Duke University Alumni Magazine


Cutting edge: skylights over the Medical Center's main lobby in Duke North
Photo: Les Todd

The action of a federal oversight agency raises national issues about clinical trials and how their human subjects are protected.

f you're a big player, people pay attention to your every move--and to every move made on you. A year ago, in a thirty-six-page report, Time singled out the Duke Medical Center as "one of the crown jewels of American medicine." Duke doctors, the magazine said, "are pushing hard against the limits of our imagination: tiptoeing electronically through the brain in search of hidden tumors, inventing vaccines that might turn lethal cancers into treatable ones, even breeding animals whose organs could one day be harvested for transplant to make up for the shortfall in human donors."

Then, on May 10, came another imagination-defying step: The federal Office for Protection from Research Risks directed the medical center to suspend enrollment of new subjects in federally supported research; research activities involving previously enrolled subjects could continue only if medically necessary. Duke Medical Center officials decided to suspend all new clinical trials, whether or not those trials were federally funded, until they could resolve the problem.

OPRR had visited Duke in December to conduct a routine review of the medical center's institutional review board, or IRB, which examines and approves research proposals that involve human participants. Afterward, OPRR pointed to some administrative deficiencies, even while reaffirming "the high priority which DUMC places on the protection of human subjects." At any one time, the medical center is conducting as many as 2,200 projects involving human subjects.

In February, the medical center submitted a plan to implement the changes; it submitted progress reports in March and April. OPRR said in its May statement that it found "the scope and pace of DUMC's implementation of corrective actions required by OPRR ...to be inadequate." Among the procedural complaints were that IRB minutes failed to record accurately all discussions of the IRB, and that quorum counts weren't detailed enough to ensure that sufficient numbers were present for each vote taken. In OPRR's view, the presence of two members of the Grants and Contracts Office posed a conflict of interest--though other institutions have followed the same practice, saying they value the expertise of those well-versed in the nuances of research funding. There wasn't a

Photo: Chris Hildreth

formal education program for the IRB and investigators, OPRR found, and the IRB had no full-time person in charge of administration.

"I was very well aware that OPRR had identified issues that they wanted us to correct," says Edward Holmes, vice chancellor for medical affairs and dean of the school of medicine. "We were working to correct them. I think it's fair to say that the speed at which we were making the corrections didn't agree with the speed with which they thought we ought to be making the corrections." He says that both he and Ralph Snyderman, chancellor for health affairs, were taken by surprise. "In all candor, when they called us on May 10, neither I nor Dr. Snyderman had a clue that this was going to happen."

In the aftermath of the suspension, Holmes --who had come to Duke from Stanford just a few months before--says there was "understandable frustration." After all, clinical research, and the contributions to patient care produced by clinical research, are basic to the mission of the medical center. There was also confusion surrounding the action: One medical investigator says his colleagues considered canceling thesis presentations by students, worrying that some of the data might have come from the clinical trials now in question. Snyderman and Holmes distributed an "Urgent Message" to faculty. The memo accented a commitment to "providing participants in clinical studies with the utmost protection against research risks," and it expressed the intention to "work closely with OPRR to ensure absolute compliance with federal requirements."

"The first reaction while we were reading the documents that shut us down was, can they do that to us?" recalls John Falletta, chairman of the medical center's IRB for the past five years and past chairman of the division of hematology-oncology in the pediatrics department. "And very quickly we recognized, sure they can. Second, people wondered, why is the problem being dealt with in this drastic way? It took a while to sink in. Then, if this is happening to us, who is at fault here? And finally, how can we fix it? Let's acknowledge the fact that we've got some things that need to be changed, and let's go about doing it.

"I'm a children's cancer doctor, and the notion of there being stages at which one grieves has been well-described. I wouldn't liken this episode to that precisely. But there certainly were stages that we went through, some of which parallel how one reacts to bad news of any sort."

Photo: Chris Hildreth

On the Monday he received word from OPRR, Holmes set up a task force under Russel Kaufman, vice dean for education and professor of medicine. On Tuesday, the task force--made up of eighteen senior members of the medical school faculty--held its first meeting. "That week, we literally worked around the clock," Kaufman says. By Wednesday, task-force members were framing ideas for a report to be handed over to OPRR. Kaufman put the finishing touches on the write-up around one o'clock in the morning on Thursday; some six hours later, a team of medical center officials--Snyderman, Holmes, Kaufman, Duke medical ethicist Jeremy Sugarman '82, M.D. '86, and a couple of others --flew to Washington with a corrective plan. Beginning the ninety-minute meeting, Snyderman and Holmes offered some general comments to the OPRR staff, and then Kaufman presented the report of the task force. "After Drs. Snyderman and Holmes told OPRR that we were committed not only to remedying and dealing with the issues raised but also to making this a premier IRB structure, OPRR's attitude changed," says Kaufman. "It was much easier for me to present in that atmosphere given the tone that had been set."

OPRR suggested some modifications in the plan. On Thursday's flight back, the Duke team revised it accordingly, then faxed back the revisions some two hours after landing. The following afternoon, OPRR lifted the research ban.

Kaufman's task force has continued to meet weekly, stepping back somewhat from the intensity of the crisis period. "I can't emphasize enough how hard everyone worked, and how well everyone worked together to get this task completed," says Kaufman. During that period of suspension, the task force "followed a diagnostic mode, to use a medical paradigm," Kaufman says. "We needed to look not just at what OPRR had criticized, but also to reflect on how the IRB was run and the resources and staffing for the IRB." Sugarman--director of the newly established Center for the Study of Medical Ethics and Humanities at Duke--was enlisted to design and implement a ninety-minute educational program. The program would encompass the history of medical research, an understanding of the ethics of research, and an overview of the regulations themselves. In the week of the crisis, more than 1,300 investigators and IRB members attended the program. Two consultants were brought in to give additional training to IRB members specifically.


Clinical trials blossomed in the 1970s, when trials involving multiple cancer centers were used to compare chemotherapies, says Duke cardiologist Robert Harrington. Harrington, a clinical-trials expert source for the News & Observer, says the winner of each trial was pitted against yet another drug. In the process, scientists worked out the basic protocols for large clinical studies. Usually, they involve a large number of medical centers and are double-blind, meaning that neither the patient nor the physician knows whether the drug being administered is the test drug or the standard drug (or, if there is no standard, a placebo).

By the 1980s, investigators were applying these techniques to a new generation of pharmaceuticals. Perhaps the most famous trial compared streptokinase, the first drug used to dissolve blood clots, with aspirin and with no treatment at all. Not surprisingly, streptokinase was found to be more effective in preventing death from heart attacks than no drug. But surprisingly, streptokinase and aspirin combined were twice as effective as streptokinase alone.

At Duke and elsewhere, subjects participate in one of four phases of clinical trials. Phase-one trials involve testing an agent on a small number of normal volunteers to see if the agent is safe and, if so, to determine the right dose. In phase-two trials, researchers are observing the effect of a drug or a device on patients with a particular disease. Those trials, which concentrate on issues of safety and efficacy, usually involve several hundred patients who are closely monitored and who are put through fairly demanding medical procedures. Researchers undertake phase-three trials to gather specific risk-benefit information about a new therapy. Phase-three trials generally extend over a long period, involve several hundred to several thousand patients--often distributed across several medical centers--and entail only occasional medical procedures.

By the time research reaches stage-four status, the drug or device has earned approval from the Food and Drug Administration. Stage-four researchers may be refining earlier studies by, perhaps, studying the results of different dosages, impacts on a different patient populations, or new timeframes.

Most of the work at Duke is in phase-two and phase-three trials; much of it is sponsored by industry or federal agencies like the National Institutes of Health.

Duke modified its IRB membership criteria; the medical center's grants office, for example, would no longer have representation. It revamped its procedures for recording and processing the minutes of IRB meetings. It assigned a thousand square feet of space to the IRB, purchased ten new computers, created a new information system for managing IRB data, and increased the support staff from two to six. It formed a second permanent IRB to handle the workload. As it searched for a permanent, full-time IRB administrator, it brought on Linda Wilkins of the department of medicine as temporary administrator; according to Kaufman, she found herself working twelve- to fourteen-hour days, seven days a week, for the next two and a half months.

And, as required by OPRR, Duke undertook a re-review of 274 research proposals--meaning lots of extra IRB sessions. Investigators had to supply a copy of their grant requests, some of which run for hundreds of pages. The re-review looked for strict concordance between human-experiments protocols endorsed by the IRB and the work envisioned in the grants.

OPRR also mandated that Duke provide minutes of all of its IRB meetings since May, and that it provide quarterly updates. "All of those things have been done, and to date all of them have been positively received," says Kaufman.

"I do believe that when this is done, we're going to have the best IRB system in the country," Holmes says. "It's been a hard lesson for us to have to go through, but in a way, we've become a teacher."

Falletta, the IRB chairman, says he never felt patients were at risk at Duke. He compares the IRB to "an accordion," getting stretched and stretched as it took on more work. "What the OPRR visitors saw, correctly, was that such a situation isn't really sustainable." Up until four or five years ago, Duke was similar to peer institutions in its IRB structure, he says. "As we reached a near-breaking point with respect to workload, we didn't make the necessary changes to increase the number of IRBs, or to lighten the load in such a way that it would allow the work to be accomplished in a more practical manner." Monthly meetings that once occupied four hours lasted six hours, and the IRB had to struggle to meet new standards for reviewing already approved protocols. It was typical that IRB members from departments particularly active in clinical research, like medicine, psychiatry, surgery, or pediatrics, would spend 15 to 20 percent of their time on IRB-related work.

Before May 10, neither IRB members nor their departments had been compensated at Duke, Falletta observes. "After all, this is clinical research that we're talking about, so we need clinicians to be part of the review process. But once you take clinicians out of the clinic, it starts hitting them in the pocketbook, and IRB work becomes really an unpopular request." IRB members were compensated for re-reviewing the 274 proposals. Yet the best compensation, in Falletta's view, will flow from the steps Duke has already committed itself to--"broadening the base of reviewers and lightening the load on everybody's part."

The process of reviewing a research protocol often starts with advice to the researcher from the IRB chairman. Then the protocol is formally submitted to an IRB representative from the department, and next, to that department's chair. From there it goes to the IRB office, where it is assigned for presentation at the next IRB meeting to someone outside the home department. The IRB as a whole may decide to disapprove a project, which rarely happens, or to approve outright, which is also rare. A couple of times in a given meeting, it might table the protocol, meaning that the protocol needs to be redone thoroughly. Most of the time, the IRB will approve the protocol with modifications, meaning the board will insist on changed--perhaps simpler or more direct--wording in the consent form.

For much of the public, the news of the suspension of clinical trials--splashed as it was across front pages of newspapers nationally--may have been a first education in institutional review boards. IRBs can be seen as

outgrowths of crisis and opportunity. The Nuremberg trials following World War II produced chilling accounts of the abuse of human subjects: Josef Mengele, chief physician of Auschwitz, had performed gruesome experiments--all carefully documented--on twins, crippled persons, and others to "prove" the superiority of the Aryan race. In the 1960s, a Harvard anesthesiologist, Henry Beecher, published an article in the New England Journal of Medicine that shook the research establishment. The article cited twenty-two research projects that, in Beecher's judgment, had violated the rights of the human subjects involved. Revelations followed about the Jewish Chronic Disease Hospital in Brooklyn, New York, where elderly patients were injected with live cancer cells without their consent, and the Willowbrook State School in Staten Island, where mentally retarded children were purposely exposed to hepatitis.

Concerns about the protection of research subjects were heightened in 1972, when the press uncovered details of the infamous Tuskegee Syphilis Study. The study involved 600 black men; at least twenty-eight died as a direct result of untreated syphilis, and many others suffered from manifestations of the disease, including blindness and insanity. In the wake of the Tuskegee case, Congress passed the 1974 National Research Act. The act required the Public Health Service to promulgate regulations for the protection of human subjects, and formed the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The commission's so-called "Belmont Report" specified "basic ethical principles" for research involving human subjects. Those principles were respect for persons, meaning that "subjects enter into the research voluntarily and with adequate information"; beneficence, or the idea that researchers should maximize possible benefits and minimize possible harms; and justice, including equity in the selection of research subjects.

What has changed in many cases, says Duke's Jeremy Sugarman, is the knowledge and attitudes of persons who think about enrolling in clinical trials. "We've seen the pendulum move from protection to access. That is, in the wake of scandals in research, some possibly did not know they were research subjects, and vulnerable persons needed to be protected from research. Now, some argue they are entitled to access to research. This change in attitude was precipitated in large part from the disease activism of HIV-AIDS and cancer in the Eighties and early Nineties. Sick patients simply want access to potentially life-sustaining therapies. Disease activists would say to doctors, regulators, and pharmaceutical companies, forget about your rules, forget your clinical trials, just give me that drug. So clinical trials became perceived as a treatment mechanism." (Investigators refer to this as "therapeutic misconception"--the assumption, as Sugarman puts it, that patients are receiving therapy when in fact they are in a trial about therapy.) One Duke researcher doing work in muscle transplantation received a barrage of phone calls from around the country from therapy-seeking patients. The work hadn't even progressed beyond animal studies.

Photo: Chris Hildreth

The other side of the drive to protect human subjects is the burgeoning of research activity. For fiscal 1999, Congress gave a $2-billion budget increase to the National Institutes of Health, the main funding agency for biomedical research, for a total of $15.7 billion. It's a trend that can be traced back more than fifty years. The NIH budget rose from less than a million dollars in fiscal year 1944 to more than a billion dollars in fiscal 1969. In the last ten years, the agency's budget has almost doubled, from $7.9 billion in fiscal 1989. Budgets are, of course, a response to political strategy and political necessity. Leaders in science and education have proved to be effective lobbyists for the NIH. And their cause has been broadly popular.

Speaking of the NIH, Duke's senior vice president for public affairs and government relations, John Burness, says, "There's probably no agency in Washington that has more broad-based political support and public support. That's for perfectly understandable reasons. The degree to which breakthroughs occur in medical care has a huge impact on the quality of life of the American people."

Such hefty sums bring expectations of accountability. The Chronicle of Higher Education reported last winter that Pete Domenici, a Republican from New Mexico and chairman of the Senate Budget Committee, had advised his colleagues that they should closely monitor the NIH's handling of the increase they were about to approve. "When you're getting increases of those amounts, it is not surprising that they come with a greater level of scrutiny," says Burness. "Each and every regulation has a public-policy basis that is probably rational. It is the accumulation of those regulations that can be difficult for organizations to handle. This is not unique to Duke; you see the business community talk about it, you see government agencies talk about regulations imposed by other government agencies."

Accountability carries a cost. While he's relieved that Duke now has a new IRB structure, Holmes, the medical school dean, says, "There is going to be a significant cost factor. Even what was going on was not inexpensive. As a consequence of some of the changes that we've made, we're not talking about a few thousand dollars. We're talking about hundreds of thousands of dollars of incremental expense." Most government and private contracts wouldn't absorb IRB-related costs as necessary overhead, he says. "I think people want to do what's right to protect human subjects. The concern of people like myself who are administrators is how you find the resources to do this. Is it going to curtail the volume of clinical research? That would be a terrible outcome, in my view."

While patients are vying to participate in clinical trials, medical researchers are vying to set up clinical trials. For decades, under the fee-for-service system, research expenditures were subsidized by patient-care revenues. Under managed care, traditional financial support for research activities has been diminishing: According to The Chronicle of Higher Education, 38 percent of teaching hospitals will be losing money by the time the Balanced Budget Act of 1997 expires in 2002. The act slashed Medicare payments; one consequence is that the University of Pennsylvania Health Services System, for example, lost nearly $90 million last year. In such an environment, commercial sponsorship has become increasingly important.

The corporate-sponsorship theme plays powerfully at Duke, where Robert Taber, vice chancellor for science and technology, says the medical center has become "more attuned to corporate funding as a source of research dollars." At the same time, pharmaceutical companies are increasingly "outsourcing" both their basic-discovery work and their clinical trials, recognizing, as Taber observes, that "it's a cyclical business and they don't need to maintain that expensive infrastructure." In 1995, Duke had 225 sponsored research agreements; last year, it had 556 agreements. Three years ago, it brought in $52.7 million from companies; last year's figure was $77.3 million. Taber says the office he directs--Science and Technology--is unique among medical centers. Set up in 1992, it encompasses (and encourages) commercially sponsored research at Duke, start-up companies, patents and trademarks, and corporate gifts.

Such changes in health care have put pressure on the 3,000 to 5,000 IRBs that can be found across the country. No one has a more precise number: IRBs reflect the different expectations and regulations of two federal agencies, the Office of Protection from Research Risks and the Food and Drug Administration. The FDA itself has said, "It should be noted that the uncertainty in the number of IRBs subject to the regulatory oversight by federal agencies is part of the problem in exercising that oversight." Usually associated with hospitals and academic centers, they are also found in managed-care organizations and government agencies like the National Institutes of Health and the Centers for Disease Control. Federal regulations require that boards have at least five members with varying backgrounds. At least one board member must have primarily scientific interests, one must have primarily nonscientific interests, and one must be otherwise unaffiliated with the institution in which the IRB resides. A quorum, including at least one member whose interests are primarily nonscientific, is needed for voting.

In their initial reviews of research involving human subjects, IRBs look at the research protocol, the informed-consent document to be signed by subjects, and any advertisements to be used in recruiting subjects. IRBs are supposed to ensure that any risks subjects may incur are warranted in relation to the anticipated benefits, that informed-consent documents clearly convey the risks and the true nature of research, that advertisements are not misleading, and that the selection of subjects is equitable and justified. They also engage in continuing review "at an interval appropriate to the degree of risk but not less than once per year."

IRBs have the authority to make research-in-progress site visits--to check whether informed-consent procedures, for example, are being implemented as promised. According to Sugarman, "It's uncertain to what extent IRBs do so, or whether they're even properly equipped to do it." In "especially risky or unusual research," IRBs might be prompted to engage in that sort of assertive oversight. "Depending on the source of research funding and the goals, there are other monitoring mechanisms. The FDA and other sponsors of research will monitor routinely."

OPRR, located at the National Institutes of Health, is ultimately responsible for ensuring the protection of human subjects. The agency sets up formal agreements with medical institutions; those agreements, or "assurances," outline each institution's commitment to conduct its research projects in an ethically sound manner. In line with the assurances, the institutions set up their IRBs, which are in effect ethical oversight committees.


The complexities --and significance-- of clinical trials are illustrated by work at Duke on Pompe disease. Last spring, the medical center announced the beginning of phase-one/phase-two clinical trials to test an enzyme replacement for the disease, which is usually lethal in children but afflicts people of all ages. And this fall, an Illinois family lobbied to enroll their desperately ill infant in the trials; the child died in late September. The family had found out about the trials from a physician who referred another child--one of three--for the Duke study.

Pompe disease is rare, affecting approximately one child in 100,000. If symptoms appear during infancy, death usually occurs before the age of two. The disease is usually less severe when symptoms first appear late in childhood, but life expectancy extends only into the second or third decade in such cases. Adults can be affected by a milder form of the disease but are still incapacitated.

The disease is caused by the lack of an enzyme that breaks down glycogen into glucose, a primary source of energy. In patients with the disease, glycogen accumulates, destroying skeletal, heart, and lung muscles. The enzyme replacement therapy, to be administered by infusion, is intended to restore glycogen levels in muscle tissue to normal. If successful, the treatment will be required for the remainder of a patient's life.

Y.T. Chen, chief of the division of medical genetics in the department of pediatrics, is leading the clinical trials. Chen is the principal investigator on an Investigational New Drug application on file with the Food and Drug Administration. His team at Duke spent more than five years developing the genetically-engineered enzyme and has shown that the enzyme helps relieve symptoms of Pompe disease in animals. The current trials--supported by Synpac, a drug development company--are testing both the safety and efficacy of the product in humans.

According to medical center officials, the Illinois family was understandably upset that Duke made the difficult decision--supported by the FDA--not to expand the trials to include their child. Unfortunately, there is only enough of the drug for the three children. Beyond that reality, extending the trials to include a fourth, which is not the approved protocol, would put the three enrolled patients at risk. That would delay results that could lead to FDA approval --and potentially withhold a life-saving remedy from others.

The action against Duke hardly occurred in a vacuum. Institutional review boards increasingly are the subject of scrutiny by government agencies and outside commissions. And much of that scrutiny hasn't been kind to IRBs--including a June 1998 study, "Institutional Review Boards: A Time for Reform," by the Office of Inspector General of the Department of Health and Human Services. According to the report, the IRB system has been pressured by changes in the research environment: the expansion of managed care, the increased commercialization of research, the proliferation of multi-site trials, new types of research, the increased number of research proposals, and the rise of patient consumerism. "Expanded workloads, resource constraints, and extensive federal mandates contribute to a rush atmosphere where sufficient deliberation often is not possible."

IRBs across the country are inundated with protocols--an average increase of 42 percent in initial reviews during the past five years, with the result that some IRBs are now reviewing more than 2,000 protocols. Despite the increase in workload, staffing levels and budgets have remained constant at many IRBs. At the same time, IRBs "frequently are hard-pressed to gain access to the scientific expertise they need to reach informed judgments about the research taking place under their jurisdiction," the report says. Protocols involving advanced biomedical techniques--such as genetic testing--raise scientific issues, as well as moral and ethical questions, that might confound the non-specialist.

The Inspector General's report expresses concern about conflicts that threaten the independence of IRBs--many of whose members are colleagues of the investigators on whom they are passing judgment. Clinical research provides revenue and prestige to the sponsoring institutions. Institutions expect IRBs to support these interests at the same time that they protect human subjects, producing a tension that "can lessen the IRBs' focus on their basic mission." Commercial sponsors "seek quick turnaround reviews for their protocols and can be tough negotiators on publication rights, liability issues, and other matters," says the report. And the "outside" members on the boards rarely provide an effective counterbalance to such pressures. "Few IRBs seem to seek or to be able, on a consistent basis, to recruit and maintain lay and/or nonaffiliated members who play an active, effective role in helping the IRBs stay focused on their mission of protecting human subjects."

As the report sees it, the IRB system fails to educate investigators to ensure sensitivity to human subjects. "Similarly, it provides minimal orientation and continuing education for IRB members--a deficiency that is especially detrimental to nonscientific and non-institutional members." For new IRB members, their orientation to the role is seldom more than a stack of materials to read and on-the-job learning. A 1995 survey of 172 university-based IRBs found that one-quarter offered no training at all to their members; at the vast majority of institutions, training was limited to less than four hours.

OPRR itself hasn't been spared from scrutiny. The report noted OPRR's own statement --quite striking in light of the later Duke episode--that the focus of investigations had shifted from "micro-level to systemic solutions." Between 1990 and 1998, the report said, there had been 438 investigations. "However, the great majority of investigations occur through paper and phone communication. Only rarely does OPRR go on site.... In fact, OPRR conducted only one such visit between April 1997 and May 1998 because of staffing problems."

According to press reports, the office allowed two other institutions--Rush-Presbyterian/St. Luke's Medical Center in Illinois and the West Los Angeles Veterans Hospital --four and six years, respectively, to correct their deficiencies before revoking their licenses. But early this fall, OPRR seemed to move quickly to shut down human subject research at the University of Illinois at Chicago. OPRR said some research at UIC proceeded without ever being submitted for approval by institutional review boards. The problems arose in part from a lack of support staff for IRBs, OPRR concluded, and they pointed to insufficient attention by UIC officials "at the highest levels."

Lately, OPRR has found itself on shifting ground. In early June, just weeks after the Duke episode, an advisory committee to the National Institutes of Health recommended that OPRR be relocated from NIH to the Office of the Secretary of Health and Human Services. The National Institutes of Health is a component of Health and Human Services --the component, as it happens, that distributes much of the largesse fueling the research over which OPRR is supposed to exercise oversight. By separating itself from NIH, as OPRR says in its own press release, the agency expects "to elevate its stature and effectiveness." In a story about the action against Duke, The Washington Post reported that Congress and other agencies were frustrated by OPRR's "hamstrung position." (OPRR has a budget of less than $3 million and just two full-time investigators.) "Several insiders speculated...that the threat of extinction may have spurred the agency to crack down on Duke, to signal its capacity to get tough." As the Post put it, "institutions under investigation by OPRR often have taken years to come into compliance, without facing the draconian measures imposed upon Duke."

Criticisms of IRB procedures aren't themselves without their critics. In a formal response to the Office of Inspector General report, the Association of American Medical Colleges declared that, overall, this is a system that has worked remarkably well. The association's president, Jordan J. Cohen, agreed that IRBs face tremendous stresses, and that they could benefit from additional resources. But he challenged the notion--supported by the title of the report, "A Time for Reform"--that the system is in crisis or on the verge of collapse. And he questioned the assumption that an IRB process should be rooted in a policing or auditing role rather than in trust.

The trust that exists between the IRB and the investigator "permits this system to work effectively because it encourages openness, responsiveness, and collaboration," he said. He took strong exception to the report's focus on presumed conflicts of interest that would seem to breach that trust. It is a "false logic," he said, to argue that "IRBs regularly have the institutional interest in heart at the expense of those of research subjects.... The fact of the matter is that nothing could be more in the institutional interest than protecting the subjects of research."

For his part, Sugarman says, "There always have been pressures for investigators to produce in clinical research. And there always have been conflicts of interest in research. Any IRB is going to have conflicts of interest, too. An IRB can fail because of the conflict of interest of needing to approve research within the institution; it is an institutionally constructed committee. The real question is, are these irreconcilable conflicts or can we work around them?" He says the IRB system has a sound basis--"looking over the research before it happens in a manner that can be sensitive to the local environment in which the research will be conducted, balancing the risks and benefits of the research, and delineating how informed consent will be obtained."

If pharmaceutical companies impress academic institutions with standards of efficiency, that's not a bad thing, he says. And while managed care might place constraints on research, it might also produce "better data on outcomes" because of the "synchronization of care that's not possible in a fractionated fee-for-service system."

In Sugarman's view, a deeper challenge for IRBs comes from the growing prevalence of clinical trials at multiple clinical sites. "The current regulations were written at a time when most research was done with a single institution and by a single investigator. Consequently, they are cumbersome to use in multi-center research, which constitutes a large proportion of clinical trials today."

The same complexity in medical research that demands cross-institutional approaches also involves expertise that isn't always available in smaller institutions. Sugarman and several Duke investigators participated in an NIH-sponsored conference that considered the dicey ethics of in-utero gene transfer experiments. Under his auspices, Duke held its own conference on the ethics of using stem cells derived from umbilical-cord blood. Those cells hold promise in treating a variety of medical conditions; but informed-consent procedures surrounding cord-blood "banking" and donation are another murky ethical area. With some cutting-edge medical technologies, those who perform and scrutinize research will gain from discussions that go beyond the scope of most IRBs, he says.

Whether or not it was intended to do so, OPRR's action sent a message to other medical centers. Duke doctors mention having received phone and e-mail messages from colleagues across the country with the common refrain, "There but for the grace of God go we." Falletta says his e-mail screen showed eighty to ninety messages a day, from investigators at Duke and from other medical centers. Says Duke administrator John Burness, "One of the costs of prominence is someone may try to make an example of you. That's true whether you're talking about the Duke English department or the medical center."

At one medical center that closely fits Duke's profile, three medical administrators declined to say anything about Duke and OPRR. A public-relations official there sees no benefit to his institution's calling attention to itself on this matter. He likens OPRR to the IRS: An eager auditor is bound to find some transgression in any investigation.

The places where Duke's Edward Holmes held administrative posts, the University of Pennsylvania (where he developed the department of medicine) and Stanford (where he was senior associate dean for research), are more forthcoming. At Penn, Glen Gaulton, vice dean for research and research training, says "we all fell out of our chairs" when word came of the research suspension at Duke. Penn has just one IRB for the university and the medical center. But that group is divided into seven subcommittees. IRB members, none of whom (as at Duke) is paid for the service, oversee what Gaulton describes as "a bit of an upswing in clinical trials"--an upswing that, in part, is a response to the need to infuse revenue into Penn's declining coffers. "There's heightened awareness--and appropriately so--that this area needs to receive a greater level of scrutiny," he says. "Someone was bound to be hit with an investigation like this."

Gaulton says an internal review left Penn feeling confident about its IRB procedures; the Duke episode, he says, "had a good byproduct, in that everyone is now taking a fresh look." Penn's look is longer-range, and it's considering more vexing IRB issues. The possibility of compensating IRB members is one. Another is the possibility of expanding the IRB's sphere of operation--performing random audits of clinical trials to gauge, for example, whether informed-consent practices conform to those outlined in the research protocol.

At Stanford, the immediate response was to gather together top officials and have them study OPRR's list of complaints against Duke. "We actually came away feeling quite good about our own procedures and policies," says Kathy McClelland, Stanford's research compliance director. At the same time, McClelland's office was under review for additional support staff--a step that's now been taken for Duke. The new staff members are coming, and they'll be supporting three medical IRBs (an increase from two) and one non-medical IRB. It's not just that the volume of clinical trials is on the rise at Stanford, McClelland says. Research protocols are becoming more complex, even as patients are clamoring to be part of the research and investigators (or sponsors) are pressing for speedy approvals. "One protocol can invoke four or five sets of regulations, some of which are conflicting. When you see the attorneys struggling with the regulations, it's a lot to expect surgeons or administrators to figure them out. That really does challenge the IRBs."

Like Penn, Stanford is looking into compensating its IRB members. (For now, the home departments of the subcommittee chairs receive funds to compensate for the time spent on non-department business.) "The time commitment is greater than for other committee service," McClelland says. "And the consequence of error is far greater. You're talking about people's safety, even their lives."

The negative consequences of the research interruption don't seem to be lasting for Duke. According to Holmes, patients and drug companies haven't turned away from the medical center. On the contrary, during the suspension, "we got numerous phone calls from individuals who viewed some of the experimental therapies as their only chance. That was one of the reasons to make the corrections as speedily as possible," he says. "And if you're an external agency, whether that's private or governmental, a four-day suspension--and thank God, it was only four days--isn't going to change your view that Duke does very high-quality clinical research."

There's evidence that Duke played it smart in getting the issue behind it as quickly as possible. About two weeks after the suspension, the medical center commissioned a national survey. It showed that the incident registered for about 6 percent. "It was below bottled-water safety as an issue," as Burness puts it. "To the degree that people remembered it, they remembered something favorable about Duke--that Duke cleaned it up, and so it was a non-problem."

If that's so, Duke handled adeptly what was as much a public-relations crisis as a medical crisis. The most notorious contrary example arose at Stanford in 1990-91. Accused of cheating the government out of hundreds of millions of dollars in indirect costs--that is, the overhead charges accompanying research grants--Stanford chose to wage a vigorous legal battle. Stanford ultimately won the legal issues but suffered significant public criticism for a decade. In one of its monthly reports to the leading universities, the Association of American Universities pointed to the different strategies between the two institutions, and accented the better outcome for Duke.

Several years ago, Jeremy Sugarman found himself involved in a medical and public-relations episode of broader scope. As a staff member of the White House Advisory Committee on Human Radiation Experiments, which began its work in 1994, he wrestled with difficult questions about the conduct of research involving human subjects. As part of that work, he was involved in surveying about 2,000 patients at medical sites around the country, including Duke. A hundred of those patients were segmented for in-depth interviews.

"One of the overriding messages we learned was that trust was crucial--trust in the individual investigators, trust in the institutions in which the research was conducted, and trust in the research enterprise as a whole. Trust was central to the willingness of people to participate in something they hoped would give them some direct medical benefit. But they would often realize over time that the benefits might not accrue to them. Despite that, they would be willing to be altruistic."

As a society, we shouldn't rely exclusively on review boards or government agencies for patient protection, he says, any more than we should rely on police forces for driver protection. Ultimately, we need to believe in good intentions.

That implicit trust explains the persistence of someone like Arlawin Ladd, a patient participating in a Duke cardiology study. Ladd, a seventy-two-year-old who lives just outside Durham, began in a clinical trial in the winter of 1998. She had been diagnosed earlier with congestive heart failure. "This is not an impersonal thing," she says of her experience. "It's done with care, with an interest in the patient." Ladd was referred to the medical center by her primary physician, who had trained at Duke. A Duke cardiologist then encouraged her involvement in the study. "Somewhere down the line, they'll be able to conquer this problem. It may be ten years from now. I may not be the beneficiary. But for all we know, this may be a hereditary condition, so perhaps my children or grandchildren will benefit. If someone's life can be saved, it'll be worth just about anything I might contribute."

Since she doesn't know if she's in an experimental group or a control group, she can't be sure that she's seeing the results of a new therapy. But Ladd--who helps manage a church pre-school for two-year olds--does know that she's benefiting from medications that weren't available until recently, and that are themselves outcomes of past clinical trials. She doesn't indicate much interest in OPRR's action. She simply says it would have been "a terrible thing" if a research dispute had intruded on a research mission.

Your Turn: Post your opinion on whether you have confidence that Instituitional Review Boards fully protect the interests of human subjects?


  • The Federal Office for Protection from Research Risks issues and monitors licenses for universities where research on human subjects is conducted. OPRR has issued more than 3,000 licenses, known as Single Project Assurances, that allow a university to conduct a single study.

  • A scientist applies for a grant from a federal agency to finance a proposed project.

  • The federal agency convenes a committee of scientists to evaluate the proposal's scientific merit.

  • The federal agency tentatively awards a grant. At the National Institutes of Health, the largest source of federal grants for biomedical research, 33 per cent of proposals win grants.

  • The approved project is examined by an Institutional Review Board (IRB) on the scientist's campus. The panel of physicians, scientists, and community representatives focuses solely on protecting human subjects of research. It makes sure that studies that include people who may be particularly vulnerable--such as pregnant women or the mentally ill--would not harm or exploit those subjects.

  • The IRB approves, rejects, or recommends changes in the project's human-subject protections (not the science). The IRB must approve the proposal before the federal agency will release the grant funds.

  • Officials at the scientist's institution sign a

  • contract with OPRR--known as a Single Project Assurance--agreeing to follow federal rules on the protection of human subjects in research. The contract acts as a license allowing institutions to use federal grants for human-subject research.

  • Research begins.

  • The IRB must check on the study once a year and report to OPRR anything unexpected that happens to research participants. In particular, the IRB is required to report "adverse events" such as the death of a subject when no risk of that was foreseen, or the passing out of a subject when no risk of losing consciousness was expected.

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