways. When the constriction occurs, people without asthma can breathe deeply and make their airways relax, but those with asthma cannot get their airways to relax.
The researchers hypothesized that nerves in the lungs controlled this relaxation. They proposed constricting the airways of volunteers with one drug and then giving them a second drug, hexamethonium. That drug temporarily blocks the nerves in their lungs from responding normally. The combination of drugs can simulate an asthma attack.
Hexamethonium, however, is not approved by the Food and Drug Administration. Dr. Togias reported to the institutional review board, or I.R.B., an ethics group overseeing his work, that had concluded that the drug's main risk was in causing a temporary drop in blood pressure. His conclusions were reflected in a consent form signed by Ms. Roche and the other study volunteers.
That form "should not have been approved" by the institutional review board, the Hopkins investigating committee concluded. The form did not mention that hexamethonium was not approved by the F.D.A., and it did not say that the drug's safety was uncertain or that the only data on the safety of inhaling it came from the experience of just 20 people. In addition, the committee found that Dr. Togias had apparently missed some papers suggesting that the drug might injure the lungs.
"The majority of the committee believed that the I.R.B. should have required more evidence of safety in the use of hexamethonium," the report says.
Ms. Roche was the third subject in the study to inhale hexamethonium. The first subject developed a cough and shortness of breath upon exertion. Those effects lasted for a week. But Dr. Togias did not report that subject's symptoms to the review board overseeing the study, reasoning that they were not serious and that they were probably due to a cold that was going around in the research unit, or to the acidity of the hexamethonium solution.
A few days after the first subject recovered, Ms. Roche took the drug, became ill and went to the hospital. Dr. Lewis Becker, the chairman of the internal committee, said he did not blame Dr. Togias for not recognizing the possible significance of the first volunteer's reaction to the drug.
"I can completely understand how he could have attributed it to a cold or the high acidity of the solution," he said. But, the committee said, Dr. Togias should have reported the first subject's experience to the review board.
The committee said the university would redouble its efforts to ensure safety in its clinical research. And that raised questions of whether the Food and Drug Administration should have been involved. The committee said in its report that the institutional review board should have asked Dr. Togias to find out whether he needed the F.D.A.'s approval to do the study. The agency, Dr. Miller said, often has information from drug company studies that can address safety questions. It could also have required the Hopkins researchers to do additional studies of their own, perhaps giving the drug to animals, before giving it to people.
Drug companies are required to get F.D.A. permission before doing a study like the one at Johns Hopkins, said Dr. Bert Spilker, senior vice president for scientific and regulatory affairs for Pharmaceutical Research and Manufacturers of America. Complying with the agency's requirements typically would take one to two years and cost $1 million to $5 million, Dr. Spilker said.
The F.D.A. used to exempt most academic research from this process, said William Vodra, a former F.D.A. lawyer who now works for the law firm Arnold & Porter in Washington. But, he said, with recent problems, including the death of a subject in a gene therapy study at the University of Pennsylvania, that policy "was shaken to the core."
But if the F.D.A. did require universities to adhere to the same standards for research studies as industry, it was not clear where the money would come from, he said.
"I don't think society will be comfortable with industry picking up the tab," Mr. Vodra said. "And I don't think George Bush wants to repeal his tax cut to pay for this."
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Johns Hopkins Medicine letter to OHRP
July 13, 2001
Michael A. Carome, M.D. Director, Division of Compliance Oversight Office for Human Research Protections 6100 Executive Blvd., Suite 3B01 Rockville, MD 20852
RE: Human Research Subject Protections Under Multiple Project Assurance M-1011
Research Project: Mechanisms of Deep Inspiration-Induced Airway Relaxation
Project Number: AAC00-07-26-02 Principal Investigator: Dr. Alkis Togias HHS Project Number: R01 HL61277 (PI: Dr. Solbert Permutt) Dear Dr. Carome:
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.”
The investigation committee probed this question extensively. Neither Dr. Togias, nor the IRB were aware of this information prior to the approval of the research. The investigation committee inquired into the extent of the literature search that Dr. Togias conducted prior to submission of the application to the IRB. The principal investigator subsequently stated to the investigation committee that he had performed a standard PubMed search for potential hexamethonium toxicity and consulted standard, current edition, textbooks of pharmacology and pulmonary medicine before submitting the application to the IRB. None of these sources mentioned hexamethonium-related pulmonary toxicity. This is why Dr. Togias did not know of the pulmonary toxicity prior to submission of the application to the IRB.
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.
The IRB had at the time of the review, and still has, members with expertise in pulmonary medicine and in use of investigational drugs. 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 Dr. Togias included 4 references to similar studies of inhaled drugs in human subjects, and the IRB neither requested nor searched for additional safety data beyond that provided in the 4 publications provided by the investigator.
(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:
As a result of our initial review of the recent serious adverse event at Bayview, we have identified some procedural and administrative issues. In particular, I want to remind you to seek approval from the Institutional Review Board/JCCI for any modification of your protocol before proceeding with an amended study. The requirement for review of amendments has been in place for years. Investigators are expected to submit amendments, so that we can ensure the safety of human subjects.
Chi Dang, MD, PhD
Vice Dean for Research
Further communications with the faculty will be developed, once the complete review process of the event has concluded.
A committee will develop a standard for literature searches to be applied to all investigator-initiated research projects. We will develop a corrective action plan to address any deficiencies identified in our system for the protection of human subjects. We will, however, await the OHRP site visit, and the joint FDA inspection of the IRB, next week. In addition, we will seek guidance from the independent outside review committee before such a plan is finalized.
In our phone conversations, you requested a copy of the autopsy report. A copy of the report will be provided to you on Monday, 7/16/2001 at the time of your visit. You requested a listing of other research projects in which hexamethonium subject #3 participated, and this list will also be available to you on Monday. All of the other documents you requested in your letter of 6/15/2001, your letter of 6/25/2001, and the July Fax communications from your colleague, Dr. McNeilly, have been sent to your office in preparation for the site visit.
We look forward to working with you to address ways to strengthen our system for the protection of human subjects. Hopkins is committed to upholding the highest standard in research ethics and conduct of clinical research. We understand the importance of having an effective and demanding review process to assure the safe conduct of human subjects research.
Chi Van Dang, M.D., Ph.D. Vice Dean for Research, JHUSOM
Gregory F. Schaffer, MS President – JHBMC CVD:GS:bls
cc: 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 Copyright © 2001, The Baltimore Sun