2 California neurosurgeons banned from human research

Jul. 22, 2012
2 California neurosurgeons banned from human research
By MARJIE LUNDSTROM | McClatchy Newspapers

last updated: July 23, 2012 06:40:44 AM
SACRAMENTO, Calif. -- ]

A prominent neurosurgeon at the University of California, Davis, was banned from performing medical research on humans after he and a colleague were accused of experimenting on dying brain cancer patients without university permission.

Dr. J. Paul Muizelaar, who earns more than $800,000 a year as chairman of the university's department of neurological surgery, was ordered last fall to "immediately cease and desist" from any research involving human subjects, according to documents obtained by The Sacramento Bee.

Also banned was Dr. Rudolph J. Schrot, an assistant professor and neurosurgeon who has worked under Muizelaar the past 13 years.

The university has admitted to the federal government that the surgeons' actions amounted to "serious and continuing noncompliance" with federal regulations.

Documents show the surgeons got the consent of three terminally ill patients with malignant brain tumors to introduce bacteria into their open head wounds, under the theory that postoperative infections might prolong their lives. Two of the patients developed sepsis and died, the university later determined.

The actions described by two prominent bioethicists as "astonishing," and a "major penalty" for the school threaten both the doctors' professional careers and the university's reputation and federal-funding status.

"This is really distressing" said Patricia Backlar, an Oregon bioethicist who served on President Bill Clinton's national bioethics advisory commission.

"UC Davis is a very respectable school, but even the best places have trouble," Backlar said. "These men have put that school in jeopardy."

Research on both humans and animals is tightly controlled in the United States and, according to federal regulations and university policy, must undergo a rigorous approval process to ensure that subjects are protected.

Alleged violations involving experimental drugs or devices can trigger a "for-cause audit" by the U.S. Food and Drug Administration. Among possible enforcement actions, the agency can issue warning letters and publicize them or disqualify researchers from further clinical studies.The FDA has not notified UC Davis what, if any, action might be taken.

The National Institutes of Health also plays a role in protecting human subjects by potentially withholding coveted research money from individuals or institutions. Among medical schools, UC Davis ranks 36th in the nation in NIH funding for medical research at more than $130 million in 2011.

Muizelaar, 65, who has been a department chairman at the School of Medicine since 1997, said last week that he and Schrot believed the FDA gave its permission early on, if the doctors thought the treatment was "beneficial to the patients." He described the research ban as an "overreaction" by the university.

"And I understand it," he said. "There are people who blatantly break the rules that endanger all of their research programs. We certainly didn't blatantly trample any rules."

Schrot, 44, who was hired by Muizelaar, wrote in an email that "the determination of 'serious and repeated noncompliance' is misleading."

Despite the disciplinary action imposed last fall, Muizelaar was honored this spring with an additional academic role at UC Davis. He was named the first holder of the Julian R. Youmans endowed chair in the department of neurological surgery, according to an April 19 news release from the university's medical school.

He said he plans to funnel endowment dollars into further research on the procedure that led to the ban.

"If I come down with a glioblastoma, I will demand that it be done on myself," Muizelaar said.

The divergent views illustrate the tension that exists at research institutions between protecting human subjects and developing cutting-edge cures.

After an inquiry from The Bee, the university agreed to release a full accounting of the internal probe into the doctors' conduct.

UC Davis officials emphasized that they moved swiftly last year after learning more about the doctors' unusual work, launching an internal investigation that lasted six months.

In October, documents show, the university's vice chancellor for research notified the FDA of "serious and continuing noncompliance" by the two surgeons.

The letter from Harris A. Lewin, along with 195 pages of exhibits, claimed that Muizelaar and Schrot sidestepped procedures in their quest to introduce bacteria into live patients' head wounds.

"We really take these matters very seriously," Lewin said. "That's why we self-reported" to the FDA.

An FDA spokeswoman said she could not comment on the UC Davis case, or whether it would trigger a federal audit.

"We pursued this very aggressively and very vigilantly to ensure that we were complying with all regulations, so that we can continue to put protection of human subjects as paramount," Lewin said.

"You can understand why. Because if you don't do so, all your funding for federal research can be in jeopardy."

Lewin said physicians at UC Davis "have a lot of leeway" in treating patients but not when it comes to using them in research.

Federal regulations require that any research involving human subjects be reviewed and monitored by an institutional review board, or IRB.

UC Davis has three IRB committees charged with protecting the rights and welfare of people involved in research studies. The campuswide committees, which include members from the general public, have the authority to approve, modify or reject all research activities that fall within their jurisdictions.

The IRBs are a formidable presence in any campus or research setting. Its members must ensure that research involving humans complies with all federal regulations and university policies, and that subjects are adequately protected.

The controversy involving Muizelaar and Schrot erupted over a project known as "Probiotic Intracranial Therapy for Malignant Glioma."

According to Lewin's Oct. 17, 2011, letter to the FDA, the surgeons were intrigued by clinical trials showing promising but unproven results in patients suffering from glioblastoma, the most common and most deadly type of malignant brain tumor.

For these patients, median survival is only about 15 months from diagnosis, according to the National Cancer Institute.

However, Muizelaar and Schrot were aware of medical literature that "seems to suggest" that patients who had postoperative infections lived longer, Lewin's letter states.

Muizelaar said he "inherited" two glioblastoma patients who had unintended infections who went on to live 15 and even 20 years with the deadly disease.

"We believed that this was innovative treatment, not research, and that IRB approval was not needed," Schrot said in an email.

In 2008, the doctors proposed treating a glioblastoma patient with bacteria applied to an open wound to "attack the tumor," then later withholding antibiotics and letting the bacteria do its work.

Schrot contacted the FDA but ultimately was cautioned that animal studies were needed first.

At Davis, IRB chairman Anderson, the trauma surgeon, was also skeptical. Anderson told Schrot in an email that denying this patient the treatment would be "likely devastating to this family," but that he believed the FDA and UC Davis "won't allow this product to be used in humans without further testing," internal documents reveal.

Despite the initial roadblock, Muizelaar and Schrot "strongly believed that the intervention with intentional wound infection was promising for patients who otherwise faced certain death," according to Lewin's letter.

And so the doctors continued with preclinical work, arranging for a rat study.

In 2010 events triggered the university's internal investigation.

From October 2010 to March 2011, the physicians went forward with three procedures on humans with malignant brain tumors, surgically introducing probiotics into their open head wounds.

Probiotics are popularly known as the "good" bacteria that live in the digestive tract. In recent years, probiotics have been marketed as remedies for stomach distress and even the common cold, and packaged in yogurt and dietary supplements.

Both doctors theorized that infection stimulates the body's immune system to help attack cancer.

The first surgery resulted from an encounter Muizelaar had with a patient suffering from recurrent glioblastoma in the brainstem. The patient "had been generally aware" of the unusual treatment option with bacteria "wound infection" and specifically requested it, according to Lewin's letter.

At Muizelaar's direction, the letter states, Schrot got IRB permission to move forward on Patient No. 1 with a "one-time procedure" that was "not associated with any research aim," the letter states.

University documents show that the physicians believed they had been given the go-ahead for all three surgeries, but officials later determined that they had been misinformed or were misunderstood by the doctors.

Muizelaar and Schrot stressed that all three patients, in consultation with their families, gave their consent.

The patients' outcomes varied dramatically. The documents reveal:

-Patient No. 1 died six weeks later after the tumor progressed. The university later determined that the patient also had developed sepsis, a life-threatening illness in which the body responds severely to bacteria or germs.

-Patient No. 2, who also underwent the procedure in 2010, was still alive when Lewin wrote his October 2011 report to the FDA. The patient was described as having a reduction in the brain tumor but also suffered a wound infection and was given antibiotics 10 months after being intentionally infected. Muizelaar noted last week that the patient has since died.

-Patient No. 3, who underwent surgery in 2011, soon developed sepsis and meningitis and died.

The same day Patient No. 3 "suddenly and precipitously deteriorated," the IRB director discovered that Muizelaar and Schrot were seeking permission from an ethics committee to infect five more patients.

The university threw on the brakes.

On March 17, 2011, the IRB director ordered the doctors to immediately stop their probiotic treatments, according to university documents.

Six months later, the university concluded its investigation and ordered the doctors to halt all human research activity "except as necessary to protect the safety and welfare of research participants."

In the case of Patient No. 1, the investigation found, Schrot had made an "incorrect statement" about restrictions on the bacteria's use, leading IRB staff to incorrectly conclude that such review was not necessary, Lewin told the FDA.

As for Patients 2 and 3, the university found that treating them with an "unapproved biologic" amounted to human-subjects research and thus required prior review and approval.

"Drs. Muizelaar and Schrot have emphasized that at all times they believed they were acting in the best interests of their patients, and that they never intended to violate any rules," Lewin wrote to the FDA.

The research ban has potentially serious consequences for both the university and the surgeons.

"To be banned from clinical research makes a career in academic medicine challenging, to say the least," Schrot said. He said he plans to ask the IRB "to identify a pathway to regain my research privileges."

A renowned U.S. bioethicist, describing the alleged violations as "a major penalty," said the university's IRB was right to intervene and quickly.

Arthur Caplan, director of medical ethics at New York University's Langone Medical Center, said that desperate people are especially vulnerable and need added protections.

"If you're dying, you're kind of like reaching out to anything that anybody throws in front of you," said Caplan, who recently left the University of Pennsylvania's Center for Bioethics to assume the New York post.

"That's why so many people over the years are pursuing quack cures in Mexico and all kinds of questionable treatments," he said, speaking in general terms. "They're not able to think straight because they're at death's door."

Caplan said that institutional review boards are often misunderstood, with many people believing that such strenuous oversight is "a lot of bureaucracy to get in the way of trying something to save lives."

In reality, he said, the committees are an essential safeguard for research subjects, who may not get an unbiased view on a researcher's consent form of the study's risks vs. benefits. Or, he said, subjects may be unaware of the financial interests a doctor or researcher might have in an experiment an aspect thoroughly vetted by an IRB.

Besides ordering Muizelaar and Schrot to stop using the bacteria in procedures, the IRB ordered both doctors to stop enrolling new subjects in any research in which they serve as principal or co-principal investigators.

Additionally, the case was referred to three other campus units for investigation into other potential violations, including the faculty code of conduct.

Those reviews are under way, said Bonnie Hyatt, spokeswoman for the UC Davis Health System.

In its six-month investigation, the IRB also looked at its own culpability and that of campus administrators. According to Lewin's letter, the IRB acknowledged that "certain systemic issues may have contributed to the errors made and has worked closely with UCD Medical Center leadership to develop a series of improvements intended to avoid any future recurrence."

Schrot responded to the IRB leadership last September, lamenting that "a serious miscommunication occurred."

"When we administered this treatment, I believed it was appropriate innovative treatment which carried the hope of battling this deadly disease," Schrot wrote to The Bee. "I wished to do everything in my power to try to help these patients."

Schrot said he now realizes that federal regulations are complex, and that "all the appropriate regulatory processes were not followed."

Muizelaar said he and Schrot had no financial incentive or underlying motive for the research.

"This treatment we did it purely to save some patients," he said. "This is not something we can take a patent on. ... We won't get a dime for it."