A.J. Anderson, a manager for the Tennes- see Park System for 35 years, retired last July because of the worsening symp- toms of his Parkinson's disease. This fall, neurosurgeon Robert Gross and his team implanted an electrode the size of a thumb- nail deep in Anderson's brain to help him control his shaking hands and head. Anderson is one of thousands of clinical trial volunteers who come to Emory each year to test innovative therapies for a wide variety of diseases and conditions.

by Renee Twombly llen Roche, a healthy 24-year-old, died for science. In the summer of 2001, she volunteered for an asthma experiment at Johns Hopkins University, where she worked. Roche inhaled a drug called hexamethonium to help researchers understand how a normal lung reacts to irritants. But the substance quickly eroded Roche's ability to breathe, and she died within weeks. The consent form Roche signed before entering the study - a document designed to disclose all risks she might be exposed to - never said the drug might be toxic. It certainly didn't say hexamethonium was not approved for use in humans. The researchers running the experiment say they didn't know the drug was lethal, even though that information was readily available on the Internet. They also thought the federal Food and Drug Administration (FDA) had approved their request to use the drug. But that wasn't the case. Federally supported research at Hopkins, arguably the nation's most respected medical center, was shut down until the institution proved it could protect its research volunteers. Jesse Gelsinger was sick, but he was able to manage his symptoms caused by a genetic liver defect. Still, the 18-year-old ultimately wanted to help researchers find a cure -- a common motivation for clinical trial volunteers. In September 1999, Gelsinger was injected with corrective gene material; four days later he was dead. At first, it looked like an unfortunate and rare immune reaction, but the FDA soon shut down the University of Pennsylvania research program after an agency investigation uncovered multiple lapses, some of which may have contributed to Gelsinger's death. Worse still, the scientist leading the work had founded a biotechnology company that might have profited from the research, prompting a conflict-of-interest investigation. Then, a Harvard-affiliated hospital quietly suspended a gene therapy experiment after three of its first six patients died. The researcher had not reported the deaths, as required, to the National Institutes of Health (NIH). The Harvard deaths were among the hundreds of serious "adverse events" in gene therapy that swamped the NIH after Gelsinger's death, the Washington Post reported in January 2000, after obtaining a Freedom of Information Act request. Federal rules demand that such reports be filed immediately as problems arise. But 652 of the 691 reports submitted after Gelsinger died had never before been seen by the NIH; that means less than 6% were filed on time. Most researchers said they didn't know they were supposed to contact the NIH if serious illness, or even death, occur in gene therapy trials. Even before problems surfaced at Penn and Hopkins, the then-called Office for Protection from Research Risks (OPRR), the government's watchdog agency, swept into Duke University Medical Center and stopped all noncritical research for a week. The OPRR said Duke's institutional review board (IRB) was understaffed and overburdened, had failed to correct organizational and administrative problems, and could not ensure that patients were being protected. It was the first time a top-tier medical center had received such a suspension, and it was followed by a clear warning from the Department of Health and Human Services that IRB systems nationwide responsible for safeguarding human subjects were in danger of a meltdown. The federal government's clarion call was heard in Atlanta, and vows were made that Emory would not be the next cited for lax protection of the volunteers entrusted to its care. Now, two years later, Robert Rich, the School of Medicine's executive associate dean for research and strategic initiatives, says Emory meets or exceeds federal regulations. "We've got a process we take considerable pride in." Nevertheless, Emory is not, in any way, complacent and is constantly striving to improve its clinical trials and research process, Rich emphasizes. Hopkins had also reviewed its procedures a year before Roche entered the lung study and had found them solid. "This is an extraordinarily challenging environment," says Rich. "Human research is always difficult, and there are always risks, but research is critical to advancing medicine." On top of that balancing act, research at Emory is rapidly expanding, now up to more than 2,000 active protocols, many of which are clinical trials that depend on patient participation. The number of IRB submissions to Emory has increased 23% in four years, with an accompanying 50% increase in paperwork. With 2,200 active clinical trials, Hopkins itself is not handling that much more than Emory. Research funding is also skyrocketing at Emory University as a whole, up 58% in the past five years to almost $248 million in federal and corporate funding for 2001, 94% for the health sciences. With so much work and so little room for error, can deaths like Ellen Roche's or Jesse Gelsinger's happen at Emory? Jim Keller, chair of Emory's IRB, has lately been assured that many safeguards are in place. But he sees it as his job to be hypervigilant against the possibility that something could happen here.

Radiation oncologist Jim Keller and mem- bers of Emory's institutional review board carry heavy responsibility as "guardians" of human subjects.

xcept for the white coats and bleeping pagers, it could be a gathering of English faculty poring over the meaning of an obscure text. "'Experimental breath condensate' and 'organic markers' just have to go," says a physician, one of many clustered around a conference table. The committee recommends 8th- to 10th-grade reading levels for most consent forms. For example, when possible, words like "equivalent" are changed to "equal," or better yet, "same." "Adverse" is changed to "negative" or "bad" or "harmful." Throughout the meeting, the 16-member IRB committee, which includes faculty, investigators, nonscientists, and community representatives, pull on and off the different "hats" they figuratively wear. Now they are civil rights lawyers, debating whether asking blind patients to sign a consent form constitutes discrimination (see "Sign on the dotted line" sidebar). As ethicists, they question whether paying patients several hundred dollars to participate in a particular clinical trial is a subtle form of coercion. The graphic artist in them suggests that formatting problems need to be corrected and that no words should be underlined. Their medical training questions how any research that involves surgery can be said to be without risk. And so it goes, every Wednesday, for hours at a time in room 307-N, Building A on the Briarcliff Campus. Five separate IRB committees - each meeting once a month - gather to judge requests to enroll people as subjects in Emory studies. The research could be as simple as an anonymous survey or a minor blood draw or as groundbreaking as testing an AIDS prevention vaccine in uninfected volunteers. Usually, each member presents a research study and recommends an action to the rest of committee, which then judges the request. Each protocol is reviewed in depth by four individuals on the committee, with one being the "primary reviewer." The primary reviewer then leads a discussion of the protocol for the full committee, incorporating the other reviewers' comments. The study is then open for full discussion and final vote of approval. The IRB committees are charged with ensuring that clinical research conducted at Emory meets standards aimed at protecting volunteers from unworthy investigation, from needless risk, and from misunderstanding what they have agreed to participate in. After a novel research proposal passes through an initial departmental review, the IRB may be the first group to review it, even before it is submitted for research funding. The IRB also sees the study proposal after funding has been obtained. The IRB is a patient's first and last comprehensive line of defense because much of the committee review revolves around whether patients understand what the consent form they sign says. That document spells out in simple terms the goal of the study and its risks as well as any conflict of interest a researcher may have. "We review the consent forms from the perspective of the patient and spend a lot of time discussing language changes that would make them more understandable," says Aaron Johnson, a retired hospital administrator who serves as one of several community representatives on the board. "The board is extremely conscientious. I have been surprised to see how deliberately committee members take their work and how they prepare themselves for a meeting. I am, in a word, impressed." Most of the protocols that come before an Emory IRB are approved pending changes made in the study design and/or the informed consent document. The majority are also considered low risk, which means that they are reviewed annually or if some amendment to the study is requested. Of the active and approved protocols now under way, 174 are judged to be high risk and must be reviewed by the IRB more frequently. The IRB sets a time frame to review progress or a maximum number of patients allowed in the study before a new review. Duke had a single IRB committee before its shutdown but this year has five IRB committees. Johns Hopkins had three before this summer but now has six. Emory's School of Medicine had one IRB in 1999, but now five committees consider health sciences studies, and one IRB considers requests from the rest of the campus. "Many IRBs around the country have gone from single to multiple committees to make sure there is sufficient time available to review protocols," says Rich, who serves on the Department of Health and Human Services' national human research protections advisory committee. This group serves the Office for Human Research Protections (OHRP), which replaced OPRR last year.

mory has also almost tripled its IRB support staff since 1996 and quadrupled its budget during that time to more than $1 million. It is also considering a web-based submissions process to ease the information flow, which is now conducted in rivers of paper (20,000 pages a month) that flow through the IRB copy machine, according to Marcia Weese, IRB director. To help researchers move their work through research hurdles, Emory opened its clinical trials office last fall under the guidance of neurologist Ray Watts. The office is expected to help investigators manage patient recruitment and research finances, among other variables, with the aim of reducing the time needed to initiate a clinical trial. Among its long-term goals is to work with the Rollins School of Public Health to help in study design and data management and analysis. A parallel office of industrial contracting has also been established to assist researchers involved in studies that are privately funded. There is also an effort to make sure research errors don't occur on the arts and sciences side of the campus. One IRB committee now considers human subject research in disciplines such as sociology, psychology, anthropology, law, history, and business. Those disciplines are generating a growing volume of research, and more and more faculty are suddenly aware they need to run their research through an IRB. If the volume of reviews in these areas continues to increase, a second committee may be created to focus on noninvasive research. The existing IRB, renamed in September as the social, humanists, and behavioral IRB, receives some interesting challenges in its mandate to protect research subjects, says its chair, Karen Hegtvedt, associate professor of sociology. A researcher studying illegal immigrants could not ask them to sign consent forms because that might constitute documentation that INS might use to ask them to leave the country. And what would informed consent mean to African villagers being observed by an Emory anthropologist? "Medical school research is fairly structured, whereas some of this research can be ambiguous and very low risk," says Hegtvedt. "But there is no question that it should be reviewed for compliance to federal guidelines." Many of these changes came about in light of Duke's shutdown and after Emory was "dinged" in a minor site visit by federal officials. In response, Emory hired consultants to ferret out deficiencies. Corrective work is ongoing, says David Blake, associate director of the Woodruff Health Sciences Center and vice president for academic affairs. The kind of mistakes seen at Penn and Hopkins "could not happen here," he now says.

ne of the critical improvements Emory made was development of an educational system to "credential" everyone involved in human studies, from the lab tech to the principal investigator. The program was implemented in October 2000 at the very time NIH issued a nationwide mandate that researchers who receive money from the federal government must prove they have been through a human protections education program. "Before last year, new researchers were taught the ropes by mentors who had experience," says Victor Lampasona, former director of the human protection education program. Today clinical trial investigators must study the history, methods, and ethics of research, while associated research personnel study two of the modules. All then take an on-line, instantly graded, open-book test. By the end of November, 2,441 people had taken the test, and 2,353 had passed it, with an average score of 91. "We have heightened awareness that good research should be a learned behavior," says Lampasona. "Even seasoned researchers have told me that they learned something new." Keller, the IRB chair, is a fan of the new educational mandate. When he started chairing the committee in 1995, he worked under the assumption that "my colleagues are people of great integrity and that we should trust them. And, for the most part, I do," he says. "But the longer I am in this job, the more I realize that physicians are just not getting adequate research training in medical school."

Sign on the dotted line? Should blind patients be required to sign written informed consent forms, stating they understand everything they have read regarding the clinical trial they agreed to join? Such a request isn"t that implausible, but illustrates the uncertainty inherent in the IRB's charge to protect human subjects. At an IRB meeting last fall, a freewheeling discussion (that had little to do with the trial being considered) started when one committee member suggested that all consent forms be translated into Spanish, given the likelihood that a Spanish- speaking patient in Atlanta might become a study participant. Researchers didn't think a Spanish con- sent form was needed, and the study was approved. But, in the meantime, another member brought up the issue of other patients who may need special considera- tion in other future trials, such as the visually impaired. But IRB director Marcia Weese said that researchers must follow the same proce- dures with blind patients that they use with all other patients. To do otherwise would be to treat them differently be- cause they have a disability, and that constitutes illegal discrimination. The blind are able to sign their names and to write checks, she says. But wouldn't it be more ethical if a researcher read the informed consent document to the blind patient, video- taping the whole process along with a witness? asked IRB chair Jim Keller. It may be, others agreed, but it could be illegal. But since no big book exists by which committee members can check detailed rules, the discussion was tabled -- until the first blind patient agrees to help medical research at Emory.

any protocols that are generated nationally have had a thorough review before they are reviewed at an institution's IRB, but that doesn't mean the committee shirks its duty, says Keller. In the past, Emory has questioned several national protocols, including a study involving implantation of fetal pig cells in the brains of patients with Parkinson's disease and a protocol for patients with Alzheimer's disease that involved placing a shunt in the brain. Sometimes investigators at Emory opt not to participate in a study that other medical centers around the country are doing "because they know the IRB will hold their feet to the fire and it may be difficult to get approval," says Keller. "Although there are federal and legal guidelines, many areas are subject to interpretation, as are the ethical issues," he says. "In the end we are all learning daily as we try to do our best to protect human subjects. We continually try to refine the process and do a better job as we see weaknesses in our system of review and learn from the audits of other institutions." Emory administrators are paying particular attention to the consent process -- the circumstances under which participants are asked to participate in a clinical trial. Are patients being told about the next great blood clot-dissolving drug while being wheeled in for a cardiac catheterization -- or, more appropriately, while talking face to face with a physician in a quiet room before any treatment decisions are made? Such oversight is now done on a case-by-case basis at Emory, but the OHRP has made it clear that institutions should start to monitor the process more closely, says Frank Stout, vice president for research administration. "Emory has always taken its responsibility to patients in research very seriously, and we will hire the appropriate number of ombudsmen as it takes to have confidence we are doing it right." Keller, a professor and clinical director of radiation oncology whose job as IRB chair is supposed to take only two half-days a week (the reality far exceeds that), would also like to have some system that provides oversight of data management, even laboratory assays. "Eventually we need to go further into the research process, and there is only so much auditing going on now." He says it's also necessary to review reporting of adverse events -- medical problems arising in study participants that require hospitalization or result in death. Last year, Emory researchers reported to an IRB special committee 1,421 adverse events that occurred to Emory participants in clinical trials. Such so-called adverse events can include anything that occurs to the patients under study, such as an approved deviation from a study's protocol, or even an unrelated accident, such as a fall, that requires a patient's hospitalization. Keller says most adverse events are not directly related to a drug or device being tested; in fact, only 92 (6.5%) of incidents last year were directly related to the trial the patient was enrolled in, and most of those had nothing to do with an error on the part of the researcher or health care team. Still, to completely eliminate doubt, the process needs to be streamlined, Keller says. When asked what keeps him motivated, given his huge task as guardian of human subjects, Keller doesn't hesitate: "Where else, but around this committee table, can a physician keep up to date about the latest medicine while watching the development of modern medical ethics?" For his part, Blake borrows a famous phrase from Winston Churchill to describe the immense work that has been done at Emory, with the realization that there is much more to do: "This is not the end, nor is it the beginning, but it is the end of the beginning...." For more information about institutional review boards at Emory, see www.emory.edu/IRB. Renee Twombly is a freelance writer.

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Weighing the risks and the benefits There is so much scrutiny of clinical research now, so many checks and balances, and that's good," says Christian Larsen, director of the Emory Transplant Center. "Still, the IRB process takes a lot of time, and it means that you can't put all your energy into the creative process the way you'd like to." Larsen's new study was up before a September IRB meeting. Although it took only two weeks from submitting the study to having it heard, he had been preparing supporting material for a long time. "We still need to streamline the process as much as we can," says Larsen. "We need to keep the investigators investigating and the system complying." His study is a good example of the kind of research that could ultimately offer a breakthrough in the treatment of thousands of patients, thereby changing clinical practice. It also illustrates the issues of risk and benefit to individual participants. Larsen"s goal is to eliminate the immunosuppressant drugs that every transplant recipient must use for life following receipt of their new organs. The drugs prevent the patient's body from rejecting the foreign tissue, but come at the cost of increased susceptibility to infections and heightened risk of developing cancer. Larsen and researchers at the Harvard-associated Massachusetts General Hospital and at Mount Sinai Hospital in New York are each enrolling two patients with failing kidneys as well as a plasma cell cancer known as multiple myeloma. Kidney transplants are not routinely performed on such patients because experience suggests their advanced cancer is untreatable and therefore fatal. However, in this trial, the six patients at three centers will receive new kidneys as well as a transplant of stem cells taken from the same organ donor. The stem cells will generate healthy bone marrow and a new immune system, and so treat the cancer. The donated cells will also match the "immune fingerprint" of the donated kidneys, and therefore the kidneys won't be rejected and the patient will not need drugs to suppress an immune reaction against the new organs. If the protocol works, this advance will smooth the way for transplanting both organs and stem cells into all recipients. But there are numerous issues behind this "very elegant piece of research" that needed consideration, according to Jim Keller, the IRB chair. One is the risk that the kidneys or the stem cell transplants will fail in study volunteers, perhaps hastening death or requiring sustained use of antirejection drugs, perhaps worsening the cancer. Or the surgery itself may be unsuccessful. Of ethical concern is the issue of whether kidney donors may feel coerced in any way to give blood stem cells as well. "We have to make sure this does not place undue coercion on donors, which can polarize families," Keller said. The IRB also noted several "mechanical" questions in its review of the protocol: Larsen signed the application, but committee members were unsure whether a department or center chair should sign his own application (one checkpoint is to have a department approve research protocols). The study had not been approved by Emory's radiation safety committee yet (another checkpoint when any radiation is needed). And they questioned whether language contained in an introductory letter to physicians could be considered an "advertisement," which would then require further review (the answer was "no"). In the end, the committee approved the protocol pending some changes, but labeled it "high risk," meaning the trial needs frequent review as it proceeds.

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A few unsung heroes Nancy Prescott of Stone Mountain gets a bone scan as part of a clinical trial testing the cholesterol-lowering medication Lipitor in women with early bone loss. A second study, says endocrinologist Patrick Bowen, involves the use of Tibolone, a drug that has been successfully used in Europe to treat menopause and protect against bone loss. More than 28 million Americans, 80% of whom are women, suffer from osteoporosis, which is characterized by low bone density and leads to skeletal weakness and increased risk of fractures.

In the first clinical trial of its kind in children, scientists will learn whether putting a topical gel in children's eyes at bedtime can halt future progression of nearsightedness. Myopic children between the ages of 8 and 12, such as Joseph Zavodny of Duluth, have signed up for the year-long study at a dozen sites across the country, say pediatric opthalmalogist Arlene Drack (left), principal investigator, and study coordinator Cameile Martin (right). Although the drug Pirenzipine can't reverse myopia, it could reduce the need for stronger and stronger glasses or contact lenses as children grow older.

After her mastectomy in 1992, Mary Davidson volunteered for a clinical trial of the drug Tamoxifen. She was cancer-free until this past August, when it was discovered that her cancer had spread to other organs. Davidson signed up again for another multicenter trial, this one evaluating the safety and efficacy of a three-drug regimen, but was taken off that protocol after suffering serious side effects. Still, she remains undaunted. "I probably will volunteer for another trial soon," says the senior office assistant in the Winship Cancer Center. "I'm very proud to work here and have faith in our mission of finding a cure for cancer." To learn more about these studies, call Emory HealthConnection at 404-778-7777.

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Conflicts of Interest While conflict-of-interest problems have surfaced across the country - such as the Penn researcher who owned a stake in the genetic product he was testing - the Emory School of Medicine's conflict of interest (COI) and commitment committee has been working hard since 1996 to prevent even the appearance of any impropriety. "We take seriously our charge to identify conflicts and assist faculty in managing or eliminating them," says Claudia Adkison, executive associate dean for administration and faculty affairs. Investigators are asked to disclose any financial ties to a study sponsor -- anything from routine consulting fees to stock options and ownership. "We have a very comprehensive program. It's important to us to take the high road and make clean decisions all the way around," she says. The whole point of conflict review and management is to protect the university, the investigators and in some cases, the patients, from even the appearance that the investigator's financial interest in the research might influence sponsor decisions about the research, the data, and the treatment of patients. "It is a huge responsibility,"Adkison says. One example is that the very people asked to test a medical device or a drug because they are the experts on that particular product may have long-standing relationships with drug companies, which offer the researchers a consulting fee in return for their work. Such financial arrangements need to be reported on disclosure statements, and if the consulting fee is more than $10,000 annually, it must be reported to the COI committee. If researchers propose a study using the product and involving human subjects, they must also notify the IRB committee hearing the application. Conflict disclosure must be made on the patient consent form and on all information about the study, including press releases, Adkison says. More problematic is the start-up company situation. A faculty member may decide to start a company to develop and commercialize a product he or she has created in the lab. The COI committee carefully manages any research proposal by that investigator that will be sponsored by the company and does not allow the investigator to be a company officer. Emory's rules prohibit a "conflicted" faculty researcher from leading a clinical trial as a principal investigator. However, in certain carefully controlled pilot studies, the faculty member can participate in limited ways. "Except for clinical trials proposed by a conflicted faculty researcher, we rarely say a researcher can't be part of the investigation. More often we form a management plan that offers close monitoring and oversight," Adkison says.

While the medical school has solid rules in place and an active supporting website, Emory as an institution has to guard against its own conflicts of interest, such as owning equity in a start-up company made up of campus researchers. It's a problem that universities around the country are now addressing. Sometimes the mere appearance of conflict of interest is more damaging than the facts warrant, Adkison says. "It's easy for a newspaper to run a story about Doctor X at Y university who's running a clinical trial and has a financial interest that looks inappropriate. But the article doesn't add that the conflict is being managed to the point that there is nothing amiss. That can ruin a person's reputation and instill doubt about an institution, and that's what we all guard against." In December, the Association of American Medical Colleges (AAMC) issued guidelines on financial conflicts of interest in clinical research. In the coming year, AAMC will develop guidelines to monitor institutional financial interests in human subjects research. For more information, see www.aamc.org/coitf.

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