Now Reading
The ‘Meltdown’ of a $3 Million Research Project

The ‘Meltdown’ of a $3 Million Research Project

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 although 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 quietly paid a severe penalty for Pavuluri’s misconduct and its own lax oversight, after the National Institute of Mental Health (NIMH) demanded weeks earlier that the public institution — which has struggled with declining state funding — repay all $3.1 million it had 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 US 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, which included interviews and the review of hundreds of documents, revealed multiple layers of failure at the university. UIC didn’t properly screen and monitor Pavuluri’s research. Even after realising 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, and then again after eight weeks of treatment with lithium. The hope was that the results would provide new information to help identify the disease earlier, lead to treatment and potentially even reverse how the disorder affects 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 from NIMH to UIC in which the agency said it had determined there was wrongdoing and demanded the repayment.

In all, 89 of the 103 subjects enrolled in the study — 86% — did not meet the eligibility criteria to participate, records show. Among other violations, Pavuluri:

  • Enrolled children younger than 10 though the study was approved only for boys and girls ages 13 to 16;
  • Included children who had previously used psychotropic medication though, under the protocol, that should have made them ineligible;
  • Managed the medical care of some of the children involved in her study though she was told to keep her clinical and research roles separate;
  • Failed to give some girls pregnancy tests before they began taking 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, known as an IRB, 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, or OHRP, who reviewed the case for ProPublica Illinois.

Carome said NIMH’s decision to demand UIC repay the grant funds “is very, very uncommon.”

“I don’t recall in my 12-13 years there that this occurred,” added Carome, now director of the health research group at Public Citizen, a nonprofit consumer-advocacy organisation. “I don’t think I would have forgotten an event like that.”

University of Illinois Medical School Campus at Chicago. Credit: College of Medicine, University of Illinois at Chicago

UIC officials declined to be interviewed. But in response to written questions, they said that “internal safeguards did not fail” and that they suspended Pavuluri’s research and took other corrective steps when they realised she was not complying with protocols. They said the university “is committed to adhering to the highest standards for research integrity.”

They said that Pavuluri’s violations were isolated to her research work, and that a review of her psychiatry practice, where she treated children with mental health issues, concluded she provided “high quality 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 named her a university scholar later that year, an honour given to about half a dozen faculty 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. And over the past five years, they 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. The decision 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 received $7.5 million in National Institutes of Health grants during her time at UIC.

“I thought I was doing the right thing and not harming any child,” she 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 gynaecology, 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 US after reading about researchers in child psychiatry here and ultimately joined the psychiatry department at the University of Illinois College of Medicine in 2000. She founded the Paediatric Mood Disorders Program, which became a nationally renowned clinic specialising 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.

What Works for Bipolar Kids, a book by Mani Pavuluri. Credit: goodreads

She did both.

Within five years of arriving at 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 stabiliser. 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 issues 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 of the children 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 five-year 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 same 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, south of Chicago. 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 that 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 six feet tall, with floppy dark hair that he brushes away when it falls into his square-rimmed glasses. He graduated from high school, has taken community college classes and currently works at a local pizza restaurant. He said that he hopes to become a therapist to help children.

On a 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 issue 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 in the interview that 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 symptoms worsened, she was hospitalised — 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 IRB, and Pavuluri did so in January. The university’s IRB chair at the time, James Fischer, a pharmacy professor, determined 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 in response to Freedom of Information Act requests. But university officials withheld or redacted many records, citing federal and state laws regarding patient privacy 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.

The records the university released, however, show that two months after its initial report of a problem, the IRB suspended Pavuluri’s research and the university launched an audit of the protocol 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 sent 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 that hadn’t been spent from a $3.2 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 control subjects — received a letter from the university saying it had found “problems” with the conduct in Pavuluri’s three studies. It said children may 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. “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 received 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 then fast-tracked approval without any justification for doing so.

And then, just four months after the study began, the IRB also approved lowering the minimum age of participants in the study to 10 — even though NIMH had specifically prohibited that — and 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 IRB-approved 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 they got in “by mistake.”

Children less than 12 years of age were included in the study and their parents were not informed completely about the risks of the medicines. Representational image. Credit: Victor Bezrukov/Flickr CC-BY-NC 2.0

The IRB also failed to catch omissions in the consent forms, including informing subjects and their parents that lithium is not FDA-approved for children under 12 and there are alternative courses of treatment for bipolar disorder.

Lithium is not 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 individuals on a study’s data and safety monitoring board, which is tasked with observing a trial’s progress and the safety of its participants, “are in no way associated with the trial.” But the board for Pavuluri’s study included Pavuluri and a co-investigator, while 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 was originally an independent member before joining the research team and that there were other independent members on the panel.

Nicholas Steneck, an emeritus professor of history at the University of Michigan who was a consultant to the US 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,” he 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.”

In fact, 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 NIH and the OHRP conducted an on-site evaluation of UIC’s system for protecting human research subjects. Federal officials determined that, in approving other research projects, university IRBs “sometimes lacked sufficient information to make the determinations required for approval of research,” according to a December 2014 letter from 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 in a statement that they have tightened oversight. IRBs, they said, now complete more detailed reviews of protocols before approving changes, and they conduct more random audits of clinical trials to determine if researchers are following protocols.

Still, in the case of Pavuluri’s studies, the officials put the blame on 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 in their emailed responses to questions.

But Amneh Kiswani, who served as an assistant director in the campus’ Office of Research Services, said the university bears at least some of the responsibility. When Pavuluri sought an amendment to expand the age of participants, for example, the IRB should have made sure that NIMH had already approved of that change, Kiswani said.

“There are supposed to be controls and policies and procedures in place so these types of occurrences don’t happen,” said Kiswani, who left UIC in 2014. “In this particular situation, both are responsible: the institution for failing to follow the rules for changes in scope and the investigator for not knowing her responsibility as a principal investigator.”

Carl Elliott, a professor of bioethics at the University of Minnesota, agreed that the NIMH’s determination of wrongdoing “sounds at least as critical of the IRB as it does” of Pavuluri.

And he noted that the problems began even before her research got underway.

“It baffles me how an IRB could give its ethics approval without reading the protocol,” said Elliott, who also reviewed the case at ProPublica Illinois’ request. “If it doesn’t have the protocol, they can’t really know what it is they are approving. It doesn’t make any sense at all.”

Pavuluri said she is shouldering more than her share of the blame when the university was also at fault.

“It was in their interest to kind of maybe see this as one person’s mistake [rather] than the responsibility of the IRB as well,” she said.

Stinging criticism

Pavuluri, in an interview, said she expanded the criteria for who could be included in the study because it was difficult to find enough subjects within the narrow age range. She said it also was difficult to find children with bipolar disorder who weren’t already taking other medication.

She said she also believed a wider pool of subjects would strengthen her findings.

“I thought it would be a better scientific outcome if I have power in the study in the higher numbers,” she said.

While her transgressions remained unknown to the general public, she appeared to address them in a chapter of the book, “Women in Academic Psychiatry,” which features 16 leading women psychiatrists discussing their careers. She described her large laboratory as a “three-ring circus” where she oversaw a flurry of grant submissions and a staff of faculty and students.

Asked to name her obstacles, she wrote: “I could not attend to some IRB amendments that were due or problem-solve the nuances in the large laboratory. No matter how angelic I was with my research subjects, or how hard I worked day and night, things crashed. Here, I learned my main lesson, which is the need to have a tight grip on research supervision. No work is done till the paperwork is done.”

A university panel tasked with investigating the integrity of Pavuluri’s research was less forgiving. UIC refused to provide the panel’s report to ProPublica Illinois or even say who took part in the review.

University officials declined to answer questions about girls not being given pregnancy tests and other shortcomings with laboratory tests, citing the pending federal investigation. Pavuluri said some of the younger children did not get pregnancy tests because she didn’t think they were sexually active.

Mani Pavuluri. Credit: Twitter/DrManiPavuluri

But after reviewing the panel’s report, UIC chancellor Michael Amiridis wrote in a July 2015 letter that the violations of protocol “collectively represent serious deviations that violate accepted ethical guidelines and professional standards in clinical practice.”

He said that Pavuluri’s behavior “repeatedly put subjects at risk and damaged the credibility of the research data.”

He cited her “reckless disregard” in deciding who to enroll in the study, the lack of pregnancy and laboratory testing, and “falsification and fabrication of research data in an attempt to obfuscate evidence of noncompliance with the research protocols.”

He ordered a review of her clinical practice, barred her indefinitely from conducting research and directed her to retract several scientific journal articles based on the three studies.

Three of Pavuluri’s journal articles were retracted after she told the editors that UIC had concluded she had “intentionally and knowingly” made false statements about the participants’ medication histories and that the falsehoods “seriously compromised” the results and conclusions. The retractions were covered in about a half-dozen posts on the Retraction Watch website, which monitors scientific misconduct.

UIC officials said the review of Pavuluri’s clinical practice did not uncover any problems and there was no reason to report her to the state’s medical licensing board.

But UIC informed federal authorities it had reason to think additional children had been harmed in her studies. Reports from parents and other evidence led the investigative panel to conclude that “claims by [Pavuluri] that no subjects were harmed in her studies were false,” according to an email from OHRP to UIC.

That conclusion was based on issues raised by parents who contacted UIC in the months after the university informed them of the problems with Pavuluri’s research, according to a response to an open-records request.

The fallout

It’s difficult to know how unusual the federal government’s demand for reimbursement is; NIH said it does not track such actions. The agency would not provide a comparable example.

An NIH spokeswoman said the agency does not discuss its decisions about specific grants but that it “takes seriously non-compliance with the terms and condition of award.”

UIC refunded the controversial grant with money from a fund that is supposed to support such areas as research, administration, student scholarships and building operations. Campus officials said they knew of no other time when UIC had to reimburse grant funds for failing to comply with guidelines on research integrity or the use of human subjects.

Officials acknowledged the $3 million payout will impact other spending, but said they do not yet know what they won’t fund as a result. UIC’s operating budget is more than $2.3 billion this fiscal year.

The financial hit comes at a troubling time for the institution, which has seen state funding decline about 10% this year following a nearly two-year budget stalemate that left universities across the state scrambling to make ends meet. The University of Illinois system recently requested $585 million in state funding for capital projects that would address “only the most urgent priorities.”

Pavuluri, meanwhile, is ending her UIC career. She was called into a meeting in February with Anand Kumar, head of UIC’s psychiatry department, and Todd Van Neck, an associate dean in the College of Medicine. They wanted to discuss NIMH’s ruling and its demand that the money be returned, emails show.

That evening, Pavuluri sent an email thanking them for giving her “options for the next step.” Most of the email is redacted, but it concludes: “I will cherish, co-operate and be grateful as the loyal UIC employee as I seek the opportunity to keep serving.”

Kumar responded several days later. He said he shared her questions with the leadership team and came to the conclusion that “under all of the circumstances” it did “not seem realistic” for her to stay at UIC in a different role — specifically, an untenured position that would have allowed her to still treat patients.

Later in February, Pavuluri submitted retirement paperwork indicating her last day will be June 30. She will collect a pension and will receive a $35,512 vacation payout, records show.

In spite of the controversy, Pavuluri has passionate defenders. One woman, whose 21-year-old daughter has been treated by Pavuluri since she was 11, called Pavuluri a “lifesaver.” She said her daughter had been hospitalised four times before seeking treatment from Pavuluri, but hasn’t been hospitalised since. She participated in a research trial that did not involve lithium.

“It breaks my heart to think someone would speak poorly of her or cast judgement on her,” said the mother, who lives in south suburban Mokena and did not want to be identified to protect her daughter’s privacy. “I know people have to be held to what they are supposed to do, but never would she put a child in harm’s way for the sake of research. Never, ever.”

Another parent, Rebecca Sikorski, didn’t know about any of these concerns when she took her 12-year-old daughter to see Pavuluri toward the end of last summer. She was impressed that the clinic was promoted as being involved in “cutting edge” research.

“If their main practitioner of bipolar disorder is being investigated, I would have wanted to know that,” she said.

At her daughter’s last appointment in February, Pavuluri told them she was retiring from UIC and hoped to open her own practice in the Gold Coast neighborhood.

When asked why she is retiring, Pavuluri said in the interview that UIC officials are upset about repaying the grant money. She said the years of investigation have been “traumatic.”

“I feel it is best if I give up my wonderful ability to really do the best I could. I tried really hard,” she said, choking back tears.

She said it was difficult to talk about the issue.

“It is giving me PTSD.”

This article was originally published in ProPublica. 

ProPublica is a Pulitzer Prize-winning investigative newsroom. Sign up for their newsletter.

Scroll To Top