Mother Jones *
September/October 2010
Clinical trials have become marketing exercises for Big
Pharma -- and cash-strapped universities are helping make the sale. Too bad for
Dan Markingson.
Making a Killing
by Carl Elliott
IT'S NOT EASY TO WORK UP a good feeling about the
institution that destroyed your life, which may be why Mary Weiss initially
seemed a little reluctant to meet me. "You can understand my hesitation to
look other than with suspicion at anyone associated with the University of
Minnesota," Mary wrote to me in an email.
In 2003, Mary's 26-year-old son, Dan, was enrolled against her wishes in a
psychiatric drug study at the University of Minnesota, where I teach medical
ethics. Less than six months later, Dan was dead. I'd learned about his death
from a deeply unsettling newspaper series by St. Paul Pioneer Press reporters
Jeremy Olson and Paul Tosto that suggested he was coerced into a
pharmaceutical-industry study from which the university stood to profit, but
which provided him with inadequate care.
Over the next few months, I talked to several university colleagues and
administrators, trying to learn what had happened. Many of them dismissed the
story as slanted and incomplete. Yet the more I examined the medical and court
records, the more I became convinced that the problem was worse than the
Pioneer Press had reported. The danger lies not just in the particular
circumstances that led to Dan's death, but in a system of clinical research
that has been thoroughly co-opted by market forces, so that many studies have
become little more than covert instruments for promoting drugs.
The study in which Dan died starkly illustrates the hazards of market-driven
research and the inadequacy of our current over- sight system to detect
them.
Mary Weiss is a slight, white-haired woman in her late sixties who smiles
ruefully at any question, no matter how painful. She is the sort of Minnesota
liberal who volunteers for political campaigns and signs her email with
flowers. When we first met at a coffee shop in St. Paul, she was wearing an
Obama pin on her sweater. Mary raised Dan alone, working a job at the postal
service. Old photographs show Dan growing into his good looks; according to
Mary, he was also a gifted student. In high school, Dan got a perfect score on
the verbal portion of his sat. He graduated from the University of Michigan in
2000 with an English degree, and that fall he moved to Los Angeles, hoping to
become a screenwriter or an actor. To support himself, he got a job as a
celebrity-tour bus driver.
When Mary went out to Los Angeles for a visit in the summer of 2003, it was
clear Dan had changed. He'd adopted a new last name, Markingson. His behavior
was bizarre. "He said, 'You haven't told me when the event is going to
be,'" Mary said. She had no idea what he was talking about. The next day,
he took her to his apartment. He'd encircled his bed with wooden posts, salt,
candles, and money, which he said would protect him from evil spirits. He
showed her a spot on the carpet that he said the aliens had burned.
I asked Mary how she'd reacted to all of this. "I panicked. I called 911,"
she replied. But when the police arrived, Dan was able to convince them she had
overreacted. "He said, 'Oh, my mother just drove from Minnesota and she's
very tired,'" she recalled. Worried that Dan was seriously ill, she tried
to convince him to return to St. Paul. He visited her in August, returned
briefly to California, and then came back to St. Paul in October.
Dan grew convinced that the Illuminati were orchestrating an event in Duluth,
Minnesota -- a "storm" in which he would be called upon to murder
people, including Mary. Some of his emails from late September 2003 suggest the
extent of his delusions:
"I'm aware that people can cast spells that can hurt you at a distance.
I'm aware that some people can read minds. I'm aware that some people might
actually be 'hybrids' and not altogether human."
In another email, Dan wrote: "I'm especially eager to attend this storm
and SLAY those who deserve slaying. I will choose victims immediately... I HAVE
NO EMOTIONAL ATTACHMENTS. I KILL FOR FUN!!"
On November 12, Dan said he would kill Mary if called upon to do so. She called
the police. Dan was taken to Regions Hospital in St. Paul. But the hospital had
no psychiatric beds available, so after a few hours Dan was transferred to
Fairview University Medical Center, a teaching hospital for the University of
Minnesota Academic Health Center. He was treated by Dr. Stephen C. Olson, an
associate professor in the university's psychiatry department, who prescribed
Dan Risperdal (risperidone), an antipsychotic drug often prescribed for
patients with schizophrenia or bipolar disorder. (In Minnesota, doctors are
allowed to give antipsychotic drugs to mentally incompetent patients without
their consent for up to 14 days, but only to prevent serious, immediate physical
harm to the patient or others.) Olson believed Dan was psychotic and dangerous,
and lacked the ability to make decisions regarding his treatment; on November
14 he signed a document that recommended Dan be committed involuntarily to a
state mental institution, noting that he "lacks the capacity to make
decisions regarding such treatment." Three days later, a clinical
psychologist also recommended involuntary commitment, reiterating that Dan had
threatened to slit his mother's throat.
In Minnesota, patients who have been involuntarily committed are given another
option: a "stay of commitment." Patients can avoid being confined to
a mental institution as long as they agree to comply with the treatment program
laid out by their psychiatrist. On November 20, Olson asked for a stay of
commitment. The court granted the stay for six months, stipulating that Dan had
to follow the recommendations of his treatment team. Olson, however, did not
simply recommend standard medical treatment. Instead, he proposed that Dan take
part in an industry-funded study of antipsychotic drugs. The university's study
coordinator, Jean Kenney, had Dan sign a consent form when Mary wasn't present,
and on November 21, he was enrolled in the study.
On the surface, the study appeared benign. Its purpose was to compare the
effectiveness of three "atypical" antipsychotic drugs, each of which
had already been approved by the FDA: Seroquel (quetiapine), Zyprexa
(olanzapine), and Risperdal (risperidone.) The study was designed and funded by
AstraZeneca, the manufacturer of Seroquel, and it called for 400 subjects
experiencing their first psychotic episode to take one of the three drugs for a
year. AstraZeneca called it the "CAFE" study, which stood for
"Comparison of Atypicals in First Episode." The management of the
CAFE study had been outsourced to Quintiles, a contract research organization,
which was conducting it at 26 different sites, including the University of
Minnesota. (For more on CROS, see "Trial by Hire," page 60.)
Yet the CAFE study was not without risks. It barred subjects from being taken
off their assigned drug; it didn't allow them to be switched to another drug if
their assigned drug was not working; and it restricted the number of additional
drugs subjects could be given to manage side effects and symptoms such as
depression, anxiety, or agitation. Like many clinical trials, the study was
also randomized and double-blinded: Subjects were assigned a drug randomly by a
computer, and neither the subjects nor the researchers knew which drug it was.
These restrictions meant that subjects in the CAFE study had fewer therapeutic
options than they would have had outside the study.
In fact, the CAFE study also contained a serious oversight that, if corrected,
would have prevented patients like Dan from being enrolled. Like other patients
with schizophrenia, patients experiencing their first psychotic episode are at
higher risk of killing themselves or other people. For this reason, most
studies of antipsychotic drugs specifically bar researchers from recruiting
patients at risk of violence or suicide, for fear that they might kill
themselves or someone else during the study. Conveniently, however, the CAFE
study only prohibited patients at risk of suicide, not homicide. This meant that
Dan -- who had threatened to slit his mother's throat, but had not threatened
to harm himself -- was a legitimate target for recruitment.
When Mary found out that Dan had been recruited into the CAFE study, she was
stunned. "I do not want him in a clinical study," she told Olson.
Just a few days earlier, Olson indicated in a petition to the court that Dan
was both dangerous and mentally incapable of consenting to antipsychotic
medication. How could he now be capable of consenting to a research study with
the very same antipsychotics -- especially when the alternative was commitment
to a state mental institution?
After Dan was enrolled, he stayed at Fairview for about two more weeks. By that
point, Olson thought Dan's symptoms were under control, but Mary was still very
worried by his erratic behavior. She recalls meeting with the doctor:
"Olson came in and sat down and opened his file and said, 'Oh, Dan is
doing so well.' And I said, 'No, Dr. Olson, Dan is not doing well.' I think he
was taken aback." Even so, on December 8, 2003, Dan was transferred to
Theo House, a halfway house in St. Paul. He was required to sign an agreement
confirming that he understood he could be involuntarily committed if he didn't
continue taking his medication and keeping his CAFE study appointments.
At the halfway house, Dan often stayed in his room for days. On March 26, 2004
nearly four months after his discharge from Fairview, his thoughts were still
"delusional and grandiose," according to a social worker's note. An
occupational-therapy report from April 30 detailed Dan's condition:
"Personal appearance disheveled. Isolated and withdrawn. Poor insight and
self-awareness." Entries in a personal journal that Dan kept during this
period don't show any obvious changes, suggesting that he was improving little,
if at all. Mary felt he was becoming angrier. "He was so tense, with this
ready-to-explode quality."
Olson saw things differently. "I disagree that he had significant
deterioration," he testified in a 2007 deposition. However, it's unclear
whether Olson actually saw Dan enough to make an informed judgment about his
condition. Records suggest most of Dan's care was managed by social workers. In
his deposition, Olson said he saw Dan approximately six times from the date he
was admitted in November until he committed suicide in May. Whatever the doctor
thought, his actions don't suggest that he felt Dan was improving. In late
April 2004, as Dan's stay of commitment was about to expire, Olson recommended
extending it for another six months -- the duration of the CAFE study. He noted
that Dan still had "little insight into his mental disorder" and
might "place himself at risk of harm if he were to terminate his
treatment."
Mary tried to get Dan out of the study or have his treatment changed. She
called Olson and tried to see him. She wrote long, detailed letters expressing
concerns about everything from Dan's diet and sleep habits to his medications.
In total, she sent five letters to Olson and Dr. Charles Schulz -- the chairman
of the university's psychiatry department and a co-investigator on the CAFE
study -- communicating her alarm about Dan's condition, especially his inner
rage. She received only one reply, dated April 28, from Schulz, who wrote that
"it was not clear to me how you thought the treatment team should deal
with this issue." Around that time, Mary left a voice message with Jean
Kenney, the study coordinator, asking, "Do we have to wait until he kills
himself or someone else before anyone does anything?"
Before dawn on the morning of May 8, a police officer and a Catholic priest
knocked on Mary's door. Mike Howard, a family friend who lives at her house,
answered. Later, in a deposition, Howard described what happened next:
"Mary jumped out of her bed and went into the kitchen and stood there, and
the priest extended his hand out and said, 'Mary, I'm here to tell you that Dan
passed away.' And Mary just literally fell down to her knees and started to
shriek and cry, and just started begging, 'Please, no, no, don't let this
happen.'"
Dan had stabbed himself to death in the bathtub with a box cutter, ripping open
his abdomen and nearly decapitating himself. His body was discovered in the
early hours of the morning by a halfway-house worker, along with a note on the
nightstand that said, "I left this experience smiling!" Later, when
the blind on the study was broken, researchers found that Dan was being treated
with Seroquel, the drug manufactured by the study sponsor, AstraZeneca.
For most of the past half-century, physicians have considered antipsychotic
drugs to be among the most unpleasant chemicals in the medicine closet.
Thorazine (chlorpromazine), the first antipsychotic, was developed in 1950, and
while it could relieve some of the worst symptoms of schizophrenia, that relief
came at a serious cost. Not only do antipsychotics often make patients feel
sedated and sluggish (they used to be called "major tranquilizers"),
they can also cause irreversible "extrapyramidal" symptoms, such as
the shuffling gait, rigid muscles, and involuntary lip-smacking sometimes seen
in patients who have been taking the drugs for years. The antipsychotics can
also cause akathisia, a type of driven, agitated restlessness that ranges from
unpleasant to excruciating. Until recently, psychiatrists reserved the drugs
for patients with very severe mental illnesses.
Over the past decade or so, however, antipsychotics have undergone an
extraordinary rehabilitation. By 2008, they were the most lucrative class of
drugs in America. Seroquel alone had nearly $4 billion in sales, making it the
country's fifth most profitable drug. The transformation began in the mid-'90s,
when pharmaceutical companies began pitching atypical antipsychotics such as
Risperdal, Zyprexa, and Seroquel as more effective than older antipsychotics,
but relatively free of their ugly side effects. The drugs were also very
expensive -- one study pegged the cost at 70 to 100 times that of an older drug
-- but if they didn't produce extrapyramidal symptoms, their enormous expense
seemed justifiable. By the mid-2000s, atypicals were being prescribed not just
for schizophrenia but also for anxiety, agitation, insomnia, attention deficit
hyperactivity disorder, and depression. The most remarkable upswing came for
patients diagnosed with bipolar disorder, which used to be seen as a rare
illness. Once bipolar disorder could be treated with atypicals, rates of
diagnoses rose dramatically, especially in children. According to a recent
Columbia University study, the number of children and adolescents treated for
bipolar disorder rose 40-fold between 1994 and 2003. Another study found that
nearly one in five children who visited a psychiatrist came away with a
prescription for an antipsychotic drug, despite early reports of alarming side
effects.
Recent years have seen a backlash. The most damaging blow to the atypicals was
an authoritative 2005 study funded by the National Institute of Mental Health
-- the so-called CATIE study -- which found that the atypical antipsychotics
worked no better than a much older antipsychotic called Trilafon
(perphenazine), which was developed in the 1950s. The CATIE study also found
that, contrary to the way the drugs had been marketed, side-effect profiles of
the atypicals were generally no better than the older drug. Other research
showed that atypicals were associated with significant weight gain, increased
risk of diabetes, and greater possibility of death in patients with dementia.
After another large analysis in The Lancet found that most atypicals actually
performed worse than older drugs, two senior British psychiatrists penned a
damning editorial that ran in the same issue. Dr. Peter Tyrer, the editor of
the British Journal of Psychiatry, and Dr. Tim Kendall of the Royal College of
Psychiatrists wrote: "The spurious invention of the atypicals can now be
regarded as invention only, cleverly manipulated by the drug industry for
marketing purposes and only now being exposed."
The cleverest manipulation has been with the clinical trials themselves. For
years, critics have charged that pharmaceutical companies massage trials to
make their own drugs look better than they really are. One common tactic is to
suppress unfavorable data. A notorious example came in the 1990s, when a Wyeth
safety officer overwrote the company's computer files, erasing evidence
indicating that its diet drug, fen-phen, caused valvular heart disease. A less
risky strategy is simply not to publish potentially damaging trials. In 2004,
the
Canadian Medical Association Journal described a leaked document indicating
that GlaxoSmithKline had deliberately hidden two studies from regulators
showing that its antidepressant, Paxil (paroxetine), could increase the risk of
suicide in children. The company has paid nearly a billion dollars in legal
settlements over Paxil, including $390 million for suicides and attempted
suicides related to the drug. Evidence of manipulation has also emerged in many
of the high- profile pharmaceutical scandals of the past decade, from Merck's
pain drug Vioxx to the recent Senate investigation into GlaxoSmithKline's
diabetes drug Avandia.
Something similar has happened with the atypicals. A 2006 study in The American
Journal of Psychiatry, which looked at 32 head-to-head trials of atypicals,
found that 90 percent of them came out positively for whichever company had
designed and financed the trial. This startling result was not a matter of
selective publication. The companies had simply designed the studies in a way
that virtually ensured their own drugs would come out ahead -- for instance, by
dosing the competing drugs too low to be effective, or so high that they would
produce damaging side effects. Much of this manipulation came from biased
statistical analyses and rigged trial designs of such complexity that outside
reviewers were unable to spot them. As Dr. Richard Smith, the former editor of
the British Medical Journal, has pointed out, "The companies seem to get
the results they want not by fiddling the results, which would be far too crude
and possibly detectable by peer review, but rather by asking the 'right'
questions."
Initially, the controversy over atypical antipsychotics was focused largely on
Eli Lilly, the manufacturer of Zyprexa. In early 2009, it settled litigation
for a record-breaking $1.4 billion for illegal marketing and allegedly hiding
the risks of the drug. More recently, however, the scandal has spread to
Seroquel. In April 2010, AstraZeneca agreed to pay $520 million to settle two
federal investigations and two whistleblower lawsuits alleging that it had
marketed Seroquel illegally and concealed its health risks. The company faces
more than 25,000 civil suits.
Documents unsealed in related civil suits suggest an alarming pattern of
deception. Sales reps were instructed to tell doctors that Seroquel doesn't
cause diabetes, even though the company knew about the link to diabetes as
early as 1997. Internal correspondence reveals company officials discussing how
to hide or spin potentially damaging studies. "Thus far, we have buried
trials 15, 31, 56," wrote a publications manager in 1999. "The larger
issue is how do we face the outside world when they begin to criticize us for
suppressing data."
One of those potentially damaging studies led back to the University of
Minnesota. In the late 1990s, a clinical trial known as Study 15 unexpectedly
failed to show that Seroquel was any better than Haldol, a generic
antipsychotic that's been on the market since the 1960s. In fact, on the main
measures, Seroquel performed worse than Haldol. The study also showed that
Seroquel increased the risk of weight gain and diabetes. Internal
correspondence repeatedly refers to Study 15 as a "failed study," and
company officials discuss possible ways to spin or bury it. "I am not 100%
comfortable with this data being made publicly available at the present
time," wrote Richard Lawrence, a senior AstraZeneca official, in 1997.
"However I understand that we have little choice...Lisa [Arvanitis, a
company physician] has done a great 'smoke-and-mirrors' job." Lawrence
referred approvingly to a strategy that he said would "put a positive spin
(in terms of safety) on this cursed study." Later, apparently hoping to
find a way to present Seroquel in a better light, the "commercial support
team" performed an analysis of a number of other studies, but even that
did not show Seroquel to be better than Haldol. Yet when a summary of the
AstraZeneca data was presented at the American Psychiatric Association annual
conference in 2000, the author claimed Seroquel was "significantly
superior" to Haldol. That author was Dr. Charles Schulz, the University of
Minnesota psychiatry department chair -- and a well-compensated consultant for
AstraZeneca. In a press release claiming Seroquel's superiority over Haldol,
Schulz praised it enthusiastically as a "first-choice
antipsychotic."
Although the documents unsealed in the Seroquel litigation do not specifically
mention the CAFE study in which Dan was enrolled, they do suggest that
AstraZeneca planned to establish Seroquel as the "atypical of choice in
first-episode schizophrenia," according to a 2000 "Seroquel Strategy
Summary." A later document titled "Seroquel PR Plan 2001"
discusses the agenda for an advisory panel meeting in Hawaii. Among the potential
topics were the marketing of Seroquel to first-episode patients, adolescents,
and the elderly. The document refers to these populations as "vulnerable
patient groups."
Even more alarming are internal documents suggesting that AstraZeneca was
designing clinical trials as a covert method of marketing Seroquel. In 1997,
when Dr. Andrew Goudie, a psychopharmacologist at the University of Liverpool,
asked AstraZeneca to fund a research study he was planning, a company official
replied that "R&D is no longer responsible for Seroquel research -- it
is now the responsibility of Sales and Marketing." The official also noted
that funding decisions would depend on whether the study was likely to show a
"competitive advantage for Seroquel."
Another set of documents from 2003 describes a glucose metabolism study
apparently designed to fend off the charge that Seroquel causes patients to
gain weight and become diabetic. One slide describes two purposes for the
study: a "regulatory" purpose and a "commercial" purpose. The
regulatory purpose was to "produce data that will help us defend the
Seroquel label." The commercial purpose was to "produce data that
will enable us to generate commercially attractive and competitive messages in
relation to diabetes and weight." The document suggests several possible
names for the study, including "Flexible Dose Approach Trial for Atypical
Responses to Metabolism," which could be usefully shortened to the acronym
FATFARM. (When I contacted AstraZeneca, a spokesperson would say only that
Seroquel has been found "safe and effective" by the FDA and that it
stands behind the CAFE study and the rest of its clinical research.)
Many clinical studies place human subjects at risk -- at a minimum, the risk of
mild discomfort, and at worst, the risk of serious pain and death. Bioethicists
and regulators spend a lot of time and energy debating the degree of risk that
ought to be permitted in a study, how those risks should be presented to
subjects, and the way those risks should be balanced against the potential benefits
a subject might receive. What is simply assumed, without much consideration at
all, is that the research is being conducted to produce scientific knowledge.
This assumption is codified in a number of foundational ethics documents, such
as the Nuremberg Code, which was instituted following Nazi experiments on
concentration camp victims. The Nuremberg Code stipulates that an
"experiment should be such as to yield fruitful results for the good of
society," and "the degree of risk to be taken should never exceed
that determined by the humanitarian importance of the problem to be solved by
the experiment."
But what if a research study is not really aimed at producing genuine
scientific knowledge at all? The documents emerging in litigation suggest that
pharmaceutical companies are designing, analyzing, and publishing trials
primarily as a way of positioning their drugs in the marketplace. This raises a
question unconsidered in any current code of research ethics. How much risk to
human subjects is justified in a study whose principal aim is to "generate
commercially attractive messages"?
In January 2005, the FDA began investigating the circumstances of Dan's
suicide. In a report issued that July, before the larger pattern of Seroquel
research had begun to emerge, Sharon L. Matson, the FDA investigator,
exonerated the university. She wrote, "I did not find any evidence of
misconduct, significant violation of the protocol, or regulations governing
clinical investigators or IRBs" -- the university institutional review
board charged with reviewing studies to ensure that they measure up to
recognized ethical standards. Matson specifically dismissed the suggestion that
Dan was mentally incompetent to consent to the study, writing that "there
was nothing different about this subject than others enrolled to indicate that
he couldn't provide voluntary, informed consent." (The FDA refused my
request to speak with Matson and would not answer questions about the case,
citing privacy concerns.) Mary Weiss eventually sued the University of
Minnesota, AstraZeneca, Olson, and Schulz, but her case did not even get to
trial. District Court Judge John L. Holahan dismissed the suit in 2008 with a
partial summary judgment. He ruled that in approving the CAFE study, the
university IRB was performing the type of "discretionary function"
that is protected from liability under the state's Tort Claims Act. The
malpractice suit against Schulz was also dismissed, and the suit against Olson
was eventually settled -- for $75,000, which Mary says wasn't enough to cover
the fees of the expert witnesses her attorneys hired. (Both Schulz and Olson
declined to speak about the specifics of the clinical trial or the resulting
suit. University spokesman Nick Hanson would say only, "To date, there has
been no finding of wrongdoing from any of the investigations or reviews done by
the university on this issue.")
The judge also dismissed the case against AstraZeneca. He blasted Mary's
lawyers, saying that they had failed to establish that AstraZeneca had a duty
to put the interests of research subjects over the interests of the company and
the researchers. But he also lamented the lack of case law about clinical
trials, saying on this particular point, "Try as it may, this Court's
independent research has unearthed not a single case or statute to evidence or
support such an alleged duty."
The judge further ruled that Mary's lawyers hadn't shown a causal link between
Seroquel and Dan's suicide: An initial drug screening during autopsy had not
found any Seroquel in his bloodstream, which suggested that Dan may not have
been taking his medication. After the judgment, however, Mary discovered that
Seroquel would not be detected in an ordinary drug screening; a special test is
required. In the spring of 2008, she called the coroner's office in hopes of
getting a special screening for Seroquel. To her surprise, she found that her
lawyers and the defendants had already obtained one. The report was dated
several days after the summary judgment was issued. It showed 73 nanograms per
milliliter of Seroquel in his blood, suggesting that Dan was almost certainly
taking the drug, although he may have missed the last scheduled dose before he
died.
Although Mary's lawsuit was unsuccessful, it revealed some disturbing financial
arrangements at the university. As a patient on public assistance, Dan's
treatment would have normally generated little income for the university. Under
its arrangement with AstraZeneca, however, the psychiatry department earned
$15,648 for each subject who completed the CAFE study. In total, the study
generated $327,000 for the department. In fact, during the months before Dan
was enrolled, the department was apparently feeling pressure from Quintiles,
the CRO that managed the study, to step up recruitment. According to emails
written by Jean Kenney, the university's study coordinator, the site had been
placed on probation for its recruitment problems, and they were still
"struggling to get patients." In November 2002, Olson had managed to
recruit only one subject in six months. That began to change in April 2003,
when the psychiatry department established a specialized inpatient unit at
Fairview hospital called Station 12, in which every patient could be evaluated
for research. By December, Olson had recruited 12 more subjects, including Dan,
and Olson had been featured in a CAFE study webcast for "turning an
underperforming site into a well-performing site."(Quintiles refused to
give comment on the case.)
Olson had another financial reason to maintain good relations with AstraZeneca.
According to a disclosure statement for a 2006 conference, he was a member of
the AstraZeneca "speaker's bureau," giving paid talks for the
company. He had similar arrangements with Eli Lilly and Janssen, the makers of
the other atypicals being tested in the CAFE study, as well as Bristol-Myers
Squibb and Pfizer. In addition, Olson was working as a paid consultant for
Lilly, Janssen, Bristol-Myers Squibb, and Pfizer. Although Olson is not
required to disclose how much industry money he received, a public database
maintained by the Minnesota pharmacy board indicates that Olson received a
total of $240,045 from the pharmaceutical industry between 2002 and 2008, with
$149,344 coming from AstraZeneca. Dr. Charles Schulz, his co-investigator and
department chair, received an even greater sum: more than $571,000 from the
industry, with $112,020 coming from AstraZeneca. The database does not reliably
distinguish between payment by drug companies for consulting and speaking, which
usually goes directly into a physician's pocket, and research grants, which go
to the university and are used to help underwrite the salaries of the grant
recipients. (Many academic physicians are required by their universities to
generate a substantial portion of their salaries by obtaining research
grants.)
In the US, the primary bodies charged with protecting research subjects are
known as institutional review boards. (Read how IRBs are becoming privatized,
next page.) According to the University of Minnesota, the purpose of its IRB is
to "protect the rights and welfare of human research subjects."
However, when the university's IRB officials were deposed under oath, they
refused to admit that protecting subjects was their responsibility. "So
it's not the institutional review board's purpose to protect clinical trial
subjects, is that what you're saying?" asked Gale Pearson, one of the
attorneys representing Mary Weiss. "That's true," replied Moira
Keane, the director of the IRB. Astonished, Pearson kept returning to the
question, to make sure that she understood it correctly. Keane refused to
budge. Instead, she claimed that the role of the IRB was to make sure that
Olson and the trial sponsor had a plan to protect subjects. (If this were true,
it would render IRBs worthless: The sponsor and investigator are the ones that
the IRB is supposed to protect subjects from.)
The University of Minnesota doesn't exactly have a stellar record of
investigating internal misconduct. In 1994, the director of child and
adolescent psychiatry, Dr. Barry Garfinkel, was sentenced to federal prison for
five felonies related to research fraud involving the Ciba-Geigy drug Anafranil
(clomipramine). The research assistant who blew the whistle in 1989 lost her
job, and under the terms of a secret agreement struck with Garfinkel, the
university kept the fraud secret for four years, until he was finally indicted.
In 1995, the university was sanctioned by the National Institutes of Health
after revelations that the head of transplant surgery, Dr. John Najarian, had
generated millions of dollars for the university by illegally manufacturing and
selling an immunosuppressant drug without FDA approval; an investigation by the
Minneapolis Star Tribune revealed that the university had known of the illegal
activity for years. Still more scandals have recently emerged, including a
Senate investigation of the chairman of spinal surgery, Dr. David Polly, for
failing to disclose $1.2 million he had been paid to consult for the device
manufacturer Medtronic, and a series of investigative reports in the New York
Times about the industry ties of Minnesota physicians, including some connected
to the university. When the scandals began to escalate several years ago, Dr.
Deborah Powell, then the dean of the university's medical school, appointed a
task force to devise a new conflict-of-interest policy. The policy was
discarded after the Star Tribune revealed that the co-chair of the task force,
Dr. Leo Furcht, had funneled $500,000 of university grant money into his own
private company, which he later sold for $9.5 million. Furcht remains chairman
of the laboratory medicine and pathology department at the university.
In 2007, the American Journal of Psychiatry published the results of the CAFE
study. Among the 18 "serious adverse events" recorded for the 400
subjects in the study were an alleged homicide and five suicide attempts,
including two successful suicides, both by patients taking Seroquel. (One of
these patients, of course, was Dan Markingson.) According to the study authors
-- three AstraZeneca employees and seven academic physicians, many of whom also
consulted for the company -- the suicides occurred "despite the close
attention provided in clinical research aftercare programs." The authors
claimed that the CAFE study showed Seroquel to be of "comparable
effectiveness" to Zyprexa and Risperdal for first-episode patients.
According to some experts, the study could hardly have shown otherwise, because
it was designed to produce a good result for Seroquel. When I showed the
published study to Dr. Peter Tyrer, the editor of the British Journal of
Psychiatry, he said,
"I would have major problems accepting a manuscript of that nature."
According to Tyrer, the main problem is the small sample size. Of the 400
subjects enrolled, all but 119 stopped taking the drug before the yearlong
study was finished. With so few subjects, the CAFE study was statistically
underpowered and thus unlikely to detect any difference in effectiveness
between the three drugs. The failure to detect a difference allowed AstraZeneca
to claim that Seroquel was as good as the other drugs (or in the language of
the study, "non-inferiority"). Tyrer told me, "In scientific
terms this study is of very little value."
That's not the only problem. The CAFE study was supposedly designed to test the
effectiveness of the three antipsychotics, but the way it did this was by
measuring the rate of "all-cause treatment discontinuation," or the
percentage of subjects who stopped taking their drug. That is, the CAFE study
counted an antipsychotic as "effective" if a subject kept taking it
until the end of the study. On the face of it, this type of measurement seems
highly misleading; simply because a patient continues to take an antipsychotic
does not mean that it is working. Many psychiatrists defend treatment
discontinuation as a "pragmatic" way of measuring a drug's overall
acceptability, but even by "pragmatic" standards the CAFE study
presents a problem. More than 70 percent of subjects in the CAFE study stopped
taking their assigned drug, and the most common reason was simply coded as
"patient decision." According to Dr. John Davis, the Gillman
Professor of psychiatry at the University of Illinois-Chicago, the authors of the
CAFE study obscured their results by failing to say why patients decided to
stop taking the drug -- whether patients felt the side effects of the drug were
too severe, for example, or if they felt the drug was not working. "It is
the hiding of the critical outcomes that gives me pause," he says.
"It does not make scientific sense to do a study and not measure one of
the most important outcomes."
Yet another problem with the CAFE study is its failure to compare Seroquel to
any older antipsychotics. "It's quite a marketing exercise to put all
patients in the CAFE study on atypical antipsychotics," says Dr. Glen
Spielmans, an associate professor of psychology at Minnesota's Metropolitan
State University. "It removes the older drugs from the discussion."
One reason AstraZeneca may have done this, he suggests, is that Study 15 had
already shown Seroquel to be inferior to the older antipsychotic, Haldol. The
bluntest assessment of the study came from Dr. David Healy, a senior
psychiatrist at Cardiff University in Wales. Healy is a former consultant to
AstraZeneca, among other pharmaceutical companies, and a prominent critic of
the industry. "This is a non-study of the worst kind," he said.
"It is designed not to pick up a difference between the three drugs. It
looks like an entirely marketing-driven exercise."
If these experts are right, then the study in which Dan Markingson committed
suicide was not simply a matter of inadequate informed consent, or financial
conflicts of interest, or even failure to monitor a subject's care. The ethical
breach was built into the study from the start. It is one thing to ask people
to take risks for science, or the common good, or to help other people. It is
another thing entirely to ask them to risk their lives for the marketing goals
of AstraZeneca.
Mary Weiss is a quiet woman, but her experience has left her angry and bitter.
It's not hard to see why. In the years since she lost her son, she has written
letters and filed complaints to one oversight body after the other, and so far
she's gotten little but form letters, rejections, and dismissals. "Well, I
don't think the loss can ever be replaced," her friend Mike Howard said in
his deposition. "There is probably not a day in Mary's life that she
hasn't thought about her son, and there is probably not a week goes by that she
doesn't shed tears." Mary told me that until she and I had coffee last
year in St. Paul, no one at the university had ever apologized or expressed
regret for her son's death. In fact, after Dan died, Mary received a plant with
a card from the CAFE study team. In words that echoed the bizarre, grisly
message in Dan's suicide note, the card read, "We will miss his
smile."
Of all the ways in which Mary Weiss has been damaged by the University of
Minnesota, there is one episode that still brings a sting of shame to my face.
When the lawsuit over Dan's death was dismissed, the university filed a legal
action against Mary, demanding that she pay the university $57,000 to cover its
legal expenses. Gale Pearson, one of Mary's attorneys, says that while such
suits are technically permissible, she had never seen one filed in her previous
14 years of legal practice. The university agreed to drop the lawsuit against
Mary only when she agreed not to appeal the judge's decision. "Maybe they
want to chill anyone who might think of challenging the university, even if her
child had died," Pearson said. "It gave me a sick
feeling."
Those interested in an investigation by a journalist of psychiatric
drug company research fraud are encouraged to obtain the Sept./Oct 2010 issue
of Mother Jones and read the
"Making a Killing" article here. Carl Elliott reveals how clinical
trials and even whole universities are manipulated by the pharmaceutical
industry.
A DECADE AGO, when the inspector general
of the department of Health and Human Services (HHS) investigated the
recruitment practices of pharmaceutical trials, researchers complained that
research sponsors were demanding unrealistically tight deadlines to enroll
subjects. Asked by the IG what sponsors were looking for in trial sites, one
researcher replied, "Number one-rapid enrollment. Number two-rapid enrollment.
Number three-rapid enrollment." Many researchers attributed the
unrelenting pressure to the fact that trials were being managed by business
people, not clinicians.
Over the past 20 years, medical research
has become a largely privatized, and thoroughly Taylorized, business.
Two-thirds of clinical trials are now privately run. Many trials are advertised
by patient recruitment specialists, carried out by "contract researchers,"
approved by for-profit ethics boards, and written up for publication by
commercial medical education agencies. The largest of the new private
industries are contract research organizations (CROS), which range from small
niche agencies to multinational corporations that manage all aspects of
clinical trials, from ethics approval and subject recruitment to the submission
of clinical data to the FDA. Quintiles, the company that managed the study in
which dan Markingson was enrolled, is the largest, with 14 percent of the $11.4
billion global market.
CROS save money for pharmaceutical
companies by deploying the principles of industrial management: breaking trials
down into narrow, discrete steps, which can be carried out with maximum
efficiency by specialized workers who can be paid relatively low wages.
According to Vanderbilt University social scientist Jill Fisher, author of
Medical Research for Hire, very little experience is required to be a CRO
"monitor" -- a middle manager, often a nurse, who coordinates the
various sites involved in a study. Monitors usually make less than their
counterparts at universities or pharmaceutical companies, and job turnover is
very rapid. Fisher says, "The goal of many monitors is to be hired by the
pharmaceutical industry."
In contrast, the private physicians paid
to supervise clinical trials are often very well- compensated. A part-time
contract researcher conducting four or five clinical trials a year can expect
to earn an average of $300,000 in extra income. Yet they generally have little
if any research training. They do not generate original scientific ideas,
design studies, or analyze the results. Their main role is to help recruit
subjects and oversee their trial participation.
Research subjects are the most highly
prized commodities in the clinical trials industry. Four out of five clinical
trials are delayed because of difficulties recruiting subjects. These delays
can be costly, as the patent clock on new drugs starts ticking as soon as the
patent is filed.
As CROS have discovered, many research
subjects can be persuaded to enroll because they have no health insurance or
because they are too poor to afford medication. (According to Fisher, a common
CRO term for these patients is "ready-to-recruit.") In the CAFE
study, for instance, a Quintiles study monitor suggested that each of the CAFE
study site coordinators try recruiting subjects at homeless shelters.
Nevertheless, early on the University of Minnesota trial site was apparently
struggling to keep subjects in the study.
"Having trouble with Subject
002," Jean Kenney, the university's CAFE study coordinator, wrote in a
January 2003 email to Quintiles. "His sister just died, his father has
terminal cancer and now the grandmother is sick. He missed a visit and now just
missed the next one." Another issue was slow recruitment. "Have had
another person show interest from inpatient and then the parent put pressure on
and said 'No' (third time this has happened)," Kenney wrote. The Quintiles
study monitor was consistently upbeat and encouraging. "Try not to get too
frustrated!" she advised. "Hopefully your hard work will start to pay
off soon!"
Many CROS market their ability to locate
subject populations that are "treatment- naïve," meaning patients who
have not yet been treated for their illness or who are not taking any other
medications. often treatment-naïve subjects are easier to find in poorer
countries, where trials can also be conducted with less oversight from the FDA.
In 2008, according to HHS, 78 percent of subjects enrolled in clinical trials
lived outside the United States, including 13,000 subjects in Peru, where the
FDA conducted no inspections.
CROS have been involved in some notable
clinical trial scandals. In the 1990s, Pharmaceutical Product development, or
PPD, one of the largest, was implicated in a notorious fraud scheme carried out
by Dr. Robert Fiddes, who used his Southern california Research Institute to
falsify records and invent patients while conducting trials for nearly every
major pharmaceutical company. In 2006, at a trial site at a hospital near
London, six healthy subjects nearly died after the CRO Parexel paid them 2,000
pounds each to become the first humans to test an experimental compound. In
2005, Bloomberg News reporters discovered that SFBC International Inc. was
paying undocumented immigrants to serve as drug guinea pigs in a converted
Holiday Inn. The Miami motel was subsequently demolished for fire and safety
violations, and the company changed its name to PharmaNet. In 2009, PharmaNet
was acquired by JLL Partners, a New York hedge fund.
Today, if cash-strapped academic centers
want to compete for the revenue generated by industry-sponsored trials, they
must play by new rules. Academic institutional review boards must approve
trials quickly to compete with for-profit IRBs (see page 63), and academic
study coordinators must recruit subjects quickly to compete with private trial
sites. The competition is even stiffer for academic physicians, many of whom
must generate part of their own university salaries by obtaining grants and
contracts from external funding sources. If academic physicians want to do
clinical trials for the pharmaceutical industry, they must compete with
contract researchers, who offer little to the body of science but carry out
industry-tailored trials efficiently. Such arrangements often reduce academic
physicians to little more than industry helpers, collecting data according to a
company protocol. All these factors, it seems, were at play in the study that
Dan Markingson was enrolled in when he died. -- C.E.
Profit pressures gut guinea pigs' only
safeguard: institutional review boards.
ESTABLISHED IN the 1970s in response to
scandals such as the Tuskegee syphilis experiment, institutional review boards
are the primary means of protecting research subjects in the United States.
Until recently, most IRBs were volunteer committees of clinicians and
researchers in the teaching hospitals and medical schools where the research in
question was being conducted. But as clinical research began to enter the
private sector, a new type of IRB emerged: independent boards that review
studies in exchange for a fee, promising a faster review. There are about 40
for-profit IRBs operating in the US, generating more than $100 million in
annual revenue. Some for-profit IRBs are professional and serious-minded, while
others present a more entrepreneurial face. Take Liberty IRB, a for-profit IRB
in Florida that boasts on its website that it is the winner of the 2008
"Make Mine a Million $ Business" competition, a contest described as
"a cross between The Apprentice and American Idol."
Paid by the companies whose protocols
they review, for-profit IRBs have a direct interest in keeping their clients
happy. If one for-profit IRB rejects a study as too dangerous, the sponsor can
simply send it to another one. defenders argue that companies have an interest
in getting a strict ethical review, if only to ward off potential litigation. But
recent events suggest otherwise. In March 2009, the government Accountability
office revealed the results of a sting operation it conducted on coast IRB, a
colorado outfit with more than $9 million in revenue in 2008. The GAO set up a
phony company testing an obviously dangerous "bogus medical device"
in a research protocol so "excessively vague" no reputable IRB should
approve it: The protocol lacked results from animal studies and didn't reveal
where the study would take place, or what institution would carry it out. The
principal investigator listed had an expired medical license; the only contact
information was a post office box and a cell phone number. Yet coast IRB
approved the product unanimously and deemed it "probably very safe."
According to the GAO, coast IRB had reviewed 356 research studies in five years
and rejected only one.
So are the old academic IRBs any better?
Located within academic health centers that now compete with contract research
organizations for clinical trials, they also face pressure to approve trials
quickly. As trials have become more complex, academic IRBs have become
expensive, costing an average of nearly $750,000 per year -- with some costing
more than $4 million. As a result, some universities are outsourcing reviews to
for-profit IRBs. others have decided to shift the cost back to the pharma
companies, like the University of Minnesota, which charges $2,500 to review
industry-sponsored studies. -- Carol Elliot
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According to PublicIntegrity.org, more than a third of pharmaceutical companies' resources go into promotion and marketing. 
The FDA also requires clozapine to carry five black box warnings for
When SSRI antidepressants such as
Prozac, Paxil and Zoloft were first introduced in the late 1980's and early
1990's there were reports of increasing violent behavior including suicide and
homicide. There were in 2003 reports by British authorities and the U.S. Food
and Drug Administration about unpublished studies showing an increased risk of
suicide in children and teenagers taking Paxil. Prior reports of suicidal and
homicidal acts in adults taking SSRIs have been minimized by the pharmaceutical
company defenders and mainstream doctors, who claim that suicide is common in
depression anyway.
In
summary the Fentress case was about a violent incident in September 1989.
Joseph Wesbecker armed himself with an AK-47, walked into the Louisville
printing plant where he had worked, and started shooting his former
co-workers. After killing eight people, wounded twelve more, and the man
finished matters by committing suicide with his gun. Only one month before,
Wesbecker had begun taking Prozac. The known problems of violent behavior
of patients on this medication had been withheld from the public, governmental
regulators and even medical professionals. The lawyers for the shooting
victims soon focused on the drug Prozac, manufactured by Eli Lilly, as the
cause for Wesbecker's unexpected violence. With the sales of the drug
Prozac at $1.7 billion in 1994 there was a lot at stake in this legal case. The
Plaintiff's counsel had information about the withholding of research findings
regarding another Eli Lilly drug Oraflex. In 1985, Lilly had pled guilty to
twenty-five criminal counts of failing to report adverse reactions to Oraflex,
including four deaths, to the Food & Drug Administration. But then suddenly
during the trial the Oraflex evidence was no longer going to be presented to the
court. 
There
was an experienced and astute Judge on the case, John Potter, who suspected
something was afoul despite the lawyers' denials and their references to a
damages phase, Judge Potter suspected that a deal had been made before closing
argument. When the plaintiffs didn't file a notice of appeal, Potter
became suspicious and thus called in the lawyers from both sides for
consultation. But the lawyers continued to deny that a settlement had
been reached. When the appeals court ruled against Judge Potter saying he
no longer had jurisdiction, Potter was not satisfied and appealed the case to
the Kentucky Supreme Court. Finally in a Supreme Court hearing, lawyers
for both sides finally acknowledged that they had indeed settled all money
issues and had agreed to go through only the liability phase of the trial no
matter what the result. Judge John Potter took the "high road,"
acting consistently with the judiciary's responsibility, and protecting the
public interest. Thus the role of the judiciary in deciding matters of
privacy and sealed records is an important balancing act of sometimes competing
interests but which must also take into account the public's right to know
especially when there is a compelling public interest. 
