Yet another instance of sloppy research

[Langue_doc]

U.S. Watchdog Halts Studies at N.Y. Psychiatric Center After a Subject's Suicide
Human research trials at the New York State Psychiatric Institute at Columbia have been paused while regulators review whether protocols were violated.

https://www.nytimes.com/2023/08/10/health/columbia-drug-trials-suicide.html

The first few paragraphs from the article:

Federal regulators have suspended research on human subjects at the Columbia-affiliated New York State Psychiatric Institute, one of the country's oldest research centers, as they investigate safety protocols across the institute after the suicide of a research participant.

A spokesperson for the U.S. Department of Health and Human Services, Kate Migliaccio-Grabill, confirmed on Wednesday that the agency's Office for Human Research Protections was investigating the psychiatric institute "and has restricted its ability to conduct H.H.S.-supported human subject research."

About two weeks before the federal order, on June 12, the institute had "voluntarily paused all studies that included ongoing interactions with human subjects," according to Carla Cantor, the institute's director of communications. The decision affected 417 studies, of which 198 have continuing participation. Of those, 124 receive federal funding.

It is unusual for the U.S. regulatory office to suspend research, and this suggests that investigators are concerned that potential violations of safety protocols occurred more broadly within the institute. Almost 500 studies, with combined budgets totaling $86 million, are underway at the institute, according to its website.

The inquiry followed the death by suicide of a person enrolled in a study led by Dr. Bret R. Rutherford, an associate professor of psychiatry at Columbia University who was testing a drug for Parkinson's disease, levodopa, as a treatment for depression and reduced mobility in older people.

The article goes on to report:

The trial of levodopa for late-life depression, which began in 2018 and received $736,579 in funding from the National Institute of Mental Health, aimed to recruit 90 adults over the age of 60 who suffered from mild to moderate depression and a slowed gait.

The team ended up with just 51, of whom 20 dropped out or were found ineligible, according to records provided to federal oversight agencies. The 31 who remained were assigned to one of two groups, one taking levodopa and one taking a placebo.

On the website clinicaltrials.gov, under the heading "serious adverse events," researchers reported that the individual who died by suicide had been assigned to the placebo arm of the study.

Dr. Rutherford and his co-authors published several articles based on the trial, reporting that levodopa, which increases dopamine concentrations, led to improvement in mobility, processing and depressive symptoms in the study population.

The promising results were flagged in NEJM Journal Watch, which said that clinicians "might consider levodopa" for patients whose cognition or mobility did not respond to standard depression treatments.

It is not clear when the suicide occurred, but records show that the study was temporarily suspended by the National Institute of Mental Health in January 2022 and terminated in May 2023. This year, three scientific journals ran retractions identifying methodological errors in studies from Dr. Rutherford's laboratory.

One of them pointed to a specific flaw: Eight subjects had only recently stopped taking an antidepressant, rather than waiting 28 days to "wash out," as required by the study's protocol. The average number of days those patients had been off medication was 10; one subject had been off medication only for a day.

A member of Columbia's faculty since 2010, Dr. Rutherford was a prolific researcher, having received 32 grants totaling more than $15.5 million from N.I.M.H. since 2010.

Subjects in the study were paid $15 in cash for weekly visits and an additional $400 for undergoing M.R.I. and PET scans.

Emily Roberts, a former research assistant in Dr. Rutherford's laboratory and a co-author on one of his papers, told Spectrum that recruiting for the study had been challenging and that some criteria had been relaxed to increase enrollment.

Ms. Roberts, who managed the clinical trial in its first year, said the experience left her disillusioned and contributed to her decision to leave the field. "I was disappointed at the rigor of the research there," she said. Ms. Roberts verified her comments to Spectrum, but she would not publicly comment further on the matter.

Some studies of psychiatric drugs require participants to "wash out" — to go off the medications they are taking and allow them to clear their system, so that scientists can test the effectiveness of a new one.

This practice is specific to psychiatric research, and it creates a tension about what is best for patients, said Jeffrey Kahn, the director of the Berman Institute of Bioethics at Johns Hopkins University.

"There isn't another category of drug trial where you ask someone to go off something they are on," he said. "It's a violation of a standard of care. You can't tell someone, 'Stop taking your chemotherapy so we can compare it to a new chemotherapy.'"

It is rare for regulators to halt research across an institution.

[jerseyjay]

This is not my field at all, and I have no knowledge of the research or the researchers involved. However, it seems that there is something more than "sloppy research" involved. I can believe there was sloppiness in the attempt to publish as much as possible and get as much research funded as possible. But, at least according to the Times article, there is a broader methodical issue.

It seems to involve the issue of having psychiatric patients "wash out", i.e., stop taking their medication long enough so it leaves their system. This seems to be justified on a scientific level (because it eliminates questions of interference between medications) but dubious on treatment grounds (since it means stopping a treatment plan).

Previous publications by the researcher had been retracted because this had been relaxed, so that some patients began taken the trial drug before their old medications had left their system. From what I can tell, in the current study, one patient in the placebo group committed suicide, i.e., one patient stopped taking their medications for depression, and then committed suicide. At least as the Times frames it, there is the question of whether the protocol of making patients "wash out" is ethical; there is also the practical question of whether this protocol inhibits getting enough subjects for the experiment.

[Langue_doc]

This is not my field at all, and I have no knowledge of the research or the researchers involved. However, it seems that there is something more than "sloppy research" involved. I can believe there was sloppiness in the attempt to publish as much as possible and get as much research funded as possible. But, at least according to the Times article, there is a broader methodical issue.

It seems to involve the issue of having psychiatric patients "wash out", i.e., stop taking their medication long enough so it leaves their system. This seems to be justified on a scientific level (because it eliminates questions of interference between medications) but dubious on treatment grounds (since it means stopping a treatment plan).

Previous publications by the researcher had been retracted because this had been relaxed, so that some patients began taken the trial drug before their old medications had left their system. From what I can tell, in the current study, one patient in the placebo group committed suicide, i.e., one patient stopped taking their medications for depression, and then committed suicide. At least as the Times frames it, there is the question of whether the protocol of making patients "wash out" is ethical; there is also the practical question of whether this protocol inhibits getting enough subjects for the experiment.

I agree that this is beyond sloppy. In addition to the issues you note, according to the article, "the recruiting for the study had been challenging and that some criteria had been relaxed to increase enrollment".

[Volhiker78]

I'm surprised this trial ever got off the ground at all. Typically, this sort of clinical trial is designed as an add-on trial. Patients already on an antidepressant but meeting the other eligibility requirements would be randomized to levodopa or placebo. One of the eligibility requirements would be that the antidepressant has already been examined with levodopa in a pk study and shown no interaction between the two drugs. 

It is true that new chemical entities looking to become approved as a new antidepressants are tested in subjects washed out from previous meds, but this is typically done in younger patients with no previous suicidal thoughts.

I can imagine recruitment was difficult. If I sat on an institutional IRB, I would have voted to reject the trial.

[Puget]

A member of Columbia's faculty since 2010, Dr. Rutherford was a prolific researcher, having received 32 grants totaling more than $15.5 million from N.I.M.H. since 2010.

Along with all the other problems with this noted here, holy cow but is that a lot of grants! Far more than most people will have in a whole career. This is only possible because academic medical centers like this have huge staffs that do much of the work, and faculty who do little to no teaching. I think this is bad for science in three ways:

1. It is so frustrating to see that much money going to one person who then misuses it for poorly designed and executed studies, while the rest of us are working our butts off just trying to get a grant or two to do good science.

2. There is no way a PI with that many pots on the fire can provide meaningful oversight to all of them. Inevitably, oversight gets delegated to postdocs and staff, who also aren't getting effective mentorship to make those decisions well, and corners get cut as we see here.

3. The incentive structure at institutes like this is very heavily weighted toward bringing in grants above all else-- these are largely soft money positions, so people literally lose their jobs if they don't. That's a hell of an incentive to cut corners and fudge results.