http://www.propublica.org/podcast/item/dead-on-the-operating-table-a-qa-with-journalist-mina-kimes/
by Marshall Allen
ProPublica,
Nov. 27, 2012, 2:18 p.m.
MuckReads_Podcast.mp3
FiDA
highlight
When the multibillion dollar medical device maker Synthes
enticed doctors to use its bone cement on people’s spines, patients died on the
operating table. The company’s actions led to indictments and prison time for
executives.
Journalist Mina Kimes of Fortune magazine investigated how it
all happened, talking to doctors who performed the treatments, former company
employees and the families of patients who died. Her report, “Bad to the
Bone: A Medical Horror Story,” lays out in detail how the
company navigated around Food and Drug Administration rules meant to inform and
protect patients.
As part of our ongoing interest in patient safety,
ProPublica health reporter Marshall Allen interviewed Kimes at ProPublica’s New
York office for the #MuckReads
podcast. The interview has been edited for clarity and length.
ProPublica: You use the term “human experimentation”
to describe what was happening in this story. That sure gets people’s
attention.
Kimes: I think that’s what it
was. The company held unauthorized
clinical trials and released and promoted a product for a use that was
unapproved [by the FDA] without informing patients that the product was
unapproved. People participate in clinical trials all the time, but they do so
knowingly, and I think that's the core transgression here: Some people had knowledge and some
people didn't. And ultimately, the people who did not were the patients.
ProPublica: Tell us about the company
and the product.
Kimes: Synthes is a
Switzerland-based device company that was bought earlier this year by Johnson & Johnson
for about $20 billion,
the biggest acquisition in
J&J's history. Before they were acquired they developed a product
called Norian, which is a calcium phosphate bone cement. Many people described
the product as miraculous because it had properties that enabled it to stimulate
the growth of actual human bone. Norian was approved for use in the skull and
the arm.
The story is about the company’s efforts to
convince doctors to use the product in the spine as a treatment for vertebral
compression fractures – painful fissures in the spine that are a common side
effect of osteoporosis. But Norian
was never approved for vertebral compression fractures, and the FDA specifically forbade the
treatment. So over the course of a couple of years, the company made a
series of ill‑fated decisions that led to
them promoting it for that use even after some alarming scientific results and
patient deaths.
ProPublica: What happened when they
used Norian in the spine?
Kimes: Well, this is really
at the heart of what they did wrong: They never did a clinical trial on people. When a
medical device maker wants to introduce a device for a new purpose, there's a
variety of ways in which they can get approval for it. If it's an untested
high-risk device, often what they'll have to do is obtain something called Premarket Approval, or PMA,
which requires clinical trials. These trials can be long and costly.
Some employees estimated that it would take about three years and cost over $1 million. They
would have had to convince a large number of patients to do it. And they could
fail. One of the things that probably deterred them from doing the clinical
trials was that the company had not had a lot of success doing this in the
past.
The other way that you can get approval is to
establish similarity to an already approved device, which is the approach they
took. However, the approval that they got from the FDA said specifically that
they could not mix Norian with other materials, which is what they needed to do
for the spine treatment. The FDA later said this cannot be used to treat
vertebral compression fractures.
Between
2002 and 2004, which was when the illegal trials were going
on, there were three
deaths. The first one was a 70‑year‑old woman whose X‑rays, in a disturbing twist, were later
used in materials to promote the product. Then later on, an 83‑year‑old
man and an 83‑year‑old
woman died, both on the operating table. In all cases, the patients’ blood
pressure dropped extremely quickly and they were unable to be resuscitated.
Experts later theorized that the cement was
forming clots and causing blockages in the bloodstream. That's also what
happened in a completely separate animal trial conducted at the University of Washington,
where scientists injected the cement into a pig that also died for the same reason.
ProPublica: So they did not have
FDA approval, but still promoted it for use in the spine. How did the marketing
work?
Kimes: We’re talking here about off‑label marketing, an extremely common crime that’s led to huge settlements in recent
years for drug companies and device makers. Doctors and surgeons are able to
prescribe drugs and use devices in ways that they see fit. However, companies
cannot promote them to doctors and surgeons for the unapproved, off‑label
uses. As you can imagine this creates a bit of tension, especially when a company recognizes
that doctors might be interested in using it in an unapproved fashion, or there's a potential revenue stream.
So what we encountered in this story was that the
company expressed interest in this unapproved use, and it was documented that they promoted it for that
use. I interviewed many surgeons who were involved in the unauthorized clinical
trials. They told me that they talked to some of these sales representatives
about this unauthorized use, and that in itself is off‑label
marketing.
There are so many ways companies cross the line,
whether it's giving information to doctors, bringing these devices into certain
surgeries, or giving them instructions on how to use it. Synthes did all of
these things and more. In one case, during a training session with surgeons,
they explicitly showed them how to do this spinal procedure. They were giving
out materials that talked about the procedure. Some of the promotional
materials did not include the warning that the FDA had told them to include,
saying not to use Norian to treat vertebral compression fractures. So there were many ways in which
they committed the crime.
ProPublica: Did regulation fail, or did
they flout the regulation?
Kimes: I think they
definitely flouted the regulation. The question, I think, of whether or not the
regulations were strong or clear enough is a matter of dispute. The FDA had
issued a public warning about this procedure being off‑label.
There was some confusion amongst surgeons and the company about the label, and
I know from my interviews
with employees that they knew what they were doing was not right. That
said, there's still a lot of gray area.
ProPublica: How much influence do you
think the marketing has over physicians?
Kimes: I think there's a great
deal of influence. There has to be a confluence of factors. The appetite for
the product was already out there. This is a procedure that was growing in
popularity at the time. Plus, there was no clear treatment. Vertebroplasties
were being conducted using a different kind of cement that had a lot of
disadvantages. So there was certainly an audience for it. I imagine it was
quite convincing when surgeons
were presented with this miraculous‑seeming
product and not told about some of the issues, such as the scientific trials.
Also, many of the surgeons were flown out to training sessions where they had
dinners and golf outings and whatnot. And at those training sessions, they were
told all the good things about it and all the potential for it, and many walked
away thinking it was a really wonderful opportunity.
One of the most surprising things I learned while
reporting this story was that in all of these surgeries there was a sales representative from the
company in the room. I didn't know that before. And I think that's
emblematic of the
relationship between doctors and companies, which is intermeshed and in some
ways co-dependent.
ProPublica: What did this story tell
you in general about patient safety?
Mina: Much of this has to do
with knowledge. I mean,
when you make a health care decision, you should be equipped with the best
knowledge possible. This story was about the withholding of that knowledge at
many crucial points, but especially to these patients who died not knowing that
this product had been used in animal trials where there were very alarming
results, and not knowing that it wasn't actually approved for the procedure
that they were about to go into. The risks weren't properly communicated.
All the patients’ families maintain that they were
not told about the unapproved nature of the product, about the animal trials
and the risks associated with them. There were three deaths that took place
during the clinical trials, but there was another death that occurred in July of 2009 after the
company had been indicted. So if that particular family had simply known
the name of the product — and they say they weren't told the name — they
could've Googled it and seen a criminal indictment filed two weeks earlier.
Have you or a loved one been harmed in a
medical facility? Tell us about
it.
Have you worked in health care? Tell us
what you've observed about patient safety.
http://features.blogs.fortune.cnn.com/2012/09/18/synthes-norian-criminal/
September 18, 2012: 5:00 AM ET
When medical device company Synthes
decided to illegally test a bone cement on people, the results were disastrous.
A disturbing tale of corporate crime and punishment.
By Mina Kimes, writer
A colored CT scan of a single
vertebra (as seen from above) during a vertebroplasty. The term refers to a
procedure, used to treat compression fractures, in which a surgeon injects bone
cement (the white material coming out of the needle) into the spine to
reinforce the bone and prevent future damage.
FORTUNE -- On Nov. 16, 2011, Georgia
Baddley, a 70-year-old woman living near Salt Lake City, received a shocking
call from a special agent at the U.S. Department of Health and Human Services.
The agent told her that the government had come across new information about
her mother's death.
Baddley was speechless. Eight years
before, her 83-year-old mother, Barbara Marcelino, had unexpectedly died during
spine surgery. At the time, Baddley didn't question what had happened; surgery
was always risky for a woman of that age. She was horrified when the agent told
her that the surgeon had injected bone cement into her mother's spine and that
the product -- which was not approved for that use -- may have played a role in
her death.
The agent explained that the
government had filed criminal charges against the maker of the cement, a
company called Synthes, and four of its executives. After hanging up the phone,
Baddley sat in stunned silence. "I was taken aback," she says.
"I had no idea that anything like that had happened."
Most people have never heard of
Synthes, a medical device maker headquartered in West Chester, Pa. But the
company became part of one of the most recognizable names in health care in
June when Johnson & Johnson (JNJ)
completed the purchase of it for nearly $20 billion -- the largest acquisition
in J&J's history. Market watchers cheered the deal, which will expand the
company's stable of high-margin orthopedic products. J&J, which has endured
a series of reputation-sullying
recalls and lawsuits in recent years, specifically cited
Synthes's "culture" and "values" as evidence of its appeal,
even as former Synthes executives awaited sentencing on charges of grievous
conduct.
In 2009 the U.S. attorney in
Philadelphia accused the company of running illegal clinical trials --
essentially, experimenting on humans. Between 2002 and 2004, Synthes had tested
a product called Norian XR, a cement that has a unique capacity to turn into
bone when injected into the human skeleton. The Food and Drug Administration
explicitly told Synthes not to promote Norian for certain spine surgeries, but
the company pushed forward anyway. At least five patients who had Norian
injected into their spines died on the operating-room table. One was Barbara
Marcelino.
The indictment of Synthes and its
executives shook the health care industry. What occurred is a classic example
of corporate malfeasance, but set inside an insular corporation run by a
reclusive and autocratic Swiss multibillionaire, the provider of the largest
individual gift in the history of Harvard University. The case offers a rare,
sometimes disturbing, glimpse inside the shrouded world of medical devices,
where surgeons occasionally turn for advice during operations to
twentysomething sales representatives.
Most of all, this is a story about a
company that repeatedly ignored evidence of potential lethal consequences.
Interviews with more than 20 former employees and surgeons involved in the
Norian project, hundreds of pages of court transcripts, and company documents
submitted in the case reveal that Synthes not only disregarded multiple
warnings that it was flouting the rules, but also brushed off scientists'
cautions that the cement could cause fatal blood clots.
The Department of Justice targeted
four high-ranking executives, all of whom pleaded guilty to a misdemeanor under
an unusual provision of health care law called the Responsible Corporate
Officer Doctrine. They accepted responsibility for the company's crime of
running unauthorized clinical trials and for engaging in off-label marketing,
or promoting products for unapproved uses, without conceding that they were
involved in the crime. At the time, no executive had ever gone to prison for
such a charge. (Lawyers for the four executives declined to make their clients
available for interviews or to comment on the facts of the case.)
Off-label marketing is so common
among drug and device makers that it's often dismissed as the equivalent of
driving slightly over the speed limit. During the past decade, pharmaceutical
behemoths such as Merck
(MRK),
Pfizer (PFE),
Abbott Labs (ABT),
and GlaxoSmithKline (GSK)
have paid billions in fines to settle charges that they engaged in off-label drug
promotion. Yet cases continue to happen, in part because the
potential profits often exceed the fines.
But this wasn't the typical off-label
marketing case. Nor was it typical of trials for medical devices or drugs.
Patients sometimes die during such clinical trials -- but only after being advised
of the risks and then granting their consent. In hiding the unapproved status
of the cement, prosecutors argued, Synthes denied patients the right to choose
whether they wanted to be test subjects.
For the Justice Department, the
Synthes case posed an unprecedented opportunity. It could finally hold
individual businessmen accountable for their actions. Mary Crawley, the
assistant U.S. attorney who led the prosecution, urged the court to send the
executives to jail for their "venal crime." The "callous
disregard of patient safety," she argued, "warrants the highest
sentence the law will allow."
* * * * * * * *
Synthes is based about 25 miles west
of Philadelphia, but its roots lie in Switzerland. In 1958 four Swiss surgeons
founded a research organization devoted to their belief -- controversial at the
time -- that broken bones could be better fixed internally with implants. They
developed products, branded with the name "Synthes," that they
licensed to a pair of Swiss manufacturers.
In the 1970s one of the founding
surgeons bought an airplane from an enigmatic Swiss businessman named Hansjörg
Wyss (pronounced hans-yerg vees). The son of a mechanical-calculator salesman,
Wyss boasted a worldly résumé. He had worked in Turkey, Pakistan, and the
Philippines, and had graduated from Harvard Business School. When he met the
surgeon, he was working for a chemical company and selling planes on the side.
Wyss struck a deal to become head of Synthes's U.S. operation.
Wyss later became CEO of the entire
company and over the next 30 years built it into an industry giant that
specializes in making plates and screws to stabilize broken bones. Along the
way he became a multibillionaire, splitting his time in the U.S. among homes in
Pennsylvania, Martha's Vineyard, Mass., and Tucson. He was CEO until 2007 and
remained chairman of the company, which has 12,000 employees, until it became
part of J&J (where it's now in the renamed DePuy Synthes division). Last
year Synthes generated $4 billion in sales. Until the J&J acquisition, Wyss
and his family owned nearly 50% of Synthes's shares.
Wyss, 76, shuns the limelight.
Unassuming, with wavy gray hair and owlish glasses, he often wore baggy
corduroys to work and drove an old Volvo for years. Wyss has generally shied
away from the press, telling a Swiss newspaper in a rare interview last year,
"Nobody knows me, and I hope that it stays like this." In a phone
interview with Fortune, Wyss declined to comment on the central issues
in this article but did address several smaller points. A Synthes spokesperson
declined to discuss the Norian case.
Wyss donates heavily to
liberal-leaning nonprofits and in 2008 gave $125 million to Harvard to fund a
biological-engineering institute. An avid hiker and outdoor enthusiast, he has
poured millions of dollars into preserving land in the Rocky Mountain states, a
region he fell in love with as a student.
Former Synthes employees portray Wyss
as an intimidating, hands-on leader. Nisra Thongpreda, the manager first
assigned to the Norian project, would testify before a grand jury that
"for somebody who is at his level and his level of success, I would say he
has a surprising amount of contact with what's going on." (Her grand jury
testimony, like other such testimony mentioned in this article, was excerpted
in a public court filing; she did not respond to requests for comment.) Several
former Synthes staffers recall meetings where Wyss probed the minutiae of their
projects. "It would feel like he wasn't paying attention," says a
former employee. "Then, all of a sudden, he'd turn and raise a question
that was far in the weeds -- maybe the single dollar amount of something you
proposed."
Wyss's level of control could verge
past micromanagement. Several former employees say he wouldn't let the company
provide Internet access in the mid-2000s; workers who wanted to go online had
to sign in to a single computer in front of everyone. Maria Maccecchini, who
was president of biomaterials at Synthes for eight months in 2004, says the CEO
was fixated on the brand of toilet paper used in company restrooms, the color
of the desks, and the shape of the plates in the cafeteria (he insisted that
they be square).
One former employee recalls how, as
he was walking into Synthes's headquarters on a fall day, he saw Wyss hunched
over in the foyer. The CEO was picking up leaves off the floor, one by one, and
then putting them outside.
* * * * * * * *
In the late 1990s a fledgling biotech
company called Norian popped up on Wyss's radar. The startup, based in
Cupertino, Calif., had developed a calcium-phosphate-based cement, also called
Norian, with almost miraculous qualities. When implanted in the skeleton, the
cement not only fills cracks but also gradually transforms itself into actual
human bone.
Synthes bought the company in 1999
for about $50 million. At that point Norian had already obtained FDA approval
to market two versions: Norian SRS, for use in the arm, and Norian CRS, for use
in the skull.
There was a third potential
application for the cement -- one that Synthes executives hoped could be
extremely lucrative -- and it's this use that would eventually prove
disastrous: filling fractures in the spine. In the 1990s specialists were
increasingly touting the benefits of a procedure called a vertebroplasty. To
perform the surgery -- typically done to treat vertebral compression fractures,
or VCFs, a common side effect of osteoporosis -- surgeons inject cement into
the spine. At the time, the procedure was performed with acrylic cement, which
contained a material used to build aquariums. Norian, with its unique
properties, seemed like a superior alternative.
When Synthes acquired Norian, the
company did not yet have permission to sell it for use in the spine. As is true
any time a company wants to market a high-risk medical device (and under FDA
rules, the cement was considered a device) for a new purpose, Synthes would
have to convince regulators that the new use was safe and effective.
The government's response was
discouraging. An FDA representative told Synthes in a conference call that it
would "almost definitely" need to pursue a path that typically
necessitates clinical trials, according to minutes of the call. To do that, the
company would have to obtain an Investigational Device Exemption, or IDE, from
the FDA. (In FDA jargon, the "exemption" grants the manufacturer the
right to conduct human tests.) Then Synthes would have to persuade a large
number of patients to undergo experimental treatment and conduct a lengthy and
expensive clinical study.
Instead of preparing a clinical
study, Synthes made the first of a series of fateful choices, deciding to
launch right into market research. In February 2000, Wyss announced at an all-hands
meeting that there would be a strong push for vertebroplasty, according to
factual findings by the judge in the criminal case. In March, employees in
Synthes's spine division began interviewing spine surgeons about Norian. Their
report, which was shared with executives, pointed out that Americans suffer
more than 500,000 VCFs each year and that the "market potential" was
"considerable." It concluded, "There is excitement about using
Norian for vertebroplasties."
Whispers of the project began spreading,
prompting the first -- but not the last -- alarm within Synthes. A strait-laced
regulatory staffer named Michael Sharp was appalled when he learned, in a
chance conversation, about the plan to promote Norian. Companies are explicitly
barred from marketing products for uses that haven't been authorized by the
FDA. Even mentioning unapproved uses to surgeons is prohibited.
Sharp fired off an e-mail to Tom
Higgins, the president of Synthes Spine, and Richard Bohner, vice president of
operations at Synthes, expressing his concern that the company was testing
Norian without going through the proper channels. "Regulatory is unaware
that this is even being considered," he wrote.
Higgins met with Sharp. The
regulatory staffer says he made it clear that Synthes employees shouldn't
discuss Norian with spine surgeons. Higgins assured him, Sharp recalls, that
the company wasn't going to promote the product for use in the spine. "At
that point," says Sharp, "I thought the issue was entirely put to
bed."
But the project didn't die there. In
February 2001 a surgeon in Santa Monica used Norian to perform two procedures
on elderly patients with vertebral compression fractures. In both cases,
according to company documents, the patients experienced rapid drops in blood
pressure shortly after the surgeon injected the cement, and an anesthesiologist
had to administer drugs to keep them from dying.
When Sharp learned about the
surgeries, he e-mailed Bohner again. Bohner alerted his boss, Michael Huggins,
the head of Synthes's North American division, who sent a cautionary message to
the sales force about the dangers of off-label marketing. Prosecutors would
later dismiss Huggins's e-mail as "anything but strongly worded" and
"confusing at best."
Despite the warnings, the
vertebroplasty project rolled on. Sharp left the company for reasons, he says,
having nothing to do with Norian. In April 2001, Higgins organized a focus
group in Cupertino with surgeons who were interested in using Norian to treat
VCFs. The doctors discussed the operations that had gone wrong in Santa Monica,
according to minutes of the meeting. Dr. Sohail Mirza, a surgeon at the
University of Washington, suggested that Norian could be causing problems if it
entered the bloodstream. The spine contains multiple blood vessels, and any
leakage into them could send cement to the lungs and heart, causing a fatal
clot. Mirza said it was critical that Synthes conduct an animal study before
using Norian in human patients. The company agreed to fund a small study.
Meanwhile, Synthes's top brass was
scheduled to meet with Wyss in November to decide whether to proceed with plans
to sell Norian for use in the spine. A few weeks before the meeting, Higgins
asked a regulatory employee to mock up a clinical trial for using Norian in
vertebroplasty. The staffer estimated it would take three years and cost about
$1 million. He told Higgins that Synthes needed government approval to test
Norian on people -- a fact that was common knowledge, according to prosecutors
and several former Synthes employees.
That November, Huggins, Higgins, and
their colleagues met with Hansjörg Wyss in Tucson. It was judgment day for the
vertebroplasty project. The attendees discussed the prospect of doing a
clinical study, according to the meeting's minutes. Then Higgins asked whether
Synthes should get an IDE and conduct trials.
The answer, according to the minutes,
was no: "Decision made not to pursue an IDE study, but to get a few sites
to perform 60-80 procedures and help them publish their clinical results."
No explanation was mentioned. Synthes wasn't taking the onerous -- but expected
-- route of getting an IDE. Instead, it would get a few doctors to do the
procedure on their own, which the company hoped would popularize the product.
It was, prosecutors later alleged, an end run.
The implications of the minutes are
clear. But their passive construction raises a question. "Decision
made" -- by whom? Nisra Thongpreda, the manager in charge of Norian, later
told a grand jury that Wyss had made the call. (Wyss declined to comment.)
Prosecutors, who never charged her, asked how she knew it was the CEO. "Because
I was there at the meeting," Thongpreda said. She later added, "Tom
Higgins asked Mr. Wyss … about the IDE study and Mr. Wyss said no."
The prosecutor pressed for more.
"Was that about it -- just no?"
"Just no," said Thongpreda.
* * * * * * * *
Former employees describe Synthes as
highly regimented -- the kind of place where employees do what they're told.
"Everybody's just a sort of a worker bee," says one former staffer.
Wyss was known for handpicking young executives, typically men who had gone to
top-notch schools, and guiding their careers. Several former employees say
Huggins and Higgins, who had attended, respectively, Wharton and Harvard,
belonged to that group. "He picked these guys and cultivated them,"
says a former Synthes manager. "They were all fiercely loyal."
They also knew, former staffers say,
that the man everyone called "Mr. Wyss" didn't tolerate dissent.
Several recall a story, well known at Synthes, about the CEO attending a
meeting at a Marriott hotel. Wyss asked a hotel employee for a banana. When the
worker ignored his request, Wyss was "boiling," says a former
employee who was in the room. Days later the company announced that henceforth
Synthes employees could not stay at Marriott hotels. (Wyss says he banned the
chain because it didn't donate the leftover food from Synthes's meeting to a
homeless shelter.)
Wyss had rejected clinical trials.
But there was a less-demanding form of regulatory approval, a process intended
for modifications of permitted devices. Synthes applied for this type of
approval and sure enough, in December 2001, the FDA blessed the use of Norian
in the spine. But there was a crucial caveat. The FDA said that Norian could
not be mixed with another substance before it was injected into the spine --
which is precisely what vertebroplasties require. (Defense attorneys would
later assert that the FDA's language was confusing.)
The general clearance effectively
prohibited Synthes from promoting Norian for vertebroplasties -- but did give
it a foot in the door to spine surgeons' operating rooms. It's almost as if, to
use a benign analogy, Synthes bought nosebleed tickets to a football game and
then tried to sneak into the VIP section.
In the spring of 2002, Thongpreda
received an unsettling e-mail from Dr. Jens Chapman, an orthopedic surgeon at
the University of Washington who was working, along with his colleague Mirza,
on the animal study funded by Synthes. The early results were alarming. Chapman
informed her that when Norian was injected into the bloodstream of a pig, "the
entire pulmonary artery system had clotted off." As he put it, "We
were expecting to kill the pig … but not suddenly and with a relatively small
dose." (Chapman declined to comment; Mirza did not respond to requests to
be interviewed.)
Over the next few weeks, according to
prosecutors, top executives at Synthes held a series of meetings about Norian.
On May 13, 2002, Huggins and Higgins met with Wyss and decided to proceed with
their plan to informally test it for vertebroplasties. On May 22, Huggins and Higgins
met again. This time there was "high concern about SRS in spine test
market," according to a document assembled by an employee who didn't
attend the meetings. On May 28, Huggins spoke with Wyss, and they
"agree[d] to go ahead with Vertebroplasty Test Market."
Then, a couple of days later, the
whole project almost blew up. One of Synthes's medical consultants at the time
was an orthopedic surgeon named Ken Lambert. An old friend of Wyss's, Lambert
had been doing work for Synthes for decades, even briefly sitting on the
company's board. One afternoon he was in Synthes's offices when he stumbled
across a box of Norian. Lambert noticed that the shipping label was addressed
to a spine surgeon. "I was starting to smell a rat, so I said, 'Let's open
it up,' " he says. "And there it was: directions on how to mix
it." Lambert called Huggins, who assured him he would look into the
matter.
Huggins was shaken. On May 30, 2002,
he e-mailed Higgins and Bohner and told them he had talked to Lambert and was
having "second thoughts" about the plan to promote Norian. "We
discussed about the need to perform a real study to test Norian," he
wrote. "It seems Spine is bypassing the needed blocking and tackling
without thinking this all the way through."
Huggins's apparent crisis of
conscience caused a stir in the lower ranks. By then Thongpreda had transferred
responsibility for the project to Josi Hamilton, a 26-year-old product manager.
Hamilton was rattled. She began assembling a timeline that would document the
internal approvals, hoping it would protect her if she got into trouble.
For a moment it seemed as though
Huggins might kill the vertebroplasty project. But then, without any sign of
explanation in the record, he let the issue drop. An internal e-mail shows only
that the executive met with Wyss a few days after expressing his doubts.
Lambert, meanwhile, was still
spooked. On June 10, 2002, he sent a late-night e-mail to Thongpreda. "In
my respectful opinion, giving SRS directly to a surgeon for him to use without
any protocol [control] is not a controlled study; given the other issues I have
mentioned, this action amounts to human experimentation whose only defense seems
to be that it will be a small study," he wrote. He forwarded the e-mail to
Huggins and Higgins, adding that the company could "suffer serious
consequences" if it didn't conduct proper studies.
The next day Lambert forwarded the
e-mail to his old friend Wyss. "Dear HJW," he wrote. "I'm never
sure what information gets to your level but some things have happened recently
that could have serious consequences. If you are aware of all of this, then the
system works."
Lambert was the second person to
explicitly caution the company against testing Norian for unapproved uses. But
like Sharp's earlier warnings, Lambert's went unheeded. He says he didn't hear
back from the CEO, and his phone calls went unanswered. Eventually, Lambert
says, Wyss contacted him -- to inform him that Synthes would not be renewing
his contract. (Wyss says the contract ended for unrelated reasons.)
Two weeks later Jens Chapman and his
colleague sent the final results of their study to Higgins. The first test
involved mixing Norian with human blood in test tubes, then watching how
quickly clots formed. The scientists noted that "a relatively small amount
of Norian results in the formation of a very large volume of clot," which
could block the flow of blood inside the heart or lungs.
The final word on the pig test was
equally worrisome. The surgeons had injected Norian into a large vein leading
to the animal's heart to simulate what would happen if the cement leaked during
vertebroplasty. The pig's blood pressure plunged. When the scientists cut into
it after its demise, they noted that volumes of blood clot containing Norian
had amassed in its lungs. The animal had died in less than 30 seconds.
* * * * * * * *
The FDA does not regulate doctors'
activity; as a result, off-label prescribing is ubiquitous. A 2006 study in the
Archives of Internal Medicine examined hundreds of millions of
prescriptions and found that more than 20% were written for off-label use.
"A surgeon can prescribe anything," says a former Synthes employee.
"If he says, 'Let's put a bowling ball in your body,' he can do it."
Physicians are quick to note that, because the FDA's approval process can be
frustratingly slow, off-label drug and device usage is a crucial part of health
care.
Surgeons regularly use devices in
unapproved ways. The culture of orthopedic surgeons is particularly aggressive.
Predominantly male, "orthopods" are the jocks of the surgical world.
Sales representatives tell stories of doctors playing loud rock music in the
operating room and throwing instruments at the wall when they get frustrated.
Several surgeons tell Fortune they simply don't have time to pore over
labels. Lambert offers a blunt appraisal: " 'Off-label' is not at all a
pejorative term -- it's almost the opposite. Reading the label is for people
who read labels."
Surgeons don't always listen to the
FDA, but they do heed the young sales representatives who bring them devices
and routinely watch them operate. "It sounds ridiculous, because here's a
guy who went to medical school and did his residency, and he's listening to
some guy in the back of the room," says one former Synthes salesperson.
Another adds: "It's not uncommon to have a surgeon with a drill in his
hand, about to drill a hole, looking over his shoulder at you saying, 'Is this
right?' "
In the summer of 2002, Hamilton, the
young Norian product manager (who had recently graduated from business school),
began training spine surgeons to mix SRS with barium sulfate in order to
perform vertebroplasties -- an act explicitly prohibited by the label. During
this preliminary trial, which Synthes employees called "test market phase
1," a select group of surgeons conducted several dozen surgeries using the
mixture, SRS-R.
Hamilton later testified that she
knew she was on thin ice. The FDA's warning was unambiguous: They weren't
supposed to talk about mixing SRS. But whenever they brought up their concerns
with their managers, they were assured that everything would be fine. Hamilton,
who was later granted immunity from prosecution in exchange for her
cooperation, explained that it was understood at Synthes's spine division that
off-label marketing was the status quo: "This is the way that it's done.
And it happens every day."
The SRS-R test market proceeded
successfully. Dozens of surgeries went off without a hitch, and Synthes was
ready to move on to phase 2. That September, Hamilton gave a presentation to
several executives -- including Wyss -- about the vertebroplasty project.
"Wyss inquired about the test-market setup and how surgeons, who are
interested in the product, were to be trained," the minutes of the meeting
stated.
That winter, employees in the
regulatory division were tasked with getting the FDA to approve the mixed
version of Norian, rechristened as Norian XR, for general use in the spine. It
was a touchy subject. The FDA had recently issued a public notification that
stressed the off-label nature of vertebroplasties. In December 2002 it approved
the mixed version. But Synthes was still stymied: The FDA ordered it to include
a warning on its label that said XR should not be used to treat vertebral
compression fractures.
The fact that Synthes couldn't
promote XR for its target market didn't seem to bother its executives. Higgins
sent the vertebroplasty team a celebratory e-mail. "Let me take a moment
to congratulate the four of you [on] getting XR approved," he wrote.
"Very Well Done!"
Less than a month later Dr. Barton
Sachs, a spine surgeon in Texas, used Norian to treat a VCF. His patient, a
70-year-old Oklahoma native named Lois Eskind, said beforehand that she was in
excruciating pain and that she'd "rather have surgery than live like
this." Fifteen seconds after Sachs injected the cement into her spine,
Eskind's blood pressure plummeted. As a Synthes sales representative looked on,
Sachs attempted to resuscitate her for 30 minutes before she died. (Sachs
declined to comment.)
Hamilton and Thongpreda called the
doctor to find out what had happened. Sachs said he didn't know the cause of
death; the family had not requested an autopsy. He didn't blame Norian, but he
was concerned, according to minutes of the call: "He did the technique the
way he was supposed to and the outcome was catastrophic."
Whenever a death or injury occurs
that may implicate a medical device, the manufacturer is obligated to report
what happened to the FDA. Synthes did not report Eskind's death. According to
an internal document, the company's regulatory staffers decided that, because Sachs
didn't conclusively blame Norian for his patient's death, they didn't have to
send a report.
If Synthes staffers were disturbed by
Eskind's death, they didn't show it. That month a group of employees met to
discuss a sales plan for Norian. The document they put together predicted
revenue of at least $20 million by 2005, with after-tax profit margins of 50%.
In mid-August, Hamilton and her team
launched the next phase of its test market with a surgeon forum in San Diego.
Spine doctors from around the country flew in (their travel expenses were paid
for by Synthes, which also organized a dinner and golf outing). Hamilton handed
out binders of information about Norian XR, her business cards tucked inside.
Sachs delivered a keynote address. There was a training session where surgeons
practiced injecting XR into the vertebrae of cadavers. "The takeaway from
the course was that this stuff is safe, and it works, and there's very little
downside risk," says one of the surgeons Synthes trained.
For the moment everything seemed to
be going fine. The forum was a huge success. Several surgeries went smoothly.
Then, on Sept. 19, disaster struck again. Dr. Paul Nottingham, a surgeon based
outside San Francisco, was operating on Ryoichi Kikuchi, an 83-year-old prize-winning
physicist. Shortly after Nottingham injected him with XR, Kikuchi's blood
pressure sank. The doctor couldn't resuscitate him, and he died on the table.
Nottingham couldn't ascertain why his
patient had died, and Kikuchi's family didn't request an autopsy. But unlike
the previous surgeon to lose a patient, Nottingham was quick to point a finger
at Norian, which had apparently leaked during the operation. When Hamilton
called Nottingham to discuss what had happened, the surgeon erupted. "He
claimed the sales consultant 'pushed' this product on him and was unclear as to
its status on the market," she wrote in minutes of the call. This time
Synthes did file a report to the FDA. But it was vague and left out key
details.
Nottingham asserts that the company misrepresented
the product to him. "Synthes is very much to blame for pushing a product
that they didn't have the indications [i.e., approvals] for," he says,
adding that he never used Norian again. "I used it once -- that was
enough."
Hamilton also called Nottingham's
partner, Dr. Hieu Ball, to discuss what happened. Ball had more experience with
Norian; according to prosecutors, he had assisted on one of the failed
surgeries that took place in 2001 in Santa Monica. He had also performed five
operations using Norian, Hamilton wrote. "Based on his own
experience," she added, "he will continue to use XR."
In December 2003, John Walsh, who had
just become head of regulatory affairs at Synthes Spine, signed off on Norian
XR's technique guide, a brochure that was given to surgeons. The guide omitted
the warning that the FDA had ordered Synthes to include on the label, which
said that Norian shouldn't be used to treat VCFs.
It also included two "case
examples" -- real X-rays of anonymous patients who had had surgeries with
Norian. One of the X-rays belonged to a 41-year-old male. The other came from a
70-year-old female. The female, prosecutors later revealed, was Lois Eskind.
Unbeknown to the surgeons who received the brochure, the case study came from a
woman who had died after being injected with Synthes's product.
* * * * * * * *
On Jan. 21, 2004, Barbara Marcelino
checked into a hospital near San Francisco for spine surgery. Her daughter,
Georgia, called her that evening to see how she was doing. Georgia had wanted
to fly out for the surgery from her home in Salt Lake City, but her mother
insisted that she didn't have to because it was an "easy" procedure.
"She said, 'I think this is going to help me a lot and make me feel a lot
better,' " recalls Georgia.
Their conversation was light.
Marcelino, an avid reader who enjoyed Proust, complained about the Stephen King
novel she was reading. Petite, with soft white hair and a small, heart-shaped
mouth, Marcelino fretted about spilling a glass of water in her hospital bed.
Her surgeon was Hieu Ball. At 10:30
that night, according to prosecutors, Ball started to operate. A Synthes sales
representative -- the same one who witnessed Kikuchi's death -- was in the
room. Ball injected the cement into Marcelino's spine at 11:10 p.m. Her blood
pressure immediately plummeted. At 11:12, Ball attempted CPR. At 12:12 a.m.,
Marcelino was pronounced dead. An autopsy later revealed foreign material in
the blood vessels in her lungs, though the results were inconclusive because of
the prolonged CPR.
Ball declines to comment on why
Marcelino died. He says he was unaware of Synthes's animal studies involving
Norian and believes he used Norian in an approved manner. "We were using
it based on the recommendation of the company." (Ball's lawyer adds that
"of the 20-30 times he used Norian, there was only one instance of
complication.")
When the company received news of
Marcelino's death, Hamilton quickly drafted a letter to surgeons that stated,
"Synthes is stopping the distribution and usage of Norian XR." Her
letter was never sent. Instead, Walsh, the spine division's new regulatory
chief, helped put together a different letter for surgeons. This version simply
stated that "deaths have been reported." Norian, it said, should not
be used to treat VCFs -- but Synthes would "continue to explore new
approaches to the treatment of vertebral compression fractures." The
letter did not mention a recall, and Synthes continued to sell Norian.
Rumors about the deaths quickly
spread at headquarters, and staffers began to panic. Then, on the morning of
May 11, 2004, the project finally imploded. Capt. Joseph Despins, an FDA
investigator, arrived at Synthes headquarters and announced that he had
received a tip that the company had engaged in off-label marketing.
Over the next month, Despins
conducted a series of interviews. Synthes's staffers denied almost everything.
Bohner said he knew nothing about a vertebroplasty test market for SRS.
Hamilton disputed having encouraged surgeons to use Norian off label. Huggins
told Despins that he didn't recall what was discussed at meetings.
Despins didn't buy it. His 143-page
inspection report concluded that the company had violated FDA rules. Synthes,
he wrote, should have applied for an IDE before testing Norian. Despins accused
the company of off-label marketing.
Around the same time, Chapman -- the
surgeon who had conducted the study in which a pig had died only seconds after
being injected with Norian -- came back into the picture. (It wouldn't be the
last time.) The surgeon wrote a letter at Huggins's behest that defended the
cement, according to prosecutors. They later pointed out that Chapman had
recently been named to the Hansjörg Wyss chair at the University of Washington,
which received a $2 million endowment from Synthes's CEO. The prosecutors
concluded: "So we submit the letter should be taken with a grain of salt."
* * * * * * * *
It took nearly five years of FDA
proceedings, investigation, and grand jury hearings before federal prosecutors
were ready to move. By 2009 they were prepared to indict not only Synthes but
also four individuals: Huggins, Higgins, Bohner, and Walsh. The executives'
attorneys negotiated a deal in which the men would plead guilty to a
misdemeanor under the Responsible Corporate Officer Doctrine. The U.S. Supreme
Court has ruled that the Food, Drug, and Cosmetic Act allows prosecutors to charge
individuals who lack actual knowledge of a crime simply because they are
"standing in a responsible relation to a public danger."
When Synthes was charged, as noted
earlier, the doctrine had never been used to send an individual to prison. Most
people expected the four executives to receive fines, or possibly probation.
On June 16, 2009, the grand jury
handed up an indictment against Synthes and the executives. It was a doozy.
Norian, the company, was charged with 52 felony counts, including lying to the
FDA and intent to defraud. Synthes, its corporate parent, was charged with 44
misdemeanors. Though the U.S. attorney's office charged the four businessmen
with just a single misdemeanor for their roles as "responsible corporate
officers," it outlined in excruciating detail the history of the Norian XR
test market and deaths. The U.S. attorney's office issued a press release
peppered with lurid details, including the allegations that Synthes had
performed "human experimentation."
The defense attorneys were furious.
They believed they were the victims of a bait and switch. In their view, their
clients had agreed to take general responsibility for their company's actions
only to find themselves charged with a litany of misdeeds -- without any need
for the prosecutors to prove that the executives had committed those acts.
There was no reason, they argued, that the judge should consider the
prosecution's allegations in his sentencing decision.
The assistant U.S. attorney who
prosecuted the case, Mary Crawley, disagreed. Just because the government
didn't have to establish that the executives were involved in the crime didn't
mean it couldn't do so if it wanted, she argued. In a filing, she wrote:
"[The] four individuals seek to transform the responsible corporate
officer doctrine from a sword intended to achieve maximum adherence to the
U.S.' food and drug safety laws into a shield insulating the genuinely culpable
parties from the consequences of their own intentional wrongdoing."
The war between Crawley and attorneys
for the executives raged on for two years. Meanwhile, in October 2010, Synthes
pleaded guilty, agreeing to pay $23 million in fines and divest Norian. In
exchange, the Justice Department promised not to bring any new criminal charges
against Synthes employees.
That included Wyss. He was not
charged in the indictment, but he was mentioned. The prosecutors cited
"Person 7" as making the initial decision not to pursue an IDE study.
A key on the last page identified Person 7 as Synthes's "CEO and major shareholder."
The U.S. attorney's office declined to comment on why it didn't charge Wyss,
but the answer may be simple: The CEO's name appears multiple times in e-mails
and meeting minutes, but only as a recipient and attendee. Wyss's name also turns
up in documents less and less as events reached their peak.
Around the time of the guilty plea,
Synthes was quietly exploring a sale. In late September 2010, Wyss met with top
executives from Johnson & Johnson, including Alex Gorsky,
then head of its medical devices unit and now its CEO. The company saw the
opportunity to achieve dominance by buying one of the highest-margin players in
a growing market. Seven months later, on April 27, 2011, J&J announced that
it was buying Synthes for about $20 billion. (J&J declined to comment for
this article.) The deal, which formally closed in June 2012, valued the Wyss
family stake at about $10 billion.
* * * * * * * *
In Nov. 21, 2011, the four Synthes
executives appeared for sentencing in a federal courthouse in Philadelphia.
Huggins went first. His lawyer touted Huggins's devotion to his family and his
community service. The judge, Legrome Davis, told Huggins to stand, and the packed
room fell silent.
Huggins's conduct, the judge said,
was "egregious" -- so egregious that he was going to send him to
prison for nine months. "I think that a lesser sentence would not speak to
the harm that has been done here," Davis said. It was the first time in
his 25-year career, he continued, that he had sentenced someone above the
federal guidelines, which suggested Huggins get no more than six months in
jail.
"But I do it because it is
necessary," he boomed. "Because what has occurred in this case, in
terms of wrongfulness -- it's 11 on a scale of 10." Davis denied Huggins's
request that he be allowed to turn himself in later. Instead, as his wife and
daughters watched, Huggins was placed in handcuffs and led directly into
custody.
Davis sentenced the next executive,
Higgins, to nine months. The third man to face the judge was Bohner. His
lawyer, Brent Gurney, took a surprising tack when asked about Bohner's guilt.
"There is another person who is not present in this process who may have a
bearing in answering your question, Your Honor," he said. That person, he
continued, was none other than the man who ran Synthes during the illegal
clinical trials: Wyss.
It was Wyss, Gurney continued, who
made the initial decision to test the bone cement without doing proper clinical
trials. It was Wyss, he charged, who created a corporate culture where people
could not "stand up and stop things that were wrong, especially when they
were coming from the top." Gurney cited Synthes employees who told the
grand jury that the chairman was "hands-on," "forceful,"
and an "800-pound gorilla" who refused to brook dissent.
Davis seemed unconvinced. Then, just
as the judge was laying into the executives' "shameful behavior," the
confrontation took a bizarre turn: Gurney suddenly collapsed, hitting his head
on a table as he fell. For a moment he lay on the floor, bleeding. When he
regained consciousness, the lawyer -- who declined to discuss the episode --
was taken to a hospital. The hearings continued, and the judge sentenced the
fourth executive, John Walsh, to five months.
Gurney recovered and returned to
court in December for his client's rescheduled hearing. This time he made no
mention of Wyss, and Davis sentenced Bohner to eight months. Gurney asked if he
could delay Bohner's sentence so that his client wouldn't have to spend the
holidays in a detention center. Davis said no. "To me, jail is not a
question of personal convenience to the defendant," he said. "In the
scheme of things, it's an incredibly brief sentence." He sent Bohner
straight to prison.
* * * * * * * *
The jail sentences in the Synthes
case stunned the industry, sparking fears of increased risk for executives.
Some defense lawyers warn that the government's strategy could backfire.
"Now that executives realize that they may be facing real jail time, they
may be reluctant to plead guilty," says Adam Hoffinger, the attorney at
Morrison & Foerster who represented Tom Higgins.
Government lawyers counter that
prosecuting individuals is the only way to stop off-label marketing, because
companies have come to view fines as a cost of doing business. As a result, the
Responsible Corporate Officer Doctrine, which was mostly dormant throughout the
1990s, is resurgent. In 2007 the government used it to pursue charges against three officials
at Purdue Pharma. In 2011 the former CEO of KV Pharmaceutical
was sentenced to 30 days in jail. The Justice Department used the Synthes case
to send a message: The threat of incarceration is real.
As for the convicted former Synthes
executives, Walsh was released from a Pennsylvania prison camp in late April
after serving a five-month sentence. Huggins, Higgins, and Bohner were all
released at the end of the summer.
Synthes itself suffered little from
the Norian debacle. After settling with the government, the company sold the
bone cement unit to Kensey Nash, a small manufacturer located just down the
road, for $22 million (just $1 million less than its fine). Today J&J's
DePuy Synthes unit is the product's exclusive distributor.
* * * * * * * *
The civil litigation over Norian is
far from over. The families of Barbara Marcelino and Ryoichi Kikuchi jointly
sued Synthes, the four executives, and Wyss. Their lawyers, Greg Rueb and
Joseph Motta, called the defendants' conduct "reprehensible, despicable,
deceptive." Wyss's attorney has filed a motion to dismiss the suit,
arguing that the families "failed to allege any specific facts indicating
that Wyss had any personal involvement" in the purported crime.
Eskind's daughter, Eva Sloan, filed
suit against Synthes in late July. "One of the most offensive things was
the little piddly sentence they got for this," she says. "They could
have gone to 7-Eleven and stolen a six-pack of beer and got more time."
Like the Kikuchi and Baddley families, the Eskinds say they were kept in the
dark about the circumstances of their relative's death for nearly a decade.
These disasters didn't put an end to
the use of Norian in the spine. Three years ago, an article in the New
England Journal of Medicine concluded that vertebroplasties are basically
ineffective. But many spine surgeons still believe in the procedure.
In June of this year, another death
came to light. A man from Enumclaw, Wash., named Russell Bryant filed a suit
against Synthes alleging that his wife, Joan Bryant, had died after being
injected with Norian. This lawsuit described events similar to the others, but
with a troubling twist: Bryant's surgery took place on July 6, 2009 -- three
weeks after the government had filed charges against Synthes. Even more
shocking, one of the two surgeons named in the complaint was Jens Chapman, the
same person who had studied Norian in the early 2000s and observed the rapid
death of a pig injected with the cement. (Chapman's lawyer declined to
comment.)
The complaint's version of the facts
is as follows: Chapman first attempted surgery on June 29, 2009. After he
started operating, Bryant began bleeding profusely and had to be transferred to
the intensive-care unit. On July 6, Chapman tried again (according to a report
filed by the company, a Synthes sales representative was in the operating
room). After Chapman injected Norian into Bryant's back, she experienced
cardiovascular collapse and died.
Bryant's suit asserts that his wife,
who was 58, was healthy when she went into surgery. She reported on a hospital
questionnaire that she "felt full of life, felt calm and peaceful and felt
happy all the time."
A few weeks after Bryant's death, two
reports were submitted to the FDA. One described a fatal surgery that took
place on July 6, 2009 -- Bryant's death, according to the complaint. The other
report recounted a death that had occurred nearly two years earlier, on Aug.
17, 2007. It stated that a woman injected with Norian had died during spine
surgery; an autopsy found cement fragments in her lungs.
The belated timing of the second
report caught the attention of Bryant's lawyer, Dan Hannula, who suspected that
Chapman had submitted both notifications. With the help of an investigator,
Hannula found a woman from Enumclaw whose operation and death matched the
description in the report. Reba Golden died on Chapman's operating table on Aug.
17, 2007, according to her daughter Cindy. She was 67. Until this summer, Cindy
says, she had no idea that Norian might be implicated in her mother's death.
She plans to sue.
--Reporter associate: Doris Burke
This story is from the October 8,
2012 issue of Fortune.
Posted in: bone cement,
criminal trials,
Hansjörg Wyss,
medical device
makers, medical lawsuits,
Norian,
Synthes
No comments:
Post a Comment