August 25, 2013

UC Davis surgeons resign after bacteria-in-brain dispute

Two UC Davis neurosurgeons who intentionally infected three brain-cancer patients with bowel bacteria have resigned their posts after the university found they had "deliberately circumvented" internal policies, "defied directives" from top leaders and sidestepped federal regulations, according to newly released university documents.

Two UC Davis neurosurgeons who intentionally infected three brain-cancer patients with bowel bacteria have resigned their posts after the university found they had "deliberately circumvented" internal policies, "defied directives" from top leaders and sidestepped federal regulations, according to newly released university documents.

Dr. J. Paul Muizelaar, 66, the former head of the neurosurgery department, and his colleague, Dr. Rudolph J. Schrot, violated the university's faculty code of conduct with their experimental work, one internal investigation concluded.

All three patients consented to the procedures in 2010 and 2011. Two of the patients died within weeks of their surgeries, while the other survived more than a year after being infected.

Two of the families later settled claims against the university for $150,000 and $675,000, creating a new tangle in the controversy that has raised complex questions about the nature of consent, what constitutes research – and how to safeguard vulnerable patients.

Muizelaar, one of the highest paid employees in the University of California system, stepped down effective June 27. He earned more than $907,000 last year, the 33rd-highest gross pay in the UC system.

Schrot, 45, an associate professor who made about $512,000 last year, will leave his post at the end of this month.

Both doctors have sharply criticized the findings, characterizing the internal investigations as biased and incomplete, according to written statements provided to the university, and in sit-down interviews with The Sacramento Bee.

The surgeons maintain they were acting in the best interests of their desperately ill patients, whose prognoses for survival were poor. Both doctors told The Bee on Friday that they opted not to appeal the university's findings because they determined it would be fruitless.

"I lost confidence, if you will, in the ability of the university administration to fairly handle it," Schrot said Friday in the office of his Sacramento attorney.

The detailed findings also identified lapses by UC Davis staff and administrators, saying that compliance problems may extend beyond the neurosurgeons' case. In a letter dated Aug. 6 to UC Davis Chancellor Linda P.B. Katehi, the university's provost concluded that "additional safeguards must be developed and implemented to further protect research subjects and patients."

"(T)he investigators I appointed heard from some witnesses that there is perception that compliance with University policies and external regulatory requirements is not a universally held value," wrote Ralph J. Hexter, provost and executive vice chancellor.

The surgeons' resignations – along with the harsh conclusions of at least eight internal and external investigations of their conduct – bring to a close a tumultuous chapter for the School of Medicine, whose dean announced her own resignation last November.

Dr. Claire Pomeroy, who stepped down June 2, also was criticized in the internal reports for her handling of the scandal.

In recent days, the university released to The Bee nearly 1,000 pages detailing its internal probes into the surgeons' controversial work, first reported by the newspaper in July 2012. Since then, the medical center has endured an onslaught of scrutiny, with state and federal regulators descending on the hospital to assess its safety and quality of care.

Earlier this month, the California Department of Public Health announced it was fining the medical center $50,000 for violations related to the neurosurgeons' experimental work that created "immediate jeopardy" to patient safety.

The controversy surrounding the untested treatments also drew an unwelcome spotlight to the university's research program. Chancellor Katehi has publicly stated she wants to see UC Davis, which includes the School of Medicine, become one of the nation's top public research universities.

It was Katehi last year who ordered a second round of internal investigations that ended with the doctors' resignations.

"It's a very serious matter," said Arthur Caplan, a nationally known medical ethicist.

"When you have deaths and serious harm, you know that should not happen at all – but it certainly shouldn't happen more than once."

Ethical boundaries breached

The most contentious issue between the doctors and the university – and even within the university – was this: Were the surgeons performing research? Or were they providing "innovative care?"

The determination would have profound meaning for everyone involved, from the patients' families to the doctors to the highest reaches of the UC Davis administration.

Research on humans is tightly controlled in the United States and, according to federal regulations and university policy, must undergo a rigorous approval process to ensure that participants are protected from harm. Innovative treatment, more commonly known as compassionate care, gives a doctor more latitude in offering nonstandard care to a single patient where evidence of safety or success is limited.

The procedure in question involved three patients described in documents only as Patients 1, 2 and 3 – two middle-aged women and one man who had a common enemy: glioblastoma.

For anyone unlucky enough to be diagnosed with the highly malignant brain tumor, the prognosis is dismal. Median survival is less than 15 months.

Muizelaar and Schrot called their novel approach "probiotic intracranial therapy," or the introduction of live bowel bacteria, Enterobacter aerogenes, directly into their patients' brains or bone flaps. The doctors theorized that an infection might stimulate the patients' immune systems and prolong their lives.

The first patient lived about 5 1/2 weeks. The second survived another year, an outcome that buoyed the doctors and seemed to bolster their theory, they said.

The institutional trouble began in March 2011, when a newly diagnosed third patient developed sepsis, became unresponsive and died two weeks after being deliberately infected. The university's first internal investigation soon followed.

After The Bee first reported the story in July 2012, Chancellor Katehi ordered the provost to conduct a "comprehensive review," and a new round of investigations was begun.

According to the newly released documents – one originating in the provost's office, the other with the vice provost of academic affairs – the university concluded that Muizelaar and Schrot had stepped well outside of regulatory and ethical bounds.

One colleague, Dr. David Asmuth, an infectious disease specialist who co-chaired an oversight committee for university research, called the surgeons' procedure "the worst case of human subjects research he had ever seen," according to one report.

The most damning report concluded that Muizelaar and Schrot had violated the faculty code of conduct by failing to get proper approval for their experimental work, as required by university policy and regulations from the U.S. Food and Drug Administration.

The investigation also determined the doctors had failed to adhere to UC's standards of ethical conduct.

Finally, the burning question of innovative treatment vs. research was officially answered, with the investigator concluding that the three procedures "clearly met the University's definition of 'research.' "

Among the university's findings, detailed in reports, email correspondence, interviews and regulatory documents:

A former top administrator said he believed the doctors went "shopping for approval" and were "doing all they could to get around" the formal approval process. A physician who served on the research oversight board said the surgeons seemed to be "gaming" the system to bypass any institutional rejection or skepticism of their plans.

Muizelaar and Schrot did not complete a study on rats before they began treating the three human patients, despite an FDA directive in 2008 that "animal studies will be necessary prior to entering into the clinic with your proposed therapy," according to an email to Schrot from an FDA official. When asked by a compliance investigator why animal trials were not done first, Schrot allegedly responded that such testing would take "10 years his entire career," one internal review states. The investigator found Schrot's "eagerness to proceed" to be concerning and his actions "reckless."

One university investigator questioned whether the doctors ever would have been able to get federal approval of their concept. According to one report, Schrot's grant application to the National Institutes of Health to study the bacterial treatment was rejected, with NIH commenting in 2009 that "(t)his is a very poorly developed scientific proposal that lacks feasibility." The NIH thought it unlikely that university or federal regulators would allow the introduction of live bacteria directly into patients, the report states.

Both doctors have repeatedly stressed they were anticipating no financial benefit from the surgeries, an assertion that one university investigator believed to be true. However, the investigator noted in her report that the neurosurgeons began the process to patent their procedure before Patient 3's surgery in March 2011, yet failed to disclose their "potential financial interest" on the woman's consent form, as required by UC policy.

Medical ethicist Caplan said academic institutions face reputational damage if they are perceived to be doing "serious, highly invasive, very risky research."

"I think sometimes surgeons and doctors can get caught up in the enthusiasm for what they really believe is going to work," said Caplan, head of medical ethics at New York University's Langone Medical Center. "That is exactly why we have FDA oversight and approval and the research ethics requirement we do.

"Every time somebody dies or is injured or we have to recall a product, what we find ourselves saying is, there is no short-cut to innovation," he said. "Finding the truth is a long, slow, arduous process."

Caplan said the university appeared to be "aggressive in its response" to the crisis and made appropriate use of outside experts.

For instance, the investigation into whether the surgeons had violated the faculty code enlisted Lisa Ikemoto, a UC Davis law school professor who specializes in bioethics and health care. Dr. Robert J. Levine of Yale University, an internationally recognized expert on bioethics and human subjects research, was also consulted.

Hexter, the provost, commissioned a two-person review panel made up of a top administrator from UCSF, Neal Cohen, and a UC Berkeley official, Sheila O'Rourke, who now also works part-time at UC Davis.

"Having this examination by peers, bringing in the outside experts, preparing a very thorough response – that is the way to go," said Caplan.

"Has the university properly trained its researchers? That's the question."

University oversight questioned

Muizelaar and Schrot were not the only ones to come under scrutiny.

The investigators also examined the role of UC Davis administrators, staff members, doctors and nurses in what even Muizelaar deemed a "commotion," according to one of his emails.

Muizelaar and Schrot had first been sanctioned by the university in September 2011, when a six-month internal investigation concluded they had conducted improper research on human subjects without approvals. At the time, both were banned from performing further medical research involving human subjects, and UC Davis reported their "serious and continuing noncompliance" to the FDA.

The first investigation was conducted by the university's Institutional Review Board (IRB), charged with protecting the rights and welfare of humans involved in research studies.

Asmuth, the infectious disease specialist who co-chaired one of the IRB committees, reportedly told the doctors at a 2011 meeting that the wound-infecting procedures they had performed were "egregious" and "overstepped the rights of patients not to be treated as human subjects," according to one report.

The two-person panel assembled by Provost Hexter concluded that the IRB and its committees had "communicated promptly and appropriately with the two doctors based on the information available to them."

But the panel questioned why the Office of Academic Personnel (now Academic Affairs) was slow to initiate an investigation into the surgeons' conduct, especially given the September 2011 findings by the IRB of serious noncompliance.

Muizelaar remained the department chairman for another 10 months, during which he was named the first holder of the Julian R. Youmans Endowed Chair. It was not until July 2012 that the university announced he would "temporarily" step down as department chair while the new investigations proceeded.

"The lack of follow-through by the Office of Academic Personnel seems to represent a lack of understanding of the magnitude of the research misconduct and misrepresentation of the research activities " the provost's panel wrote.

Pomeroy, former dean of the School of Medicine, was criticized for recommending Muizelaar's appointment to a prestigious endowed chair in the midst of the scandal. The panel deemed her actions "inappropriate."

Pomeroy told university investigators she knew little about Muizelaar's cases, as they had constituted "just a mention" from him at the time. She defended his endowed chair by saying it had been established as being automatically given to the department's chair, a role Muizelaar was then filling, according to the provost panel's report.

The Bee's review of internal documents shows the university has flip-flopped in its position over whether the doctors were conducting research or innovative care.

However, the university says it has made numerous changes to address the confusion and prevent a similar occurrence. Among them: a new innovative care policy that screens and tracks any proposals for unconventional treatments.

The doctors speak out

With the probes now complete, and the doctors' resignations accepted, Muizelaar and Schrot have pushed back against the university, filing lengthy written responses. The doctors also agreed for the first time to meet in person with The Bee.

At a long conference table in a sleek Campus Commons office building, Muizelaar and Schrot, accompanied by their attorneys, answered questions about the procedures, the investigations and their futures.

Both neurosurgeons continued to assert they were never performing research or doing any kind of clinical trial when they treated the three patients. They deny there was any master plan or secret agenda.

Instead, they say, they were only trying to give their patients a last-ditch option for a predictably horrible disease.

"I was simply thinking that I could help patients," Muizelaar said. "My whole medical practice is guided by actually only one principle, namely: What would I do for my mother, my son, myself?"

Muizelaar said he never believed the procedure could be patented and only pursued the matter at a colleague's suggestion, thinking he was following proper internal procedures for inventions.

The doctors said they are pleased that the university adopted a new innovative care policy. But they said they believe their consent process was thorough and fair and expressed disappointment that two families threatened to sue before receiving settlements.

"I felt I went overboard talking about all the risks that were involved," Schrot said.

Muizelaar and Schrot were especially critical of the report to the vice provost of academic affairs, prepared by Ikemoto, the UC Davis School of Law specialist in bioethics and health care.

In his seven-page response, Muizelaar complained that the Ikemoto report "is presented in as negative (a) light as possible." For instance, he wrote, Ikemoto failed to mention that Patient 2 "lived almost a year longer than expected."

"If Professor Ikemoto's assumptions and findings were to guide medical treatment policy in the future, terminal patients with no hope of recovery will have only the option of hospice and death available to them," Muizelaar wrote. "Innovative care will be mired in committee reviews and delays while the patients die."

Muizelaar said Friday he also believes that campus politics influenced the outcome. The Dutch-born neurosurgeon, who has been at the medical school since 1997, said that strained relations between the main campus and the School of Medicine – which tripled its outside research funding during the last decade – likely contributed to his demise.

"Katehi wants to establish her authority over the medical school," Muizelaar said. "And one way to do it is to get rid of some people she doesn't like and showing that she's the boss."

In his nine-page response, Schrot charged that Ikemoto had "misinterpreted, misconstrued or overlooked critical factual evidence in reaching her conclusions."

Schrot stressed to The Bee – and to the university – that all three patients were Dr. Muizelaar's, not his, and that he had had "no role in recruiting" any of them. Schrot went on to say it was Muizelaar who performed the actual procedures, implanting the bacteria into the patients, while he had no surgical role in the operating room.

"Thus the central accusation against me – that I infected patients with bacteria in contravention of (university) regulations – is simply false," stated Schrot, who began his residency at the school in 1999 and later was hired onto the faculty by Muizelaar.

In her response, Ikemoto dismissed Schrot's contention that the patients were all Muizelaar's as being "not significant or relevant," since she determined that Schrot had an "extensive role" in all the cases, from drafting consent forms to meeting with families to organizing delivery of the bacteria to the operating room.

On Friday, both neurosurgeons said they are moving on.

As Schrot's last week of work approaches, he said he is exploring his options and plans to continue work as a neurosurgeon. He said he is not angry or embittered and remains "very fond of people at UC Davis."

At 66, Muizelaar said he is not ready to retire and hopes to be working soon at another academic center. He said he has heard from a number of former residents and colleagues, saying, "Hey, we need you, we want somebody like you on our faculty."

"Neurosurgeons like to work," Muizelaar said, "and I do, too."

Call The Bee's Marjie Lundstrom, (916) 321-1055.

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