In the aftermath of a research study volunteer's death and the subsequent imposition of serious sanctions by federal officials, Johns Hopkins University's renowned research arm faces a long road ahead in reestablishing its program of 2,800 medical experiments involving human subjects, officials say.
The June death of Ellen Roche, 24, a healthy volunteer for an asthma experiment who worked as a lab technician at the Baltimore institution, precipitated an investigation into Johns Hopkins' research evaluation and human subject protocols by the federal Office for Human Research Protection.
The agency's inquiry culminated last week in a decision to suspend all Johns Hopkins research involving human subjects because of "systemic problems throughout the institution" in reviewing human subject clinical trials, according to Bill Hall, spokesman for the Department of Health and Human Services, which oversees the agency. The suspension was a serious blow to Hopkins, the nation's top recipient of federal medical research money, including more than $300 million last year alone.
The university attacked the action as "unwarranted, unnecessary [and] paralyzing," and HHS officials partially reinstated its human research privileges--subject to numerous restrictions--in an agreement announced Monday.
Still, the school must now thoroughly reexamine the review process that resulted in the approval of thousands of its research projects, which could set back many of the experiments by several months. Also, Johns Hopkins may face possible legal action by Roche's family, which has retained a Baltimore lawyer.
Doctors from Johns Hopkins' asthma laboratory and research review boards were unavailable for comment. Roche's family, through an attorney, declined a request for an interview.
Questions on Death Remain Unanswered
The story of Roche's involvement with the experiment, and the sudden onset of illness that eventually took her life, is marked by many unanswered questions.
Roche worked at the university's Asthma and Allergy Center and volunteered for an experiment designed to study the way healthy lungs respond to irritating chemicals that cause attacks in asthmatics.
As a healthy subject, she would not receive any medical benefit from the study and would have been paid up to $365 for her participation, according to the experiment's informed consent form.
On their first five visits, participants in the experiment inhaled methacholine, a commonly used drug that simulates "mild asthma attacks."
On the sixth visit, subjects inhaled hexamethonium--an experimental drug the consent form describes as "capable of stopping some nerves in your airways from functioning for a short period"--before taking methacholine.
Subjects were told that "the question that is being asked is whether hexamethonium can reduce the ability of your lungs to resist the asthma-like effects of methacholine" and that the only risks of hexamethonium were temporary dizziness and reduced blood pressure.
Nevertheless, the drug apparently proved fatal to Roche: She fell ill May 5, a day after inhaling it, was admitted to the hospital, spent weeks in an intensive care unit and, after her lungs and then other organs failed, died June 2.
Doctors have struggled to pinpoint the connection between hexamethonium and Roche's symptoms. But in an internal review after her death, even university medical officials conceded in their report that the drug "was either solely responsible for the subject's illness or played an important contributory role."
In investigating this asthma experiment, federal officials cited a number of flaws in the conduct of researchers and a university screening panel--commonly known as an institutional review board--that violated safety protocols.
Officials concluded that researchers and the review board failed to obtain adequate information on hexamethonium's effects and toxicity. They pointed out that the drug is not approved by the Food and Drug Administration for use in humans, and researchers had not obtained an "investigational new drug" exemption from the FDA.
Board's Approval Called Not Unusual
A Johns Hopkins spokeswoman, however, indicated that the review board's approval of a non-sanctioned drug was not unusual.
"The FDA guidelines have been somewhat unclear on the issue of when an [exemption] is needed," said Joann Rodgers.
Also, investigators said, the consent form did not clearly inform subjects of the experiment's components, and the researcher amended the plan without informing the review board.
According to HHS spokesman Hall, the Roche case pointed to larger problems in the review process at Hopkins, which "led to concerns for the safety of people volunteering in research studies at Hopkins."
After the suspension announcement last week, university officials rushed to assemble a plan to address each of the 31 findings cited by federal regulators and vowed to revamp their review process.
Hall said the regulatory agency "worked very diligently and exhaustively with Hopkins officials throughout the weekend to support them and guide them in developing a corrective action plan," and by Sunday the agency informed Hopkins of the limited reinstatement and its accompanying restrictions.
Only noninvasive studies that pose no more than minimal risks to subjects can immediately resume, officials informed Hopkins.
If researchers believe their experiments must continue so that patients can receive life-sustaining or painkilling drugs, they must provide separate justification for this.
Every other study will now be closely scrutinized by Hopkins officials to determine whether the review board performed a sufficiently thorough, exhaustive examination of its protocols.
The studies in which the reviews are deemed inadequate will have to go through the process all over again, which could take several months.
The university will also have to provide federal officials with monthly progress reports of their improvements.
Hall likened the sanctions to the grounding of an airline whose planes are determined to be unsafe by the Federal Aviation Administration.
"Hopkins is at the point where they've come up with a corrective action plan," he said. "Now they have to go back and inspect the planes and put them back in service one by one until their full fleet is back in the air."