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Experimental ethics
In the wake of a settlement in the negligent death of Nicole Wan, medical researchers are re-evaluating the process and ethics of using student volunteers
by Margaret DorisThe ads dot the back pages of college newspapers. Volunteers needed for research project. They're posted on the bulletin boards of student unions, and stuck under windshield wipers at football games. A few hours of your time . . . a blood sample, a brain scan . . . breathe into a tube, sleep in a lab, swallow a pill. Sometimes a professor will urge students to volunteer. Compensation will be provided. Fifty dollars, $100, $200. Big money to a kid on financial aid who's scraping dishes in the dining hall or scrubbing Pyrex in the chem lab.
Last spring, 19-year-old Hol Yan "Nicole" Wan, a sophomore at the University of Rochester, answered such an ad. Researchers at the University of Rochester Medical Center (URMC) inserted a tube into her lungs and removed cell samples, some of which were bound for use in a research project at MIT. For her efforts, Wan was to receive $150. She planned to use the money to visit her immigrant parents in Queens.
Instead, within hours of undergoing the procedure, Nicole Wan suffered cardiac arrest. Two days later, she was dead.
Late last month, the New York State Department of Health (DOH) found that the University of Rochester was conducting research involving human subjects with "insufficient safeguards to adequately minimize risk and protect" volunteers. That lack of safeguards allowed researchers to administer a lethal overdose of topical anesthetic to Nicole Wan.
The finding reinforces growing concern within the scientific community that existing safeguards are no longer adequate to protect research subjects from exploitation or physical harm. Increasingly, research for a single study may be conducted in two or more settings -- often hundreds, if not thousands, of miles apart -- which makes it difficult to monitor the research. In response to such concerns, President Bill Clinton issued an executive order last year creating a National Bioethics Advisory Commission. The commission, which met for the first time this month, will advise and make recommendations to federal agencies concerning the rights and welfare of human research subjects.
Shortly after the DOH findings were released, the university announced it had reached an out-of-court settlement in a multi-million dollar lawsuit filed by Wan's family. In addition to a cash settlement, the amount of which has not been disclosed, Robert Loeb, public information director for the University of Rochester, says the institution will establish eight one-year scholarships for Chinese-American students in Nicole Wan's name, fund a lecture series or symposium on issues related to human experimentation, and erect a "permanent monument or plaque" to honor the student. Wan family attorney Salvatore Aspromonte refused to comment on any aspect of the case.
Rather than bringing closure to the incident, the DOH report has raised disturbing new questions about the extent to which the University of Rochester has failed to be forthcoming with all information relevant to the incident. According to university records, cells taken from Nicole Wan were to be used in at least two federally funded studies. Yet the university told the DOH about only one of the studies, a University of Rochester project on "human macrophage surveillance and response" (a study of the cells whose job it is to protect the lungs from foreign particles).
University officials did not tell the Department of Health that the URMC was responsible for the human-subject component of an important MIT lung-cancer study and that it had accepted Wan into the MIT study as well. A review of the MIT study protocol would have revealed that, for scientific reasons, only persons aged 25 or older were to be accepted into that study. Further, it would have revealed that the Rochester researchers failed to obtain informed consent from Wan for the MIT study, and that they had failed to document that they had monitored her clinical status properly in accordance with the study guidelines.
University of Rochester public-information director Robert Loeb says the university felt it had no obligation to inform state investigators of the existence of the MIT study. "We gave the health department what they asked for," he says.
For their part, DOH officials say that though they knew Rochester was "giving cells" to MIT, they were not made aware that Rochester and MIT were cooperating in a study, and thus could not ask for the relevant documents. "We were not aware that there was an agreement," or grant relationship with MIT, says DOH spokesman Robert Hinckley. "The bottom line for us is they weren't even following their own protocol." Hinckley adds that he could not speculate on why University of Rochester officials were not "open and forthcoming" about their relationship with MIT, especially since "we are talking about the protection of human subjects here."
The university's attempts to distance itself from the MIT study also has some people at MIT puzzled, particularly William G. Thilly, director of both the lung-cancer research program and MIT's Center for Environmental Health Sciences. "On one hand, my colleagues at Rochester have confirmed as recently as last week . . . [that] they regarded Nicole Wan as part of our study," he said Monday. But, he continued, "to the best of my knowledge," when the individuals at the university have discussed the incident with investigators, they have referred only to their study.
The university also declined to share with Thilly any information from its own investigation into Wan's death. "I believe it's important, and specifically asked for the information starting in April," he says. "I had no knowledge then or now of what actually happened."
What is known is that, on March 29, Nicole Wan went into cardiac arrest within hours of undergoing a routine bronchoscopic procedure to obtain lung cells for research. Although emergency personnel were able to resuscitate her, she suffered "irreversible damage" and died two days later.
On April 30, the Monroe County, New York, medical examiner ruled Nicole Wan's death an accident due to acute lidocaine toxicity. But, as one county government source explained at the time, "Accidental means `not homicide.' It does not necessarily mean `not negligent.' " The medical examiner's tests on clinical samples taken shortly after Wan was brought to the hospital emergency room showed her as having dangerously high levels of lidocaine, the anesthetic used to make the procedure more comfortable, in her system.
The DOH report concludes that, based upon those levels and what is known about the way the drug is metabolized, Wan "likely received more than four times" the maximum dosage established in previous research protocols at the university. The report goes on to note that "The University [believes] that since there was no mention of a maximum amount," of lidocaine in the current University of Rochester protocol, "the researchers were not bound by any specific limitation."
Although recommended maximum safe dosages have been established by the drug's manufacturer, and although the Rochester researchers failed to take the precaution of noting how much of the drug they were giving Wan as they administered it, the researchers seem to be suggesting they should be absolved of any blame. They say the protocol writers did not explicitly set limits, but rather assumed researchers would be responsible enough not to overdose subjects.
In a footnote to its report, the DOH quotes from a 40-year-old medical-journal article on fatalities that follow topical application of local anesthetics. "In a review of the protocols of fatalities," the passage reads, "the following findings are consistent: the operator had little regard for dosage, was unaware of the maximal allowable quantity and was unable to indicate the exact amount used."
Serious reactions to lidocaine, while rare, are thought to be swift. Physicians are taught to look for the onset of such reactions within minutes of exposure. But Wan, even with dangerously high levels of the drug in her system, managed to complete the procedure, leave the research center, and return to her boyfriend's apartment before going into cardiac arrest. According to the Monroe County medical examiner's office, it was the way in which the physicians administered the drug -- as an aerosolized spray into Wan's throat and air passages -- that apparently delayed the onset of acute symptoms. Wan, who reportedly experienced unusual discomfort during the procedure, was either inadvertently or negligently overdosed in an effort to relieve her pain and coughing.
"Certainly she was in pain and she wanted it [the bronchoscopy] stopped," Wan family attorney Salvatore Aspromonte told this reporter last spring. He said it was possible Wan may have suffered "the beginning of a heart attack" while she was undergoing the procedure -- signs Aspromonte said may have been missed if she was not being monitored in accordance with the MIT-approved medical protocol. The New York State Department of Health report observed that there was no evidence in the medical record that a physician or nurse assessed Wan's medical condition at the time she left the bronchoscopy unit.
The MIT lung-cancer study was designed to investigate how environmental air quality may affect the development of lung cancer. Begun in July 1994, using a three-year, $4.5 million grant from the National Institute of Environmental Health Sciences, the program's focus was on the "mutagenic effects of airborne toxicants in human lungs."
Researchers hoped to discover if the mutations, especially cancerous mutations, in the bronchial cells of nonsmokers' lungs are principally caused by exposure to airborne chemicals in urban outdoor and indoor environments. Information gleaned from lung cells taken from approximately 40 volunteers at the University of Rochester was being used to develop laboratory cell models, which in turn were used to determine which chemicals present in air samples are responsible for cell mutagenicity. The volunteers' cells were analyzed for airborne chemicals, for the enzymes that metabolize those chemicals, and for genetic mutations. Preliminary results are quite promising, according to MIT's Thilly, and results may eventually challenge the widely held scientific understanding of the mechanics of lung cancer.
MIT sought a first-rate institution to conduct the human-subject research, Thilly explained last spring. "As soon as we wandered away from surgical discards, blood samples, and what have you, [we] were walking into an area where we were going to rely on the clinical expertise and experience of others. I looked carefully for persons with reputations that were really tops." That search led him to the University of Rochester.
The bronchoscopic sampling of lung cells, approved by the MIT committee overseeing human-subject research, was critical to the study, says Thilly, as it provided information that could not be obtained from cadavers or surgical discards. He himself had volunteered for the procedure while visiting Rochester, but says that "something went wrong with their setup," adding, "I would have probably done it this year.
"I wouldn't get involved in it again unless I went through it myself," says Thilly, who is troubled by Wan's boyfriend's report that she suffered significant pain both during and after a procedure that was supposed to cause only minor discomfort. "The fine line between uncomfortable and torture is something I'm . . . concerned about," says Thilly.
The MIT protocol clearly spelled out that volunteers were to be at least 25 years old. According to Thilly, MIT researchers originally thought it was important to have volunteers who had had significant exposure to the air that was being tested. As the data came in, it became evident that this requirement was not as important as first thought. Still, Thilly does not know why the Rochester scientists allowed Wan to participate in the study. "No, I can state categorically that I didn't discuss [lowering the age limit] with anyone," he says, "but had it been discussed, I see no scientific reason not to have done that . . . and would not have raised objection."
But it was not discussed with Thilly, and the protocol remained unchanged. Did the University of Rochester scientists, who apparently had a protocol-set minimum age of 18 for their own study, have the right to ignore the MIT protocol?
"It's not only out of compliance with the ethics, but it's bad science," Arthur Caplan, PhD, director of the Center for Bioethics at the University of Pennsylvania, told this reporter last spring. "You're still opening the door for criticism for methods -- you risk undercutting the whole study."
URMC spokesman Robert Loeb reaffirmed last week that researchers there were confident they had the authority to accept volunteers under the age of 25 into the study. He declined to elaborate further.
Last spring, Aspromonte, the Wans' attorney, voiced serious concerns about the way in which the URMC solicited informed consent from Wan. Should researchers be allowed to solicit consent from college students without first informing their parents? Aspromonte called upon the New York State legislature to introduce a bill requiring exactly that. While Caplan is not sure that parental collaboration is warranted, he believes students may feel a subtle pressure to volunteer for research projects at their own university. The "loyalty or special trust" they feel toward the institution may also influence what should be objective decision-making, he says.
As part of the procedure, Rochester researchers removed not only the lung epithelial cells needed for the MIT research, but alveolar macrophages (the cells that protect the lung from foreign particles) to be used in their own study. Though that makes scientific sense, according to Thilly -- it should pose no additional risk to the volunteer, and it reduces the number of volunteers that must be recruited for both studies -- both he and Caplan are adamant that the volunteers must be provided with a consent form or forms explicitly covering each and every study. Not only did Wan not receive such forms, according to Aspromonte, but the consent form she signed does not seem to give permission to extract and use the type of cells needed for the MIT study. Aspromonte says Wan was provided with a consent form for a "human alveolar macrophage surveillance and response" study. The form made no mention of epithelial cells. Curiously, Aspromonte claims, William Thilly's name was listed as one of the project investigators.
If Aspromonte is correct, Thilly has no idea why his name would appear on a consent form for someone else's study. "As program director, I know the macrophage research is not in the present (MIT) program." Still, when University of Rochester officials announced Wan's death, they said she was a part of the MIT study, and that is also what they told MIT researchers.
URMC spokesman Loeb acknowledged last spring that Wan signed a consent form for a macrophage study. However, he said then that even though the form did not explicitly mention epithelial cells or the MIT study, it was implicit in the wording of the consent form. According to Loeb, the form reads, "following the lavage [to extract the macrophages], cells lining the airway may be sampled through the bronchoscope using a small brush."
"It says that a brush sample may be taken," says Loeb. "The cells lining the airway, those are the epithelial cells required" for the MIT study. According to Loeb, that is how the university interprets the language.
In a news conference held shortly after Wan's death, university officials explained their informed-consent procedures. According to the Rochester Democrat & Chronicle, medical school dean Dr. Lowell A. Goldsmith said that Rochester's Institutional Review Board "makes sure that the language in the consent form can be understood by anyone.
"For example," said Goldsmith, "if someone were going to have blood drawn, the amount would be listed not only in cubic centimeters but in teaspoons."
As of last week, Loeb still could not confirm or deny that Thilly's name appeared on the consent form.
The amount Wan was to be paid for participating in the study, $150, is the amount MIT study volunteers were to be compensated. It is not clear how much, if any, compensation volunteers in the macrophage study at Rochester were to receive. When asked last week to provide the Phoenix with documentation of the payment source, Loeb declined. The copy of the original NIH grant proposal supplied to this reporter seems to indicate that University of Rochester researchers were claiming no funding from other sources for work that would overlap with the MIT study. Yet if they were also doing a macrophage study, it seems probable that funding from at least one other source was involved. If so, MIT's grant should bear only a proportional share of the costs. Officials at the University of Rochester declined to discuss volunteer compensation, the existence of another study, or possible funding sources.
Before beginning work with human subjects, Thilly says, a researcher has to ask himself the question: is the information you're going to gain really important, and not something you do in order to publish another paper? As Thilly continues to agonize over Nicole Wan's death, he says, "I've reflected on, Was there any point here? Was this information important? And I think it was, I think it is. Could it have been done without taking the bronchial cells? No, I don't think it could have been. . . . It's not the kind of thing you can do in rats or dogs."
But the first objective of human research should be to protect human volunteers from harm, Thilly says. The Rochester researchers' failure to do so continues to haunt him.
While no more bronchoscopies are planned for the lung-cancer study, Thilly said on Monday, "The center has to continue to do clinical studies with a sadder but wiser center director." The New York State Department of Health has submitted its report to the federal Office for Protection from Research Risks, and will work with it to develop a plan for monitoring human-subject experiments at the University of Rochester.
Thilly already knows how his monitoring of the human-experiment components of MIT research projects will change. In the future, "We'll always be dealing directly with the physicians that are cooperating and collaborating. There won't be any intermediaries. It won't hurt to have us non-physicians making sure we understand at a higher level than I did . . . what's going on. I will not have any problem personally challenging the medical colleagues . . . because I think it's a good thing that we ask these questions and not assume everything is the way it should be, perfectly."
Margaret Doris reported on the Democratic convention for the Boston Phoenix.