FAQ: U drug trials, patient safety and the death of Dan Markingson

More than a decade after the suicide of a patient in a University of Minnesota drug trial, the incident is prompting the university to make some changes to the way it conducts such trials.

The changes are coming about now through the persistence of critics who demanded further investigation into the death of Dan Markingson. After years of little action, the case has generated a flurry of activity in just the last few months — new reports, proposed reforms, staff changes. Here are some of the key points to emerge:

What has all of this been about?

Critics believe some University of Minnesota researchers have coerced vulnerable patients into participating in studies, and then neglected their welfare during the research. Much of the focus has been on a few researchers in the Department of Psychiatry, which often conducts clinical drug trials sponsored by drug companies. Critics say university officials have ignored years of requests to look into the matter.

What prompted it?

It all started with the suicide of a mentally ill man named Dan Markingson over a decade ago. He'd seen Dr. Stephen Olson, a university psychiatrist, who enrolled Markingson in a corporate-sponsored drug trial for an anti-psychotic drug. Markingson's mother, Mary Weiss, believes Olson coerced her son into participating and kept him in the study despite her repeated warnings that he might hurt himself. Markingson's suicide in 2004 prompted her to sue the university in 2007.

A series of articles in 2008 by the St. Paul Pioneer Press brought the case to light.

A court ruled the university was immune to litigation. Weiss later settled with Olson for $75,000.

Was any wrongdoing proven?

The federal and state investigations that Markingson's death sparked have been a subject of contention for years. They included reviews by the university's research oversight panel, the U.S. Food and Drug Administration and the Minnesota Board of Medical Practice.

University officials argued the results exonerated the U.

But the Pioneer Press stories raised the suspicion of U of M bioethicist Carl Elliott. He looked into the case, and began a campaign of articles and letters pointing out what he saw as flaws and inadequacies in the investigations. He pushed the U's top officials to launch another investigation of the case, and their refusal led Elliott to accuse them of a cover-up.

Why did the case make news this year?

The work by Elliott, who was later joined by U of M colleague Leigh Turner, caught the attention of some university faculty, alumni and scholars from around the world, who began pressuring university officials to reopen the case.

Former Gov. Arne Carlson also wrote letters to both regents and lawmakers criticizing the university's actions and asking for another investigation.

After mounting pressure from faculty, President Eric Kaler in December 2013 agreed to launch an outside review of the U's clinical research practices. And in 2014, two leading legislators asked the state legislative auditor to look into the Markingson case specifically.

The results of both cases came out earlier this year, and sparked reaction from both lawmakers and the university.

What did the investigations find?

In February, the external panel hired by the university said the university had weak oversight of research. The reviewers noted that personnel didn't feel the U's leaders were committed to protecting test subjects, and they expressed special concern over a "culture of fear" in the psychiatry department they said kept people from raising safety concerns. It suggested dozens of reforms.

In March, Minnesota Legislative Auditor Jim Nobles criticized the U for its handling of the Markingson case.

Nobles said it was impossible to link Markingson's death to the drug study, but said he found "serious ethical issues and numerous conflicts of interest." He said the conditions under which researchers recruited Markingson were potentially coercive, and that researchers ignored repeated warnings about Markingson's deteriorating condition.

The report noted multiple potential conflicts of interest among the researchers and subsequent investigators. Nobles said the FDA investigation had been "limited," and that the U's own investigation had been "superficial." He said university leaders had repeatedly made misleading statements about the thoroughness of past reviews, and that they'd damaged the university's reputation by rejecting calls for further investigation.

Since those reports, more information about university researchers has surfaced.

This month, an internal review found some Fairview Health Services personnel held a "profound" distrust of some U of M psychiatric researchers working there, and it blamed leadership at Fairview and the U for ignoring it.

In a separate case this month, the university wrote a letter of apology to a former test subject, saying researchers had failed to follow several safety procedures during a 2007 university drug trial he participated in. The U issued the letter after an outside consulting firm said Olson and his staff had made the mistakes, calling two of them "serious."

However, the report rejected the patient's claims that Olson and his staff had coerced him into participating.

How has the U reacted to all of this?

Although Kaler said he didn't agree with all of the findings in March's legislative audit, he accepted it, as well as the findings of February's external review.

Kaler said he thought the medical school was doing better than it was in protecting test subjects, and called it "worrisome that we have such a distance to go to reach the very highest standards."

He apologized to Markingson's family "for his death under our care." He also apologized for the university's prior misleading statements on the matter, saying they were not meant to mislead and that he'd relied on investigations he thought were credible.

Kaler suspended patient enrollment in 17 active and pending drug studies until they're reviewed by an outside firm, and ordered an action plan to carry out the reforms.

What's changing?

According to the draft plan the university released Monday, it will add personnel, boost training and increase oversight in an attempt to make sure a case like Markingson's doesn't happen again.

Many of the changes focus on strengthening oversight panels so the U can make sure researchers in all departments are conducting their experiments appropriately. It's instituting a tougher patient consent process, and is giving researchers more training so they can better judge whether patients are mentally capable of consenting to a study. The U will also work to curb conflicts of interest among researchers and drug companies.

Campus leaders say they're trying to change the research culture by injecting more checks and balances into the power structure, and enable those who are not physicians to have more say in the research process. And the U will be offering physicians more education and training in ethics and the new standards.

Has anyone been disciplined as a result of all this?

Not publicly, at least.

However, last month Dr. Charles Schulz, who was a co-researcher with Olson in the Markingson study and led the psychiatry department at the time, resigned his leadership of the department. Recently, he said he'd also agreed to step down as executive medical director of behavioral health services at the university hospital.

What happens now?

The public has through June 1 to comment on the reform plan, which regents are expected to vote on next month. Medical School Dean Brooks Jackson said he hopes to see most reforms in place within nine months. Legislative auditor Nobles says he'll return late this fall to see check on the U's progress, and wants to follow up several times in the next few years.

Nobles called the reform plan "very encouraging," and university leaders say elements go far beyond what other institutions do. Some critics say it does have the potential to improve things, but remain skeptical that it will bring about significant change.

Meanwhile, Nobles hopes to release in the next few weeks the results of his review of the past decade of university drug trials. He's trying to determine whether the university's files contain more cases such as Markingson's or other major mishaps.

How has all of this affected the U?

Its reputation has taken a beating, and multiple colleges in the U.S and abroad use the Markingson case as a study in how not to conduct research and handle criticism.

Meanwhile, drug studies remain suspended as an outside consultant reviews them.

The reforms will cost the university lots of paperwork and millions of dollars to carry out — all during a time when it's trying to boost its national ranking as a major medical research institution.

Jackson said in an email, however, that higher rankings and protecting subjects "are not mutually exclusive." He acknowledges that some reforms could increase red tape, but said others could actually make some studies get started more quickly.

"Expansion of research should in no way come at the expense of patient safety," he said, "so we don't anticipate these reforms impeding us as we look to grow our research portfolio."