Impatient treatment 

Documents offer rare glimpse into politics of human research at UAMS.

BARLOGIE: Drug company withdrew after 'deficiencies' in his trials.
  • BARLOGIE: Drug company withdrew after 'deficiencies' in his trials.

The University of Arkansas for Medical Sciences praises Dr. Bart Barlogie’s “pioneering research” into the cause of a deadly cancer known as multiple myeloma.

It touts the “superior clinical outcomes” seen by the thousands of patients who have come to the school’s Myeloma Institute for Research and Treatment (MIRT), which Barlogie directs.

UAMS issued a press release in 2004 when the National Cancer Institute approved an $18 million grant to MIRT, so that Barlogie and his team could continue their “outstanding and strikingly innovative” work.

But the high-stakes world of biomedical research is as secretive as it is complex.

No press releases were issued last year when:

• a drug company withdrew from a clinical trial, citing “deficiencies” in the way the study headed by Barlogie was being conducted;

• after confirming multiple “violations/deviations” in the study, a UAMS audit warned that “appropriate drug accountability has been a long-standing problem at MIRT” and that “significant changes must be made to safeguard participants and to ensure the responsible conduct of research,” and

• a federally mandated oversight group expressed its “unanimous concern” that Barlogie appeared to be acting “in a manner that does not distinguish clinical medicine from the rigid standards required in human experimental research.”

Barlogie is a superstar of Arkansas medicine. Admirers, including thousands of patients, laud his skill and compassion.

Barlogie himself says he’s a “perfunctory, precise perfectionist” whose worst habit is impatience. On the day he was interviewed for this article, he had just received galleys to review of his most recent article accepted to run in the New England Journal of Medicine.

The article will be about thalidomide.

In 1997, Barlogie demonstrated that the once-horrifying drug was effective against myeloma. That discovery, followed by the creation of MIRT, catapulted UAMS to the forefront of the world’s institutions studying and treating myeloma.

In less than a decade MIRT has become a mecca for myeloma sufferers, a leader in bone-marrow transplants, and a center for state-of-the-art research into the disease. Barlogie employs an approach called “total therapy,” in which one or more bone marrow transplants are used in combination with experimental chemotherapies.

Barlogie’s approach was so successful that MIRT quickly became an economic engine for UAMS. Last year it generated more than $100 million — 12 percent of UAMS’ gross revenue. In the past decade, MIRT’s success has underpinned much of the growth at UAMS.

But the intersection of research and treatment has always been a delicate one. Urgency to find a cure does not always coexist peacefully with regulatory precautions. The kind of outside-the-box thinking that can produce life-saving discoveries may bridle at institutional constraints. Egos can scorn oversight.

But oversight and review are crucial, especially of biomedical research being conducted on humans.

For that reason, since 1987, the federal government has required that all institutions that conduct testing on humans maintain independent oversight groups called institutional review boards, or IRBs. Members of an IRB stand on the side of the human participants: They must assess, approve and review the protocols — the plans for a patient’s medical treatment and for the scientific experiment — to assure that the research is safe, or that where risks do exist, subjects are fully informed of those risks before they consent to participate.

The IRB at UAMS has about 50 members. All except the chairman and vice chairmen are volunteers who serve four-year terms. Most IRB members work in medically related fields, though a few “lay” members, including retired clergy, also participate.

UAMS’ IRB oversees research at that campus, as well as at Arkansas Children’s Hospital, the Arkansas State Hospital and all veterans hospitals in the state. The IRB currently has about 1,600 protocols under review — and the number is steadily rising.

Some studies are funded by the university, others by government agencies, and others by corporations, such as pharmaceutical companies that manufacture experimental drugs. Some of the research conducted at UAMS is being done to see which experimental medicines will eventually win approval by the federal Food and Drug Administration for use in standard treatment.

Dr. Jimmie Valentine, the IRB chairman, explained that, since the IRB is so large and has so much work to do, it is divided into five committees. Each committee meets every Tuesday afternoon, usually for three or four hours.

Prior to those meetings, Valentine and a small staff at UAMS send members reports on protocols that have been submitted for approval, on any changes that may be sought to existing protocols, and on protocols that are scheduled for review.

Just preparing for the weekly meetings can require three or four hours’ work, Valentine said. He praises the members’ dedication.

All IRB meetings and materials are supposed to be confidential. Members, as Valentine put it, pledge to maintain “graveyard silence.”

But by early 2005, frustration with Barlogie’s conduct — and what was seen by some IRB members as a failure of UAMS administrators to hold him accountable — prompted some members to break that silence.

Members who spoke to the Arkansas Times on a condition of anonymity said they and others complained for at least two years that Barlogie was not adhering to UAMS and federal standards.

Specifically, they charged that Barlogie was changing the treatment plans, or protocols of some patients enrolled in his studies, and that he was doing this on his own, without obtaining proper approval.

One source reported that Valentine’s immediate predecessor, former IRB chair Dr. Marisue Cody, a Ph.D. nurse, had fought a vigorous but losing battle to have Barlogie comply with IRB demands. The source said that Cody not only failed to win the backing of UAMS administrators, but that she was ultimately “canned” as IRB chair by Dr. Larry A. Milne, the university’s vice chancellor for academic affairs and research administration.

Cody subsequently left UAMS. She now works at the U.S. Department of Veterans Affairs in Washington, D.C., where she is again responsible for the protection of human subjects in research. When contacted by phone, Cody would not comment on the IRB at UAMS.

None of the current IRB members who spoke to the Times said they harbored fears for patients’ safety. Rather, they said, their concern was that by straying from protocol, Barlogie eroded patients’ informed consent, compromised his studies, violated agreements with sponsors and regulatory agencies, and set himself outside of requirements to which other researchers were bound.

Sources say the situation persisted for at least a year after Cody’s departure, and that it was not addressed by UAMS administrators until a pharmaceutical company complained that a clinical trial involving one of its products — a trial headed by Barlogie — did not meet “basic research standards.”

In early 2005, officials of New Jersey-based Celgene Corp. notified Milne that it was withdrawing its drug, Revlimid, from the clinical trial titled UARK 2003-35, for which Barlogie was the “PI,” or principal investigator.

The study was to test the effectiveness of two new drugs — Velcade, manufactured by Millennium Pharmaceuticals, and Celgene’s Revlimid — in the treatment of advanced multiple myeloma.

Participants were told that the study was being done to learn more about the best way to administer these drugs, either alone or in combination.

Since it is not known which treatment was best, participants were to be randomly placed in one of the three treatment groups: one with Velcade alone, one with both drugs, and one with a lower dose of Velcade plus Revlimid. Celgene’s decision to withdraw Revlimid from Barlogie’s trial was a closely guarded secret at UAMS. Some who learned of it found it astounding.

Celgene had profited handsomely off its drug Thalmid, which was developed based on Barlogie’s thalidomide research. As recently as 2002, the company had honored Barlogie by creating a new “Career Achievement Award in Hematology Research” and naming him its first recipient.

But now, as one IRB member put it, the company was “very unhappy” with Barlogie and UAMS. As a result of Celgene’s action, UAMS officials ordered the university’s Office of Research Compliance to conduct an immediate, seven-day audit of the Revlimid study.

The auditors’ report was scathing. It cited 31 “major findings,” practices they said did not comply with federal or state requirements or UAMS policies and procedures.

“Overall,” the auditors concluded, “the conduct of this study is unacceptable, and significant changes must be made to safeguard participants and to ensure the responsible conduct of research.”

The report noted “multiple protocol violations/deviations” involving “most subjects” in the study. Several of the “deviations” pertained to dosages of chemotherapy.

According to the audit report, “Three of the eight subjects enrolled received [the] study drug despite having toxicities requiring that the drugs be [with]held.”

The report added: “Study staff, including the chemo room, clinic and research nurses, should be instructed to verify that subjects have undergone all required tests and procedures (e.g. the EKG) prior to drug administration.”

The auditors also noted that the violations might have to be reported to the federal FDA.

That could present a problem since, according to the report, “Appropriate drug accountability has been a long-standing problem at MIRT and has been a significant concern to the FDA.”

While the audit was underway, Vice Chancellor Milne was negotiating with officials at Celgene. At the end of March, the company agreed “to allow for the re-activation” of the Revlimid study, provided that UAMS agree to strict conditions.

In a letter to Milne last March, Dr. Jerome B. Zeldis, Celgene’s chief medical officer, outlined a “detailed plan of action” for UAMS to follow. Celgene demanded:

• That the protocol be revised, with dosages of Revlimid reduced.

• That the IRB “be made fully aware of the regulatory, safety, and compliance violations that have occurred to date” and that it “provide written approval for the ongoing conduct of this study.”

• That patients who had been participating in the study be notified of the changes and asked for their consent again.

• And, extraordinarily, that a clinical research associate be assigned to monitor all interactions with subjects and submit written reports to Celgene.

Zeldis’s letter concluded:

“We are committed to continuing our collaboration with UAMS. However, I must be perfectly clear: Revlimid is at a critical juncture in its clinical and regulatory development. We will not jeopardize the future viability of this novel compound by conducting clinical research in which basic research standards are not being met.”

The study was not reinstated. Zeldis did not return a call for comment. However, other studies involving Revlimid are continuing at other institutions.

(An outline of the cancelled study can be found at a website managed by the U.S. National Institutes of Health. Go to: http://clinicaltrials.gov/show/NCT00093028.)

Soon after the IRB was informed of Celgene’s withdrawal, its chairman, Valentine, issued a memorandum about — and to — Barlogie. The memo noted that, “While the IRB has and will continue to protect the welfare of subjects in MIRT studies, the overwhelming belief of the IRB Committee was that the philosophy of not distinguishing clinical medicine from human experimental research has to be addressed by University Administration.”

Valentine added that IRB members had voted unanimously to have him “arrange a meeting within seven business days between representatives of the IRB membership and UAMS administration to discuss the serious ramifications of violations that have occurred in this protocol, along with past MIRT issues that have come before the IRB.”

The Times filed a Freedom of Information request seeking records of those “past MIRT issues,” but UAMS officials denied it, citing exemptions in the state FOI law pertaining to medical records, employee job performance records, and “information that would give advantage to competitors.”

Milne also declined to be interviewed.

Valentine did consent to speak to the Times. The interview could not be conducted, however, unless Leslie Welch Taylor, the university’s associate vice chancellor for communications and marketing, was present.

Taylor said the requirement was a university policy. The interview took place in her office.

Valentine said that, for contractual reasons, he could not comment on the disputed Celgene study. He was willing, however, to speak in general terms about IRB’s relationship with Barlogie.

“It’s been a challenge,” he said.

“Dr. Barlogie is very prolific,” Valentine said. “He’s at the forefront of new and innovative treatments. He has a very large number of individuals coming here for treatment because of his fame as a myeloma researcher.”

The problem, according to Valentine, was that, “On some of Dr. Barlogie’s protocols, we were getting an unusual number of protocol deviations. The modifications were being reported — that’s a very firm rule — but we were having so many of them that it was getting to be overwhelming.”

Valentine stressed that the situation “was not affecting the safety of patients, or what Dr. Barlogie was trying to accomplish.” Moreover, he added, “We have fixed it.”

“MIRT is functioning very well,” Valentine said. “The protocols we get from them now are picture-perfect. We’ve made it so Dr. Barlogie’s protocols now are really well done.”

Still, when asked how, if modifications had been properly reported, Celgene auditors could discover deviations that were unknown to the IRB, Valentine again said he could not comment.

He noted instead that “in the past year, we’ve seen dramatic changes.”

Barlogie also agreed to be interviewed. He sat at a small table in his office at UAMS. A plaque behind him read: “Go where there is no path and leave a trail.”

Taylor was again present. She warned that Barlogie was “at a disadvantage” because he could not directly address the content of documents that were supposed to have been confidential.

But Barlogie said he was “a very transparent person.” When the documents were outlined, he responded:

“These were medically trivial issues. Obviously, I disagree with the accusations, or the concerns, that have been raised.”

He said the Celgene study “was shut down when it became apparent that the two agents [Velcade and Revlimid] in combination were likely to cause greater bone-marrow suppression.”

“It is up to any sponsor of a new drug to withdraw,” he added, “and if this is in the context of fearing that their product may be more toxic than they anticipated, that’s one way to do it. So I have no recourse in that setting.”

Studies elsewhere involving Revlimid, in combination with another drug, however, have exceeded expectations. Based on that data, Celgene is pursuing FDA approval for Revlimid as a treatment for myeloma.

As for Celgene’s withdrawal from his study, Barlogie said, “When you deal with a pharmaceutical industry that invests huge amounts of money in a product, I think there are issues of politics and other concerns behind their decisions.”

When reminded of the award Celgene had given him a few years ago, when it seemed he was “golden” in the company’s eyes, Barlogie responded:

“I don’t care if I’m golden in their eyes. I can look myself in the mirror and know I am careful and precise and I live up to research principles every day. I wouldn’t practice otherwise.”

Asked about the follow-up audit by the UAMS Office of Research Compliance, and its finding of “significant deficiencies” in the study, Barlogie reiterated, “I don’t believe that the basic standards were not met.”

“As long as there are humans involved in the administrations of these kinds of things, there will be errors,” he said.

Barlogie laid the blame for any errors that occurred on weaknesses within UAMS. “I cannot personally do everything at every minute everywhere, and I do rely on institutional support providing the infrastructure, the training and continual education,” he said.

“If there’s an issue, perhaps it’s more with the university than with Bart Barlogie.”

Barlogie was educated in Germany. He joined the University of Texas M.D. Anderson Hospital and Tumor Research Institute in 1974.

In 1989, Barlogie moved to UAMS to become director of hematology/oncology and research at the Arkansas Cancer Research Center (ACRC). He took over as director of MIRT when it became a separate entity in 2001.

“I was responsible, and have been, over the past 17 years I’ve been here, to put the overall theme and program together,” he said.

“I cannot possibly be held accountable to micro-manage my institutional infrastructure. I think I am responsible to the best of my ability, and no patient was put in harm’s way.

“But I think when an institution wants to play big, they have to put in the resources. If one looks at the ratio of research subjects and infrastructural support, there are institutions where you have better-educated nurses, data managers, and so forth.

“Maybe it has something to do with the education of Arkansas people. Probably we were lagging, like we do in many other things, in that support, behind other, more established institutions.”

Asked then about the IRB’s complaints that his studies were conducted in a way that did not “distinguish clinical medicine from the rigid standards required in human experimental research,” Barlogie responded:

“The issue is that we constitute, in my program, I would guess 60 to 70 percent of all clinical research conducted at this institution, and we have trials of an exceedingly complex type that involve several hundred patients. Close to 6,000 have been treated so far.

“And these are very complicated interventions, transplants and additional therapies. So the volume of per-patient interventions is absolutely enormous, and these studies are monitored by outside consultants and separately audited, as required as part of our grant from NCI, and we have been performing very well.

“This particular study was a very tiny segment.”

Reminded of Valentine’s memo, which noted that, prior to Celgene’s withdrawal, the IRB had “expended great effort” in working with Barlogie and the MIRT staff, “performing rigorous reviews and requiring remediation efforts where necessary,” Barlogie was dismissive.

“I think the IRB and that entire infrastructure didn’t even exist when I came here in 1989, and it was gradually established over the years.”

Asked then if he considered Celgene’s action, the faults found with his protocols by the Office of Research Compliance, and the IRB’s insistence on a meeting with the UAMS administrators to discuss this and “past MIRT issues” little more than growing pains, Barlogie nodded.

“Institutional growing pains,” he said, “rather than my growing pains.”

He pointed out that, before the NCI awarded MIRT its recent $18 million grant, a large review committee had “scrutinized both our basic science and clinical research, and we got outstanding reviews.”

He added, “I’m sure we would not have been able to secure that funding if there had been issues.”



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