Saturday, April 18, 2015

For the Record: A Drug Trial’s Frayed Promise (#markingson Seroquel)

From the New York Times:

Last fall, an article in the American Journal of Psychiatry caught the attention of specialists who treat borderline personality disorder, an intractable condition for which no approved drug treatment exists.

The article seemed to offer a glimmer of hope: The antipsychotic drug Seroquel XR reduced some of the disorder’s worst symptoms in a significant number of patients. “It was an exciting development,” recalled Mark F. Lenzenweger, a professor at Binghamton University and Weill Cornell Medical College and an expert in borderline personality disorder.

In the realm of clinical trials, however, reality is sometimes far messier than the tidy summaries in medical journals. A closer look at the Seroquel XR study shows just how complicated things can get when a clinical trial involves psychiatric disorders and has its roots in intersecting and sometimes competing interests: a drug company looking to hold onto sales of a best-selling drug, a prominent academic with strong ties to the pharmaceutical industry and a university under fire for failing to protect human study subjects.

The trial was paid for by AstraZeneca, the maker of Seroquel XR, and was conducted by Dr. S. Charles Schulz, the head of psychiatry at theUniversity of Minnesota. Two of the study participants were living in a residential treatment facility for sex offenders and may have lied about their diagnosis to qualify for the trial. One of those men slipped the drugs to unwitting treatment center residents and staff, an alarming development that nevertheless did not seem to ruffle the university oversight board that is charged with looking into such episodes.

The University of Minnesota’s clinical trial practices are now under intense scrutiny. In February, a panel of outside experts excoriated the university for failing to properly oversee clinical trials and for paying inadequate attention to the protection of vulnerable subjects. The review, commissioned by the university after years of criticism of its research practices, singled out Dr. Schulz and his department of psychiatry, describing “a culture of fear” that pervaded the department.

In March, after another critical report by Minnesota’s legislative auditor, the university announced that it would halt all drug trials being conducted by the psychiatry department until outside experts could review them. And this month, the university announced that Dr. Schulz would step down as head of the psychiatry department. The dean of the medical school, Dr. Brooks Jackson, said in a statement to reporters that Dr. Schulz’s decision “was completely his own” and that he would “remain a valued member of our faculty.”

“Medical research involving drugs like this — involving potentially vulnerable human subjects — shouldn’t be done sloppily,” said Dr. Michael Carome, director of the health research group at Public Citizen, a consumer advocacy organization. “Because when we do things sloppily, we do things where people could potentially be harmed.”

Spiked Oatmeal

One morning in May 2010, residents and staff members at Alpha Human Services, a residential treatment facility for sex offenders in Minneapolis, sat down to breakfast and noticed something strange about their oatmeal. It was pink.

Later in the day, several people reported feeling unusually tired. One employee approached the director, Gerald T. Kaplan. “There’s something going on here,” he recalled being told. “I’m a morning person, and I can’t keep my eyes open.”

After some digging, Mr. Kaplan discovered that the facility’s cook, a resident, had crushed up a large quantity of Seroquel, which hassedative effects, and mixed the pink pills into the morning oatmeal.

The director’s alarm deepened when he learned that the man, as well as another resident, had secretly enrolled in a clinical trial at the University of Minnesota. Their motivation, Mr. Kaplan said, was most likely financial: The trial promised participants up to $300 for completing the study.

Participating in a drug trial was prohibited by the rules of Alpha, which is licensed by Minnesota’s Corrections Department. Most of the people living there were fulfilling the terms of parole or probation. Prescription drug use is closely monitored, and residents are not permitted to take unapproved medications.

But even more concerning, Mr. Kaplan said, was that the men did not have a diagnosis of borderline personality disorder. Somehow, he said, they were able to bluff their way into the study.

At that point in the trial — over a year after enrollment had begun — the researchers were well behind in their recruitment goals.

Borderline personality disorder, which is estimated to affect 1 percent to 2 percent of Americans, is characterized by extreme mood swings,impulsivity and fears of abandonment. Studies have shown that the most successful treatments are specialized forms of talk therapy, but finding practitioners who are trained in these methods can be difficult. Many doctors prescribe antipsychotics and antidepressants to help with some symptoms.

Studies have examined the use of antipsychotics, including Seroquel, in patients with the disorder, but they have been small and did not measure patient progress compared with a placebo, which is considered the gold standard for clinical trials.

Dr. Schulz said he had hoped that a larger, placebo-based trial — involving about 100 patients followed over eight weeks at three study sites — would help clarify whether antipsychotics such as Seroquel could help people with the disorder, and he proposed the trial to AstraZeneca.

He already knew the company. He had served on one of AstraZeneca’s scientific advisory boards, and from 2002 to 2007 he received more than $112,000 from AstraZeneca in speaking and consulting fees and other payments, according to records collected by the Minnesota Board of Pharmacy. Dr. Schulz said that the relationship did not affect his objectivity and that, in any case, he ended his financial ties to the company after the borderline personality disorder trial got underway.

The trial was expected to take about two years, but soon after enrollment began, one of the three clinical sites, McLean Hospital in Massachusetts, essentially dropped out, citing lack of interest from patients. That left the University of Minnesota and the University of Iowa, the other site, to find more study subjects.

In April 2010, one month before the resident spiked the oatmeal at Alpha, a report from the study’s safety officer noted that enrollment was “less than half of what it is expected to be” and that it was now expected to take five years instead of two.

Dr. Schulz said that AstraZeneca was disappointed to learn of the delay. Seroquel was a top seller for the company, bringing in billions of dollars a year. But by the time Dr. Schulz proposed the borderline disorder study in 2007, the company knew that Seroquel’s blockbuster days were limited: It stood to lose its patent protection in 2012. When that happened, a flood of cheap generic alternatives would cause sales to plummet. Seroquel XR, the extended-release version and the subject of Dr. Schulz’s study, would keep its patent protection until 2017, but with generic competition for the standard version, sales were unlikely to be robust.

“I know that they wanted things to be done quicker,” he said, “but they said we could keep our grant and finish the study.”

Questions Raised

The man who drugged his fellow Alpha residents was sent back to prison, and Mr. Kaplan called the university to let them know what had happened.

“They were mortified,” he recalled, and the men were removed from the study. But no one ever followed up with a more detailed investigation, he said.

A university spokesman said in a statement that the institutional review board, which is charged with overseeing all medical studies, did not investigate because the men had already been terminated, and it was not clear the investigators could have done anything to prevent it.

But while some outside ethics experts acknowledged that the story appeared to be a bizarre fluke, they also noted that the episode revealed evidence of lax reporting practices.

The man who drugged the oatmeal, for example, had failed to return his pill bottle at his previous clinic visit, which was necessary so investigators could see if doses were missed. The claim that the two men may have faked their way into the trial should have also raised eyebrows, some said, as well their being under court supervision.

Under guidelines governing federally funded clinical trials, the men would have been considered prisoners and their participation given special scrutiny, several outside ethics experts said. Although the trial was not federally funded, many universities follow similar rules for research involving human subjects. (The university asserts the men were not prisoners.)

Other concerns about the study were raised even before the oatmeal drugging. The study’s safety officer, Dr. Scott Crow, noted in a memo that not a single patient had failed the screening process for enrollment in the study, even though outside experts said it was unlikely that everyone who applied would meet the criteria. Dr. Schulz said the failures were not recorded because the patients were formally screened only after undergoing an initial telephone interview that eliminated unlikely candidates.

“What a sloppy trial,” said Nancy Dubler, a bioethicist who served for years on the Institutional Review Board, or I.R.B., at Montefiore Medical Center in the Bronx. She is an expert on the inclusion of prisoners in clinical trials and said closer attention should have been paid to the events at Alpha. Dr. Schulz said he was disturbed and upset about what had happened at Alpha, but he remained convinced the men had the disorder but had not previously been diagnosed. “We felt we had been screening the people very well,” he said, “but we were also aware that these are patients that do have a lot of impulsive, aggressive behavior.”

After the episode, he said, he reviewed the study protocol with the trial’s project coordinator. They decided not to make changes, but to be more careful about whom they enrolled.

Others said that the event was troubling, given the recent scrutiny of research practices at the university.

“If I’m on an I.R.B. and I see problematic studies and public controversy coming up again and again,” said Carl Elliott, a bioethicist at the University of Minnesota, “I’m going to look carefully at those studies. And yet our I.R.B. seems to do the opposite.”

Mr. Elliott obtained documents relating to Dr. Schulz’s borderline personality disorder trial through a public-records request and made them available to a reporter. In January, he filed a complaint with the Food and Drug Administration about the university’s research practices in the trial.

Mr. Elliott has spent years calling on the university to overhaul the way it conducts research on patients. His activism began after the death of Dan Markingson, a psychiatric patient who committed suicide in 2004 while he was a participant in a clinical trial of Seroquel. Last year, the university commissioned an external review of its research practices, and the report that came out in February was unsparing, taking the university to task for paying inadequate attention to securing the consent of vulnerable patients.

The experts had harsh criticism for the department of psychiatry, as well as for Dr. Schulz and another researcher, whom it described as “two investigators whom faculty and staff do not trust and who fail to communicate a set of priorities that align their own research agenda with the best interests of patients and patient care.”

The outside committee recommended that Dr. Schulz and the other investigator “receive supervision, coaching in leadership, and advanced training in human subjects protections.”

Dr. Schulz’s name was not on the public copy of the report, but an unredacted version was provided to The New York Times by a member of the external review committee.

In an interview, Dr. Schulz painted much of the criticism as stemming from years of campaigning by Mr. Elliott. He said that under his leadership, the department was thriving.

When the university announced that Dr. Schulz was leaving his post as head of psychiatry after 16 years, it said he would continue to serve as the executive medical director, which “will allow him to focus his time more exclusively on patient care.”

“ I felt it was time for me to step down in order for the medical school to make a recruitment for a new chair,” Dr. Schulz said, “so the department can continue its excellence.”

Still No Treatment

In March 2013, four years after recruiting the first patient, the investigators closed the trial after enrolling almost 100 patients. A statistically significant number of participants who took a lower dose of the drug, the researchers concluded, saw their symptoms improve over eight weeks.

But even as some said the study offered a new treatment option, others questioned spending so much on a trial that was unlikely to lead to major improvements in the way the condition was treated.

Dr. Lenzenweger, the borderline personality disorder expert who cautiously praised the trial, also noted that the short time period limited its applicability. “This trial only lasted eight weeks, and personality disorders last for years,” he said.

And even during that short period, about one-third of the participants — many citing the sedating effects of the Seroquel — dropped out.

“There is something phony — wrong — about doing a study that can only run for eight to 12 weeks in what’s basically a long-term condition, and where the side effects of the drug are really the big issue,” said Dr. Ross McKinney, director of the Trent Center for Bioethics at Duke University. “Unless you have an immediate plan to take it into something long term, I’m skeptical that it’s of any value at all.”

But Dr. Donald W. Black, the investigator at the Iowa site, said short-term trials were the norm for testing drugs for psychiatric conditions.

“Ideally, these studies would last six months, one year, two years or longer, but who’s going to do it, who’s going to pay for it, and what patient is going to stay in a study that long?” he said.

The study of Seroquel XR was valuable, he said, because even with about 100 patients, it was larger than the previous trials.

“Bottom line,” he said, the drug “seems to work in borderline patients, who improve in many different ways.”

People with borderline personality disorders, meanwhile, do not appear to be any closer to getting an approved treatment for their condition. After five years and the $700,000 that AstraZeneca paid for the trial, it seems the company has no plans to market Seroquel XR for use in borderline personality patients.

Michele Meixell, a spokeswoman for the company, said that while trials like this one were once approved “in areas where the company may have had a therapeutic interest,” she added, “we do not currently have a further interest in borderline personality disorder.”

Jack Begg and Christina Capecchi contributed reporting.

A version of this article appears in print on April 19, 2015, on page BU1 of the New York edition with the headline: A Drug Trial’s Frayed Promise.

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