$ 3 MIL. RESEARCH BREAKDOWN AT UIC
Psychiatry professor Mani Pavuluri founded a renowned clinic to treat children with bipolar disorder and secured millions of dollars in federal funding. But the university paid a severe penalty for her misconduct with tests involving lithium.
For nearly two decades, the University of Illinois at Chicago has touted child psychiatrist Mani Pavuluri as one of its stars: She founded a renowned clinic to treat children with bipolar disorder and secured millions of dollars in coveted federal funding to help unlock the mysteries of the disease.
Parents from around the country brought their children to see her. She helped boost the university as a leader in the field of child psychiatry.
But as Pavuluri’s reputation grew, she put some of these particularly vulnerable children at serious risk in one of her clinical trials. She violated research rules by testing the powerful drug lithium on children younger than 13 even though she was told not to, failed to properly alert parents of the study’s risks and falsified data to cover up the misconduct, records show.
In December, the university paid a severe penalty for Pavuluri’s misconduct and its own lax oversight, after the National Institute of Mental Health demanded that the public institution — which has struggled with declining state funding — repay all $ 3.1 million it received for Pavuluri’s study.
In issuing the rare rebuke, federal officials concluded that Pavuluri’s “serious and continuing noncompliance” with rules to protect human subjects violated the terms of the grant. NIMH said she had “increased risk to the study subjects” and made any outcomes scientifically meaningless, according to documents obtained by ProPublica Illinois.
Pavuluri’s research is also under investigation by two offices in the U. S. Department of Health and Human Services: the inspector general’s office, which examines waste, fraud and abuse in government programs, according to subpoenas obtained by ProPublica Illinois, and the Office of Research Integrity, according to university officials.
A ProPublica Illinois investigation has found multiple layers of failure at the university. Among them: UIC didn’t properly screen and monitor Pavuluri’s research. And even after realizing she had broken rules meant to protect her subjects, it continued to promote her to the public and within the university.
Pavuluri’s study, which began in 2009 and was shut down in 2013, was designed to use imaging to look at how the brains of adolescents with bipolar disorder function during a manic state, then again after eight weeks of treatment with lithium. The hope was that the results would provide information to help identify the disease earlier, leading to treatment and potentially even reversing the disorder’s effects on the brain.
But Pavuluri, a professor of psychiatry, strayed from the approved guidelines and abandoned safety precautions written into the study protocol, according to a November letter to UIC in which NIMH said it had determined there was wrongdoing and demanded repayment.
In all, 89 of the 103 subjects enrolled in the study — 86 percent — did not meet the eligibility criteria to participate, records show.
Among the violations, the federal agency found that Pavuluri:
◆ Enrolled children younger than 10 though the study was approved only for boys and girls 13 to 16.
◆ Included children who were previously given psychotropic medication though that should have made them ineligible.
◆ Managed the medical care of some of the children involved in her study despite being told to keep her clinical and research roles separate.
◆ Failed to give some girls pregnancy tests before they started on lithium even though consent forms said they would be tested. The drug can lead to an increased risk of birth defects.
Pavuluri isn’t solely at fault, according to NIMH. The agency determined that the university’s institutional review board — a faculty panel responsible for reviewing research involving human subjects — conducted an “insufficient” initial assessment of Pavuluri’s research plans. The board didn’t even have a copy of her research protocol at its initial review.
Officials documented other oversight shortcomings as well.
“These are clearly egregious problems that occurred,” said Michael Carome, a former senior official at the U. S. Department of Health and Human Services’ Office for Human Research Protections who reviewed the case for Pro- Publica Illinois.
Carome said NIMH’s decision to demand that UIC repay the grant funds “is very, very uncommon.”
“I don’t recall in my 12 to 13 years there that this occurred,” said Carome, who is now director of the Health Research Group at Public Citizen, a nonprofit consumer- advocacy organization. “I don’t think I would have forgotten an event like that.”
UIC officials declined to be interviewed. In response to written questions, they said “internal safeguards did not fail” and that they suspended Pavuluri’s research and took other corrective steps when they realized she was not complying with protocols. They said the university “is committed to adhering to the highest standards for research integrity.”
They said Pavuluri’s violations were isolated to her research work and that a review of her psychiatry practice, in which she treated children with mental health issues, concluded she provided “highquality patient care.”
University officials halted Pavuluri’s lithium research in 2013 and also shut down two other federally funded projects she ran, returning nearly $ 800,000 that hadn’t yet been spent on those two studies.
Yet they gave her a “university scholar award” that year, an honor given to about half a dozen faculty members each year who excel in research and teaching and show “great promise for future achievements.” The award included $ 30,000.
They allowed her to keep her prestigious position as a faculty chair and paid her a base salary of nearly $ 200,000 a year, plus bonuses. Over the past five years, they also allowed her to treat and oversee the care of more than 1,200 children and teens.
The accolades didn’t stop even after UIC’s chancellor, having reviewed an internal research- integrity investigation into her grants, concluded in 2015 that her conduct reflected a “pattern of placing research priorities above patient welfare.”
As recently as January, just weeks after the university sent off the multimillion- dollar check, its psychiatry department boasted on its website that a survey had named Pavuluri a “top doctor.”
Pavuluri, 55, recently filed paperwork to retire in June. That came after a meeting with her supervisors to discuss the NIMH decision, records show, and after ProPublica Illinois began asking UIC about the matter.
In a telephone interview, Pavuluri called her mistakes oversights and said her decisions were made in the best interests of her patients. She said she received minimal guidance and training from the university throughout the research process, though she has received $ 7.5 million in National Institutes of Health grants while at UIC.
“I thought I was doing the right thing and not harming any child,” Pavuluri said. “I treated them like an angel, all of them. I was careful and tried to do my best with each individual child. I thought that I could manage that pretty reasonably, and that is something that I didn’t estimate that this would have such serious consequences, quite frankly.”
‘ Someone who could fix him’
Raised in India, Pavuluri graduated from medical school in New Zealand and began her training there, she wrote in a 2016 book profiling prominent women in academic psychiatry.
She started in obstetrics and gynecology but didn’t like it. When supervisors suggested she try psychiatry, she discovered she was fascinated by the “intimacy” of trying to solve people’s problems.
Pavuluri decided to move to the United States after reading about researchers in child psychiatry here and joined the psychiatry department at the University of Illinois College of Medicine in 2000. She founded the Pediatric Mood Disorders Program, which became a nationally renowned clinic specializing in diagnosing and treating children and teenagers with bipolar disorder and other mood- related mental illnesses.
As her career got underway, her motto was “dream it and do it,” she wrote in the book. She did both. Within five years of arriving at
“I THOUGHT I WAS DOING THE RIGHT THING AND NOT HARMING ANY CHILD. I TREATED THEM LIKE AN ANGEL, ALL OF THEM. I WAS CAREFUL AND TRIED TO DO MY BEST WITH EACH INDIVIDUAL CHILD. I THOUGHT THAT I COULD MANAGE THAT PRETTY REASONABLY, AND THAT IS SOMETHING THAT I DIDN’T ESTIMATE THAT THIS WOULD HAVE SUCH SERIOUS CONSEQUENCES, QUITE FRANKLY.” MANI PAVULURI
UIC, she had tenure. She set her sights on combining psychiatry and neuroscience to understand how the brain functions in children with mood disorders, including bipolar disorder. She won national awards, was named a distinguished fellow at the American Academy of Child and Adolescent Psychiatry and wrote a book for families, “What Works for Bipolar Kids: Help and Hope for Parents.”
Pavuluri began seeking NIMH funding in 2006 for research to examine the effects of lithium on children by imaging their brains before and after they took the mood stabilizer. The drug had long been used to treat bipolar disorder in adults, but its effectiveness in children was less understood.
Pavuluri’s early requests for funding were denied. During reviews and consultations with NIMH staff, Pavuluri was “made keenly aware of critical human subjects issues,” records show. Those included the “significant risk” of providing lithium to children under 13 and the importance, in this study, of not providing direct medical care to the research subjects. The roles of researcher and clinician, according to documents, were supposed to be separate so the treatment wouldn’t be influenced by the needs of the study.
She amended the application to resolve NIMH’s concerns. UIC got the $ 3.1 million grant, and the fiveyear study — “Affective Neuroscience of Pediatric Bipolar Disorder” — began in January 2009. Activity in her research lab picked up, and, soon after, she secured two more NIMH grants.
Around the time the lithium study began, Cynthia Mallard was distraught. Her 10- year- old son, Luke, was defiant at school and had trouble controlling his emotions.
“I wanted to find someone who could fix him,” Mallard said.
Mallard first took her son for counseling near their home in Bourbonnais. When that didn’t help, she sought referrals and decided to try to get Luke into Pavuluri’s UIC practice; she knew of Pavuluri’s reputation. But every time Mallard called for an appointment, she said, she was told Pavuluri wasn’t seeing new patients. She pleaded and was told Luke could get an appointment if he entered a clinical trial, she said.
“They told me I could get Dr. Pavuluri to see him every week if I were to get in the study,” she said.
Pavuluri prescribed lithium, and Mallard, a developmental therapist, immediately noticed changes in her son. He paced, walked in circles around their living room and heard voices in his head. He thought he saw other people when he looked in a mirror.
“When he was on lithium, he turned into a different kid,” said Mallard. “I told Dr. Pavuluri, ‘ I don’t care what you have to do, get him off this stuff.’ ”
Luke took the lithium for at most two months, according to the family’s records. Then, Pavuluri switched his medication. The family’s records show he continued to see Pavuluri for therapy for several more years and enrolled in at least one other study she led. UIC officials said that study has not been called into question.
Luke, now 19, is 6 feet tall, with floppy dark hair he brushes away when it falls onto his squarerimmed glasses. He graduated from high school, has taken community- college classes and works at a pizza restaurant. He said he hopes to become a therapist to help children.
One recent evening, he sat at his kitchen table and described his years of therapy and medication. He enjoyed taking part in Pavuluri’s studies, he said, if only because he was paid to participate and got a day off from school to travel an hour or more each way to her clinic.
“Every time I saw her, she was very nice, very sweet,” Luke said.
But he said the lithium had side effects he didn’t like. He quickly went from being a skinny kid to an overweight preteen. He said he’s upset she prescribed the drug when he was so young.
“I have these issues now, and I don’t know if they will go away,” he said. “I don’t know if lithium was a direct cause of it, but it didn’t help anything.”
An ‘ adverse event’
Pavuluri’s research program began to unravel in 2013, the lithium study’s final year. The issues started with a patient who came to Pavuluri when her medications for manic symptoms no longer were effective. Records do not identify the patient, but Pavuluri said she was a girl.
Pavuluri had the girl withdraw from those drugs and put her on other medication to ease her into the lithium study. But she began to experience “heightened irritability,” according to records, and, when her symptoms worsened, she was hospitalized — her first time for a manic episode.
Pavuluri said the drugs weren’t an issue. She said the episode was caused by conflicts at home.
Research guidelines require that a serious and unanticipated “adverse event” involving a human subject be reported to the institutional review board, and Pavuluri did so in January. The university’s IRB chair at the time, James Fischer, a pharmacy professor, determined that the study “likely contributed to the increased severity” of her symptoms. According to records, he reported the incident to the NIMH and OHRP. It was the only adverse event reported during the study.
ProPublica Illinois obtained hundreds of documents related to Pavuluri’s studies through Freedom of Information Act requests. But university officials withheld or redacted many records, citing federal and state patient- privacy laws and the confidentiality of research.
Those records include some communications between the university and the federal agencies that likely would provide more detail about the extent of the research failings and how the university responded. The university also withheld Pavuluri’s research protocols.
But the records the university released show that, two months after its initial report of a problem, the IRB suspended Pavuluri’s research, and the university launched an audit to determine what had gone wrong. In a letter to OHRP, Fischer commended Pavuluri for her “cooperation and forthrightness” in addressing the issue.
But as the IRB dug deeper into Pavuluri’s three studies, it found more problems. In subsequent letters, Fischer reported “serious non- compliance” in the study and by the IRB, and he proposed a corrective- action plan. By April 2013, the university also had suspended Pavuluri’s other two active NIMH- funded studies, for a minimum of six months, while her research privileges were revoked.
After reviewing the other two studies, the IRB determined they also were out of compliance, according to letters in June 2013 from the university to OHRP. Those studies had similar problems. Patients were enrolled despite not meeting eligibility requirements, research procedures began before the dates on the permission forms, and some children were enrolled in multiple studies.
UIC officials decided to shut
down the other two studies and return the unexpended funds, emails and other documents show.
For one, the university returned $ 356,810 it hadn’t spent from a $ 3.1 million grant. For the other, in its early stages, the university returned $ 431,256, university officials said.
In June 2014, the Mallard family and about 350 others — including healthy subjects who served as “controls” — got a letter from the university saying it had found “problems” with the conduct in Pavuluri’s three studies. It said children might have been put at greater risk than what had been explained in consent and parental permission forms.
Cynthia Mallard, dealing with a particularly tough time in Luke’s life, filed the letter with other paperwork on his illness. Another family wrote back. “We have been struggling with this letter since we received it and have been deeply disturbed, specifically regarding the parental consent and the quality of care,” according to their reply, obtained by ProPublica Illinois, though the authors’ names were redacted for privacy reasons. “Have you turned this over to your malpractice carrier? If not, we would request that you do so at this time so that we can see what course of action to take from here.”
A longer follow- up letter to the university’s claims office was entirely redacted except for the last sentence: “I hope that we can settle this amicably and in the interest of all parties.”
UIC said no claim was ever filed. A failure of oversight
UIC is a federal research powerhouse with one of the largest medical schools in the country. Over the past five years, the university has gotten a total of more than $ 950 million in federal research funding, placing it among the top 60 research universities during that period.
The institution had faced trouble for lax research oversight before. In 1999, federal regulators temporarily shut down all research involving humans after finding deficiencies in the scientific and ethical review process.
The university’s role in supervising Pavuluri’s research suggests similar shortcomings. Not only was there insufficient initial review by the IRB, NIMH found, but the panel fast- tracked approval without justification.
Then, just four months after the study began, the IRB also approved lowering the minimum age of participants to 10 — even though NIMH had specifically prohibited that — and it did so without requesting Pavuluri’s rationale for the change. The IRB approved an amendment allowing participants to have previously taken other medications as long as lithium was not among them.
NIMH said it was never informed of these changes.
“The changes were significant because they increased risk to study subjects,” according to the November letter in which NIMH demanded repayment from the university.
Five subjects younger than 10 enrolled in the study. Pavuluri said only a few that young were enrolled and that they got in “by mistake.”
The university’s review board also failed to catch omissions in consent forms, among them to inform subjects and their parents that lithium is not FDA- approved for children under 12 and that there are alternative treatments for bipolar disorder.
Lithium isn’t FDA- approved for that age group because there have not been enough studies of its use. The drug continues to be tested in clinical trials. Some psychiatrists say it is one of the best available treatments.
As Pavuluri’s study progressed, there were other oversight failures. NIH policy recommends that members of a study’s data and safety monitoring board — which observes a trial’s progress and the safety of participants — “are in no way associated with the trial.” But the board for Pavuluri’s study included Pavuluri and a co- investigator, and a report by the monitoring board, submitted partway through the study, was prepared by a member of Pavuluri’s research staff, records show.
UIC officials said Pavuluri’s co- investigator initially was an independent member before joining the research team and that other independent members were on the panel.
Nicholas Steneck, an emeritus professor of history at the University of Michigan who was a consultant to the U. S. Office of Research Integrity, said it is difficult to understand how such a large research institution could have such a “poorly functioning IRB.” He called the UIC board’s failures “IRB 101 mistakes.”
“In this case, it is the institution that failed,” Steneck said after reviewing the case for ProPublica Illinois. “It could be a case of an overstressed system simply losing a sense of what they were responsible for and where they needed to draw lines.”
UIC’s research- oversight problems were not limited to Pavuluri’s studies.
In 2014, prompted at least in part by the problems with Pavuluri’s research, the NIMH and the OHRP conducted an on- site evaluation of the university’s system for protecting human research subjects. Federal officials determined that, in approving other research projects, university review boards “sometimes lacked sufficient information to make the determinations required for approval of research,” according to a December 2014 letter from the OHRP to UIC. The letter cited a study — not a Pavuluri project — that the IRB approved before it had enough information and other studies for which research approval was expedited when it shouldn’t have been.
UIC officials said they have tightened oversight, that IRBs now must complete more- detailed reviews of protocols before approving changes, and they conduct more random audits of clinical trials to determine whether researchers are following protocols.
In the case of Pavuluri’s studies, university officials blame her.
“The principal investigator is responsible for the ethical and professional conduct of sponsored research projects in compliance with applicable laws and regulations, including for timely and accurately informing the IRB of all changes in scope,” UIC officials said.
But Amneh Kiswani, who served as an assistant director in the campus’ Office of Research Services, said the university bears at least some responsibility. When