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MAMIE
JOHNSON: I'm a
very angry woman that this medicine have destroyed my health.
ANNOUNCER: Each year, toxic side effects from
prescription medicines injure tens of thousands of Americans, and sometimes it
becomes big news.
NEWSCASTER: Tonight, one of the most popular drugs taken for allergies-
NEWSCASTER: -is being pulled off the shelves in the U.S.-
ANNOUNCER: Since 1997, over a dozen drugs had to
be taken off the market because of severe side effects.
NEWSCASTER: -off the market-
NEWSCASTER: -pulled from the market-
ANNOUNCER: FDA administrators say these problems
could not have been prevented.
PAUL
SELIGMAN, MD, MPH, Dir, Office of Drug Safety, FDA: At the time a drug is approved, we don't have all the information that
we would like to have.
NEWSCASTER: -off the market-
NEWSCASTER: -off the market-
ANNOUNCER: But is there pressure on the FDA staff
to allow dangerous drugs on the market?
MICHAEL
ELASHOFF, PhD, Former FDA Drug Reviewer: I was told
very explicitly, "Don't write in your review that you're recommending against
approval."
ANNOUNCER: Tonight, FRONTLINE investigates the
integrity of our drug safety system.
NARRATOR: Outside Washington, D.C., sit the main
offices of the U.S. Food and Drug Administration, the guardian of drug safety
in America. Here, every day, some
100 reports arrive indicating that somebody somewhere has experienced a serious
side effect with a drug.
Back
in 2000, an unusual number of reports started coming in about people like Angus
McLean, a retired naval intelligence expert. While raking leaves one weekend, Angus suddenly felt intense
muscle pain all over his body, a severe reaction to a new "statin" drug he was
taking to lower his cholesterol.
ANGUS
McLEAN: I was just sore, like you'd worked out
too much. As this progressed over
just a couple of days, it didn't respond to limbering up or my wife trying to
give me a little rubdown. In fact,
it accelerated.
NARRATOR: When his symptoms became severe, his
wife rushed him to the hospital, where he was diagnosed with a life-threatening
muscle-wasting condition called rhabdomyolysis. It's a rare side effect that can cause a person to lose vast
numbers of muscle cells, which then have to be eliminated from the body.
Angus
required emergency kidney dialysis. For an entire week, he hovered on the edge of death, drifting in and out
of consciousness.
ANGUS
McLEAN: When you're afraid to go to sleep
because you think, "Man, if I go to sleep and don't fight hard, then it's going
to be over"- you don't know how many times that creeps into your mind, but once
is enough.
NARRATOR: The drug that caused Angus's problem,
Baycol, had recently been approved by the FDA.
RAYMOND
WOOSELY, MD, VP, U of Arizona Health Sciences Ctr.: I think Americans need to recognize
that every time they put a pill in their mouth, especially a new pill that
they've never taken before, it's an experiment.
NARRATOR: Dr. Raymond Woosely runs a national
center to study the side effects of drugs at the University of Arizona College
of Medicine. He worries that most
people don't understand how much about new drugs is unknown.
Dr.
RAYMOND WOOSELY: When a drug goes on the market, only
about 3,000 patients have ever been given that drug. We will never know all the toxicity that can occur,
especially the 1 in 10,000 or the 1 in 20,000 that could be seriously
harmed. Our detection of that will
only happen after the drug is on the market and exposed to huge numbers of
patients.
NARRATOR: Precisely because of such
uncertainties, there's a special division at the FDA to monitor drugs after
they go on the market.
FDA
STAFFER: I'm calling from the FDA Office of Drug
Safety. I'm calling in regard to a
report that you had sent into us earlier this year where the patient went into
renal failure. And I wanted to
get-
NARRATOR: The Safety Office at the FDA is staffed
by about 50 pharmacists, doctors and epidemiologists, plus support staff. They find out about what's going on in
the outside world through Medwatch reports.
Director
of the division, Paul Seligman.
PAUL
SELIGMAN, MD, VP, U of Arizona Health Sciences Ctr.: We receive approximately 1,000 reports
every day at the FDA.
NARRATOR: Medwatch reports typically start out
when a doctor or nurse notices a problem after a patient gets a drug. But there's no legal obligation to
report such problems.
Dr.
PAUL SELIGMAN: In the United States, the initiator of
the report does so on a voluntary basis. But it's critical that we get these reports. There's no other way that the FDA has for understanding
what's going on with a medicinem once it's been marketed, without the voluntary
reporting by astute clinicians and health care providers.
NARRATOR: Doctors rarely contact the FDA
directly. They usually send the
reports to drug companies, which then are obligated tell the agency about any
adverse events.
Dr.
PAUL SELIGMAN:
If an adverse event is serious - which means it could cause death, it resulted
in hospitalization or was potentially life-threatening, or prolonged
hospitalization - the manufacturer has a legal responsibility to report that
case to the FDA within 15 days of receipt.
NARRATOR: Medwatch reports often don't contain
enough details to determine if the suspected drug really caused the
problem. So then the staff here
has to contact the doctors who made the report. With nearly 300,000 Medwatch reports coming in every year
and over 3,000 drugs on the market to monitor, some critics say the job is just
too overwhelming for the small staff here.
Dr.
RAYMOND WOOSELY: The number of people hired at the
agency to protect, to analyze data on drug safety is criminal.
NARRATOR: Dr. Woosely was a top candidate to head
up the FDA last year and believes safety should be a much higher priority at
the agency.
Dr.
RAYMOND WOOSELY: The teams that are needed to do drug
safety are infinitely more than what they've got right now. We don't have a safety system in this
country.
NARRATOR: Dozens of new drugs come onto the
market each year, continually adding to the FDA's burden. Some are completely new, while other
are variations on existing products, like the many statin drugs, which are
hugely popular for lowering cholesterol.
America
spends some $12 billion a year on statins, so there's a strong incentive to
enter this competition with new products. And health insurers are always looking for cheaper alternatives.
Which
brings us back to the story of Angus McClean. For more than a year, he had taken the industry leader,
Lipitor, which effectively controlled his cholesterol and didn't cause him any
problems. But then the U.S. Navy
switched him over to a new statin drug, Baycol, which was dramatically cheaper.
Around
the time Angus made the switch, Baycol was just capturing a significant share
of the U.S. market. It had been a
tough battle because the originally approved dose didn't lower cholesterol as
much or as fast as many other statins.
KIP
PETROFF, Attorney, Petroff & Associates: The FDA originally approved it at .2 milligrams, and .3 became an
accepted use. But the problem was,
to really compete in the marketplace, they had to be a much higher dosage than
that.
NARRATOR: Kip Petroff represents Angus McLean and
many others who have sued Bayer, the manufacturer of Baycol. He and other lawyers have uncovered
detailed information about how the Baycol problem got out of hand. Two years after approving Baycol, the
FDA OK'd a higher dose, .4. Sales
started to rise. But soon Bayer
began getting a troubling number of reports that patients were developing that
muscle-wasting condition, rhabdomyolysis.
Since
many had also taken a second cholesterol drug, Gemfibrozil, in December 1999,
Bayer sent out a letter warning physicians not to use the two drugs in
combination. But almost half had
taken Baycol alone. So the company
continued its investigation.
KIP
PETROFF: When Bayer realized that they were
getting increased numbers of reports, what they wanted to do was try to compare
it to the other statins, to see if the other statins had just as high an
incidence.
NARRATOR: To do that, the company asked the FDA
for copies of all Medwatch reports associated with Baycol and its
competitors. While Bayer was
waiting for the information, a company memo shows there was growing concern
among some doctors that Bayer wasn't being honest about what was going on.
"Board
member thinks Bayer is not forthcoming," "Dr. Palmer thinks Bayer is hiding
something," "Boston-area cardiologists seem to be concerned about Baycol."
After
some rhabdomyolysis patients died, another company memo shows that Bayer was
worried about the news getting out. A company safety officer addressed this memo in a deposition.
[Deposition]
KIP
PETROFF: Was there some effort being made at
Bayer to try to keep information regarding these deaths related to Baycol
quiet?
ROGER
CELESK, Sr. Clinical Safety Officer, Bayer: No.
KIP
PETROFF: Doesn't this, that ends with, "So much
for keeping this quiet"- doesn't that imply to you that somebody, at least,
wanted to keep this quiet?
ATTORNEY: Objection.
ROGER
CELESK: I don't know what the context was. I can't get into the mind of the
writer.
KIP
PETROFF: Well, the context is right here. There's widespread concern, people are
hearing of things, and "so much for keeping this quiet."
NARRATOR: In the spring of 2000, Bayer received
and analyzed the Medwatch reports it had requested from the FDA. Company officials compared Baycol with
the industry leader, Lipitor, and got discouraging results. For every 100,000 prescriptions given
without other cholesterol drugs, Baycol had 20 times more reports of
rhabdomyolysis than Lipitor, also known by its chemical name Atorvastatin.
The
situation was discussed at a July 2000 teleconference, where extensive notes
were taken by Bayer safety officer Raj Sharma.
RAJESHWAR
SHARMA, Bayer Drug Safety Officer: My note says, "Clearly, substantial
increase than Atorvastatin reporting rate. Very strong signal."
ATTORNEY: Very strong signal.
RAJESHWAR
SHARMA: That's correct.
ATTORNEY: And you underlined that.
RAJESHWAR
SHARMA: Yes.
KIP
PETROFF: A signal is meant to alert you to
act. And there were people at that
time, in the middle of 2000, who, according to their own memos- "We would do
something now," is what some of these people were saying.
If I had
been at that meeting in July of 2000 and asked you, "Dr. Sharma, can you tell
me if you think this drug is safe," you would have said, "I don't know"-
ATTORNEY: Objection.
KIP
PETROFF: -in July of 2000, wouldn't you.
RAJESHWAR
SHARMA: At that time, we did not have the
complete data to say whether it is safe or not safe.
KIP
PETROFF, Attorney, Petroff & Associates: And what the drug company chose to do was study it further and continue
marketing the drug as aggressively as possible. And that's where they crossed the line, in terms of drug
safety.
NARRATOR: At the head office of the FDA's drug
division, FRONTLINE asked deputy director Steven Galson if anybody
at the FDA knew about the Lipitor-Baycol comparison.
STEVEN
GALSON, MD, Dpty Dir, FDA's Drug Division: We weren't aware, at that point, of the difference between Baycol and
the other similar classes of drug. Our expectation is, when a company becomes aware of a specific problem
with their drug, they come to us.
NARRATOR: With the FDA in the dark about Bayer's
Medwatch report analysis, in the summer of 2000, the agency approved sales of
Baycol .8, an even higher dose that Bayer needed to compete effectively against
Lipitor.
David
Archer was one of many patients put on the new Baycol .8 dosage. He also was switched over from Lipitor,
and his wife, Lucy, remembers that her husband was in excellent health until he
began taking Baycol.
LUCY
ARCHER: David was always very active. He would chop trees. He would do a lot of things. But then, as he was taking the Baycol,
I noticed, as we walked, especially, he would complain about his toes. Then he would complain about the calf,
his legs, and then his muscles, his back. Finally, it got so that he just couldn't seem to bend over to put his
socks on and shoes. And no way had
I ever thought that this Baycol was doing this. He took it October, November. And December, he was gone. He should have never, never died.
NARRATOR: Lucy Archer's husband died more than
five months after Bayer had strong indications their drug might be less safe
than Lipitor.
Bayer
declined FRONTLINE's request for an interview to explain why the
company continued selling Baycol despite the safety concerns.
ROGER
CELESK, Sr. Clinical Safety Officer, Bayer: And in no case
is a reporting rate from spontaneous data-
NARRATOR: But company safety officials have had
to answer questions in legal proceedings, where they have attacked the findings
of their own Medwatch analysis. The problem, they said, is that this data depends on voluntary
cooperation. Side effects for some
drugs can get reported more often than for others. And only 1 to 10 percent of all side effects ever get
reported.
Dr.
STEVEN GALSON: The system is imperfect, and without
being able to require people to make those reports - and we don't have the
authority to do that - it's hard to increase it beyond that.
NARRATOR: While sales of Baycol continued, Bayer
conducted a new story that didn't use Medwatch data. After almost a year had gone by, the FDA began noticing
increased problems with the higher Baycol dose and asked the company for its
information.
Dr.
STEVEN GALSON: They came to us with this study, which
tended to minimize the problems with the drug. We didn't agree with them on this analysis, and this is why
the action occurred.
NEWSCASTER: The cholesterol-lowering drug Baycol is being pulled off the market-
NEWSCASTER: It's been linked to 31 deaths in the U.S. from muscle destruction.
NARRATOR: Under pressure from the FDA, Bayer
voluntarily took Baycol off the market in August, 2001, two years after first
getting reports there might be problems with the drug. Although the company hasn't
acknowledged any wrongdoing, Bayer paid an undisclosed amount to settle a
lawsuit brought by the widow of David Archer. Bayer also settled a lawsuit with Angus McClean, who now
spends many hours each week trying to rebuild his muscle strength.
ANGUS
MCLEAN: I didn't choose this, nor did I do
anything that is overtly the cause on this. So I'm angry about it happening. But now that it's happened, what can I do about rectifying
it?
NARRATOR: Although Bayer has won a few jury
trials in cases where it was unclear that Baycol caused the damage, the company
has settled more than 1,200 lawsuits and paid over $430 million to victims.
Beyond
the harm done to individuals, though, the Baycol story reveals how dependent
the FDA is on information supplied by drug companies.
LEO
LUTWAK, MD, Former FDA Drug Reviewer: The FDA is wholly dependent on trust, on trusting that the company is
providing all the truth, all the time, that the company is not hiding
information, the company is not covering up information, the company is not
changing information.
NARRATOR: Dr. Leo Lutwak, a retired FDA drug
reviewer, says reliance on companies was central to the biggest disaster in the
agency's history, the Fen/Phen tragedy, in which two FDA-approved weight loss
drugs injured tens of thousands of Americans. Lutwak struggled within the agency to keep those drugs out
of consumers' hands.
Dr.
LEO LUTWAK: I felt it was an open-and-shut
case. This was a dangerous group
of drugs with very little, if any, benefit, and that they should immediately be
removed from the market, removed from use, discontinued, disappeared. When that didn't happen, I became
disturbed. I became concerned
about the system. I became
concerned about the drug company's role in this. And I was particularly concerned with the potential effect
on the thousands and millions of people who would be using the drug.
NARRATOR: Mamie Johnson, from Houston, Texas, was
just the sort of person Lutwak worried about when he considered the dangers of
those diet drugs.
MAMIE
JOHNSON: I was really ready to lose some weight. That was the main reason I got on the
Fen/Phen because I thought it was a safe drug.
NARRATOR: Mamie started taking Fen/Phen in
1995. A year later, she developed
pulmonary hypertension, a constriction of blood vessels inside the lungs that
dramatically reduces their ability to absorb oxygen.
MAMIE
JOHNSON: It's a terrible feeling. You feel like you're passing out
because you're not getting any oxygen.
Oh,
wait a minute. I got- I have to
rest a little bit.
And
then you start aching in your chest and your arms, and then your fingers and
things become numb- oh, Lordy! And
right now, still, after me getting my wind back, there's still a pain up in
here.
Curtis,
you need to turn that oxygen up all the way.
NARRATOR: The only cure is a lung transplant, but
Mamie's overall condition made her ineligible.
MAMIE
JOHNSON: It's a very serious disease. And you know yourself, without your
lungs, you can't live. There's no
future. You know, death is soon.
NARRATOR: The Fen/Phen Mamie and others took
wasn't actually a single drug. It
was a combination of fenfluramine - sold under the name Pondimin in the U.S. -
and Phentermine. Thus the name
Fen/Phen. Both were diet drugs,
but only Pondimin caused pulmonary hypertension, which was thought to be an extremely
rare side effect.
In
the early '90s, the maker of Pondimin, Wyeth, and a partner company asked the
FDA to approve an updated version called Redux, already on the market in
Europe. Because it was so similar
to Pondimin, Lutwak, in his review of Redux, investigated how much of a
pulmonary hypertension risk it would pose.
Dr.
LEO LUTWAK: When I started looking at the actual
reports, it didn't seem that rare. And I was told by the company that, no, this just doesn't occur in
enough individuals make it worth being concerned about.
NARRATOR: The question was soon clarified by
Chicago cardiologist Stuart Rich and colleagues, who were finishing a
three-year European study on pulmonary hypertension and diet drugs. Their results showed the risk for Redux
was real, and increased the longer you took it.
STUART
RICH, MD, Cardiologist, Rush Heart Institute: What was particularly shocking to me was that on the heels of reporting
that this drug caused a fatal, incurable disease in Europe, that the company
was planning to put it on the American marketplace. When I had heard this, I'd said, "Well, you can try, but
it's never going to get in this country." The FDA would never permit a drug that had little benefit, terrible risk
on the American marketplace. The
FDA is your watchdog that looks out for your safety.
NARRATOR: FDA reviewer Lutwak also believed the
agency would not approve the drug.
Dr.
LEO LUTWAK: According to what I read and the way I
interpreted the Food and Drug Administration's role, we're supposed to evaluate
drugs for their safety and efficacy. And when the safety is questionable, it requires an awful lot of
efficacy to be warranted.
Dr.
STUART RICH: If you look at the efficacy studies,
you found out that it's efficacy was minimal, at best- 3 percent weight loss
after one year. If you
weighed 300 pounds, I could say, "End of a year, I'll get you down to 291, with
a risk of dying of pulmonary hypertension."
NARRATOR: With controversy surrounding Redux, the
FDA called an advisory committee meeting to get the views of outside
experts. Lutwak presented data
showing that the average weight loss was unimpressive.
Dr. LEO
LUTWAK: The use of the drug provided
approximately a 3-kilogram greater weight loss than the placebo alone.
NARRATOR: Rich was there, too, warning about the
dangers of long-term use.
NARRATOR: The drug companies that were seeking to
sell Redux also got a turn to speak. They presented data showing that some patients lost a lot of weight and
argued that for society as a whole, obesity was more harmful than any side
effects. Eventually, the 11
committee members had to come up with a recommendation, which the FDA could
either accept or ignore.
[www.pbs.org:
More on the drug approval process]
Dr.
STUART RICH: The committee voted unsafe, so they
voted thumbs down for safety. But
they were leaning towards yes for efficacy. But if you're not safe, you're not going to get approved. That meeting was suddenly and unusually
halted by Jim Bilstead, who was the director of the division.
NARRATOR: He was the FDA official overseeing the
meeting, and late in the day, after several of the committee members had
already left, he posed an extra question: Were the benefits of Redux sufficient to make the risks acceptable?
Dr.
LEO LUTWAK: It was a rather unusual move, but some
of the higher-level managers, administrators at the FDA announced that a second
advisory committee meeting would be held to review this in a few months.
Dr.
STUART RICH, Cardiologist, Rush Heart Institute: It was at the other meeting, where none
of the consultants were invited to come back and testify, that that was
approved, 6 to 5 in favor.
NARRATOR: Before that second meeting, Lutwak had
agreed to support the approval of Redux, so long as there were restrictions
that severely limited the number of people who might get the drug. But some of those restrictions were
never adopted.
Dr.
LEO LUTWAK: I was very disturbed. And then we talked about it internally,
within the division at the FDA. And there is one tool that's left, and that's the labeling. And so we would see if we could get the
company to put these warnings in what's called a "black box."
NARRATOR: About 10 percent of all drugs have
"black box" warnings, and these always appear at the beginning of the
information sheets that come with drugs. Such warnings are never good for sales, and Wyeth documents show the
company wanted to do everything possible to avoid a black box on the Redux
label.
A
top Wyeth executive explained the company's view in a deposition.
JOSEPH
MAHADY, Pres., Wyeth Pharmaceuticals, NA: We have many
responsibilities, as a company. We
have responsibilities to patients. We have responsibilities to those in the company, to those who support
the research of the company, to shareholders, that we accept and produce
appropriate black-box, as appropriate, labeling. And there are many reasons. And to sacrifice a company's sales just for the purpose of
accepting an approval with the black box is not a responsible action.
NARRATOR: When the FDA sided with Wyeth, people
at the company were jubilant. Leo
Lutwak was devastated.
Dr.
LEO LUTWAK: I thought it was wrong that the company
was allowed to have a second chance at the advisory committee. I thought there were wrong decisions
made. I expressed that. I started feeling enough heat to make
me recognize that my opinions were not only not respected, but they would be
disregarded and pushed out of the picture.
NARRATOR: So Redux entered the market, joining
the related drug. Pondimin. Now it
was up to the FDA's Medwatch system to monitor any serious side effects of both
drugs.
The
agency would soon be put to a severe test. The story begins in Fargo, North Dakota, at a small regional
medical center.
KAREN
BERGER, Echocardiogram Tech, MeritCare: Hi,
Marlee. My name is Karen. I'm going to do your ultrasound here
this afternoon.
NARRATOR: Ever since 1994, when millions of
Americans began taking Pondimin as part of the Fen/Phen craze, young women were
showing up here with strange heart problems.
KAREN
BERGER: Most of the patients that we saw came
to us because they had a new murmur. There was an extra sound in their heart that the physician hadn't heard
before.
NARRATOR: Each time a new patient came in,
echocardiograms were ordered to get a better look at their hearts. Over the course of two years, Karen
Berger and fellow technicians saw 10 young patients with heart valve
problems. With every heartbeat,
blood was rushing around their valves in the wrong direction.
KAREN
BERGER: I just was struck by the
unusualness. It was just very
curious. We commonly see that in
the elderly. The valve will get
stiff and not open or close properly. But these patients were very young, and it just didn't fit.
NARRATOR: Karen's curiosity led her to ask the
very first patient if she was taking any medications. Marlee Siewert answered "Fen/Phen."
MARLEE
SIEWERT: I was taking Fen/Phen because I was
morbidly obese. I was well over
100 pounds overweight. And this
looked like the solution, according to my doctor. There was some media, oh, probably about six months after I
started with it on how fabulous this product was, and it was touted as the
miracle drug.
TELEVISION
COMMERCIAL: What about a pill that tells your brain
you're not hungry?
MARLEE
SIEWERT: And I had to agree because I was having
the results that they said you were going to have.
TELEVISION
COMMERCIAL: And I had lost 31 pounds. Take it off. Lose the weight with Fen/Phen or Redux-
MARLEE
SIEWERT: I was on Fen/Phen for 15 months, and
the first 12 months, it was the miracle drug. I was losing weight. I felt great. I was doing everything
exactly the way they said it should happen. And then my miracle turned into my nightmare.
NARRATOR: After hearing other similar stories,
Karen and fellow technicians told the hospital cardiologists they believed
Fen/Phen was causing valve problems. Cardiologist Jack Crary was skeptical.
JACK
CRARY, MD, Cardiologist, MeritCare: We
shared their concern, but we just couldn't substantiate it. When we looked at the echoes, clearly
there were valvular abnormalities. The patients were on Fen/Phen, along with other medications. And to go from one to the other, at
least no one in the department was convinced that the connection was real.
NARRATOR: Crary remained unconvinced for many
months, until a patient of his own became a victim. One day she was fine, then, soon after taking Fen/Phen, she
had severe valve damage. In his
head, he calculated that if so many people were getting harmed in a small city
like Fargo, then huge numbers must be getting hurt nationwide.
Crary
knew the FDA was completely unaware of the possible heart valve problems, and
he also knew he might have to pay a high price if he reported them.
Dr.
JACK CRARY: There was going to be potential major
litigation, if this was real. I
mean, I was very happy with my life. I didn't really want to rock the boat. But I couldn't just walk away from that and just say,
"Well," you know, "let somebody else sort this out." I just don't think that I would have been able to face
another patient.
NARRATOR: In January, 1997, Crary decided to take
action. Seeking the credibility of
a prestigious academic medical center, he contacted the Mayo Clinic in nearby
Minnesota and told them about Fargo's 11 cases. As it turned out, Mayo had two similar cases of its
own, and one patient needed valve replacement surgery.
After
some back-and-forth discussions, in late February, a doctor from Mayo called
the Pondimin and Redux manufacturer, Wyeth, to inform the company about the
heart valve cases. Within a few
weeks, Wyeth officials went out to Fargo and Mayo to investigate further and
concluded there might be a connection between their drug and the heart valve
problem.
It
had been over two years since the problem was first noticed in Fargo. And now, in mid-April, 1997, Medwatch
reports were finally on their way to the FDA. But there wasn't any red flag to alert the agency that a
serious new side effect had been discovered. Wyeth simply met its legal obligation to inform the
FDA through the Medwatch system.
By
mid-May, Crary was puzzled why the FDA hadn't taken any action yet.
Dr.
JACK CRARY: I was frustrated enough that I had
called the FDA, and the person I talked to at the FDA knew nothing about it.
NARRATOR: Despite Crary's urgent call, the FDA
treated his reports in a routine manner until a call came in from Mayo six
weeks later, saying they and Crary were holding a press conference.
MAYO
PHYSICIAN: Today, my colleagues and I from the
Mayo Clinic, in conjunction with Dr. Crary from MeritCare in Fargo, North
Dakota-
NARRATOR: It was early July, 1997, and this is
how the world found out about the heart valve problems caused by the drugs
known as Fen/Phen. Only now did
the FDA swing into high gear, and within a few weeks, Pondimin and Redux were
off the market.
NEWSCASTER: In the United States, two highly popular diet drugs are being pulled
from the market-
NEWSCASTER: One is fenfluramine, sold under-
NARRATOR: Just before the withdrawal, the FDA
discovered that from 1992 to 1996, Wyeth had actually sent in almost two dozen
Medwatch reports from Europe, which were headlined "pulmonary hypertension" or
"renal failure," but that contained clear references to heart valve problems.
LEO
LUTWAK, MD, Former FDA Drug Reviewer: The company had this information. The company had the information that people had heart valve
disease. And that was reported to
the FDA in a way that was very difficult to pick it out.
NARRATOR: Without Wyeth red-flagging the heart
valve problems, the FDA didn't catch their significance. But it would be the company's failure
to warn the public about these problems that would give lawyers their smoking
gun.
1st
ATTORNEY: So who knows where the FDA box is? It's a whole box of FDA documents.
2nd
ATTORNEY: I've got that in my office.
NARRATOR: Over 200,000 Americans have sued or are
planning sue Wyeth for damages. These are all videotapes of echocardiograms just at Kip Petroff's firm. To date, the cases have cost Wyeth
nearly $13 billion. And in the
end, it could cost the company much more.
KIP
PETROFF, Attorney, Petroff & Associates: This is probably unprecedented, in terms of anything that's been seen,
other than perhaps asbestos.
NARRATOR: It's too late for monetary settlements
in the case of Mamie Johnson. Three months after we filmed her at her 65th birthday, she died from
lung problems.
As
for Marlee Siewert, some day soon she'll probably need surgery, with all its
risks, to replace her leaky heart valve.
MARLEE
SIEWERT: I am mad, angry and frustrated for the
fact that they took a good part of my life away. They may have taken a good section of my life away just by
using this drug. And I do
understand they're in the business to make money, but I'm in the business to
live.
NARRATOR: Wyeth declined FRONTLINE's invitation to be
interviewed for this program, but in a written response to some of our
questions, they said the company issued appropriate warnings about Pondimin and
Redux in letters sent to doctors and in the "general cautions" part of their
labels.
We
asked the FDA's deputy director Galson what the agency learned from Fen/Phen.
Dr.
STEVEN GALSON: Our system isn't perfect. It sometimes can detect things after
other parts of the medical care system is able to detect it. In this case, what happened is some
very astute physicians were lucky enough out in Minnesota to see a series of
similar cases, where they saw heart valvular abnormalities and they put the
link together. Again, looking at
our data after the initial case reports that came in from the Mayo Clinic, we
could see the signal. I think that
the lesson is that there's a lot of room for us to go, in terms of making
improvements with the system.
NARRATOR: Some critics say the agency needs to
learn more from disasters like Fen/Phen.
RAYMOND
WOOSELY, MD, VP, U of Arizona Health Sciences Ctr.: We need for the pharmaceutical industry
something analogous to the National Transportation Safety Board, so that when a
plane goes down, they go in and analyze what happened. And they may find that the plane was
the problem and the manufacturer, or they may find that the regulations were
inadequate. But they're
independent. When a drug comes off
the market, we have no analysis to say, "Should it have ever have gone on the
market? Was it a mistake at the
agency, or was it a mistake at the industry? Or was it something that was totally unpreventable?"
[www.pbs.org:
Read Woosely's interview]
NARRATOR: But is the FDA ready for such
scrutiny? In the aftermath
of Fen/Phen, Leo Lutwak says he was actually punished for having opposed the
drugs.
Dr.
LEO LUTWAK: I didn't expect the Congressional Medal
of Honor for this. I didn't even
expect a $50 bonus for it. But it
would have been nice if somebody had said, "Hey, you did a good job." And the opposite happened. I found myself trivialized within the
FDA, and I was reassigned to areas that I found very dull, unrewarding.
NARRATOR: Lutwak retired from the FDA a few months
after FRONTLINE interviewed him, and he is now consulting for plaintiff's
lawyers.
Back
in the 1930s, when the FDA was originally set up, scientists there were
encouraged to be skeptical about the claims made by companies. But critics say a major pro-industry
shift occurred at the FDA, particularly after this 1988 rally in front of
headquarters.
Demonstrators
complained it was taking too long to approve new AIDS drugs. In response, Congress passed the
Prescription Drug Users Fee Act, or PDUFA, a law that requires companies to pay
up to a $500,000 fee with each new drug application, to help the FDA hire more
reviewers and get drugs onto market quicker. Today, over half the FDA's drug reviewers are paid with
industry money, and the approval time for many drugs has gone from over two
years to less than six months.
That's
all good news, according to drug industry spokesman John Kelly.
JOHN
KELLY, MD, PhD, Drug industry spokesman, PhRMA: The pharmaceutical industry has been
pleased with PDUFA and has been very supportive because what it has done is to
improve the efficiency of the review process. It's in the pharmaceutical industry's interest and in the
public's interest to have that review process as thorough and effective as it
can be.
[www.pbs.org:
More on industry lobbying efforts]
SIDNEY
WOLFE, MD, Health Research Group, Public Citizen: The culture at the FDA has become
"Please the industry, avoid conflict, look upon our role as getting out as many
drugs as possible."
NARRATOR: Sidney Wolf of Public Citizen's Health
Research Group in Washington believes industry funding has created an FDA
that's reluctant to challenge company claims about safety and effectiveness.
[www.pbs.org:
How independent is the FDA?]
Dr.
SIDNEY WOLFE: This system has created a very
unhealthy relationship between the industry and the FDA, where the FDA says,
"We have to be nice to these people because they are paying our bills."
NARRATOR: Michael Elashoff thinks this new
relationship partly explains what happened to him at the FDA three years ago,
when he opposed the approval of a new anti-flu drug called Relenza.
[television
commercial]
WOMAN: [sound of doorbell] Who is it?
MAN AT
DOOR: It's me, influenza- you know, the
flu? Coming in!
MICHAEL
ELASHOFF, PhD, Former FDA Drug Reviewer: Simply stated, Relenza just didn't work in the United States clinical
trials. It really had no effect at
all on the symptoms of influenza. It had no effect on influenza complications.
ANNOUNCER: Introducing Relenza, a new prescription medicine to help you start
feeling better sooner.
MICHAEL
ELASHOFF: It maybe knocked half a day or less off
the duration, and even that wasn't established statistically. So it was pretty much no different from
placebo, as far as efficacy.
ANNOUNCER: Those with chronic lung disease or asthma may experience wheezing-
NARRATOR: What also bothered Elashoff was a
life-threatening side effect that caused some users to have trouble breathing.
TELEVISION
COMMERCIAL: Relenza is an antiviral medicine that's
inhaled. You should be shown how
to use the inhaler.
MICHAEL
ELASHOFF: One of the concerns during the review
was that Relenza had the potential to cause bronchospasm, or constriction of
the airway, and it was observed in several patients in the clinical trials.
NARRATOR: To sort things out, the FDA called an
advisory committee meeting. Elashoff told the panel of 17 experts that Relenza had little benefit
and real risk.
MICHAEL
ELASHOFF: Ultimately, they decided that it was
not worth approving, and voted 13 to 4 to reject the drug. The next day after the advisory
committee, several people in FDA management told me that they blamed me for the
drug getting turned down at the advisory committee, that I wouldn't be allowed
to present at the advisory committee meetings in the future for any other
drugs.
NARRATOR: Elashoff still had to write up a formal
review of Relenza, and here he says he got reined in again.
MICHAEL
ELASHOFF: I was told very explicitly, "Don't
write in your review that you're recommending against approval. Write that the data is unclear, you
could go either way." So it was-
it was quite explicit.
NARRATOR: Where Elashoff wrote that patients
would be exposed to risks while deriving no benefit from the drug, supervisors
weakened his report to say that safety data should be "considered" in making
risk-benefit decisions.
In
the end, the FDA approved Relenza after the manufacturer, Glaxo, sent the
agency a strong letter complaining that Elashoff was judging their drug by
stricter standards than what had been agreed upon before the review began.
Nine
months later, the FDA forced Glaxo to put a new warning on the Relenza label
saying that deaths and injuries can occur from bronchospasm, the very thing
that worried Elashoff. By then,
Elashoff had left the agency after working there five years. He says his experience wasn't an
isolated example of an FDA scientist being asked to brush aside bad news about
a drug.
MICHAEL
ELASHOFF: In nearly all the cases I was familiar
with, both that I worked on and other people in my division worked on, there
would be a pressure to approve those drugs or soften the language in the
review, soften the language in the labels, so that they could have a more easy
justification for why they were approving. So I would say it was very common.
NARRATOR: FRONTLINE asked the FDA's Steven
Galson about Elashoff's charge.
Dr.
STEVEN GALSON: We're certainly not proud to hear that
there's anybody that has opinions like that, but we just don't think it's average
or even reflective of what most people think. We wouldn't condone anyone being asked to change their
review. I think the idea of
forcing someone to change something that they've written or something that
they've analyzed is highly unusual.
MICHAEL
ELASHOFF: That's a joke! I mean, it happens all the time. I guess the only reason it doesn't
happen as frequently as it might otherwise is people start censoring
themselves, that they say, "OK after the first time I've noted a problem and
it's been glossed over, well, you know, why bother the second time?"
[www.pbs.org:
Read Elashoff's interview]
NARRATOR: An investigation by Sidney Wolfe's
Heath Research Group revealed that charges like Elashoff's are common at the
FDA.
Dr.
SIDNEY WOLFE: In the context of the large number of
drugs that had to come off the market in the late '90s, we did a study of
physicians at the FDA who are in the drug approval division and found that,
between them, they had identified 27 drugs that they thought were too dangerous
to come on the market. But those
drugs were approved over their objection.
NARRATOR: In late 2000, soon after the Health
Research Group study was published, the FDA completed its own survey about
morale at the agency. FRONTLINE obtained the results of
this internal study. Among those
who responded, a number said their reports were edited and they had been asked
to change negative opinions about pharmaceuticals. One third said they feared being stigmatized if they
recommended that a drug not be approved. And a third also said that they were uncomfortable expressing differing
scientific opinions.
Dr.
STEVEN GALSON: I don't think it's characteristic of
how our scientists feel. For one,
this is a 3-year-old survey. For
two, it was not done as scientifically as some of the more recent surveys that
we've seen in the last few years. The people that work here are challenged, they're gratified, and by and
large, they enjoy what they're doing.
NARRATOR: Whether or not there are morale
problems at the FDA, administrators insist, safety is not being compromised.
PAUL
SELIGMAN, MD, VP, U of Arizona Health Sciences Ctr.: For the consumer, they need to
understand that the FDA's mission is to ensure that drugs are safe and
effective before they are approved for marketing and that the vast majority of
medications meet that very high standard prior to their approval. We have in this country, and I think
throughout the world, achieved extraordinary benefits from the use of
pharmacologic agents. We, as a
society, are living longer, and that, in large measure, is due to the high
quality of the medicines that we, as a nation, receive.
NARRATOR: To demonstrate how seriously safety
questions are taken at the FDA, administrators invited us to film a staff
meeting about a drug that recently went on the market.
1st FDA
STAFFER: Now that the drug is available and it's
being used by larger numbers of people, in fact, there are rare but severe
cases of liver toxicity.
NARRATOR: The meeting was held just for our cameras,
and the name of the drug was kept secret. But the staff members took positions they had argued at a real meeting a
little earlier.
1st FDA
STAFFER: None of the drugs that are available to
treat this disease really provide a perfect remedy.
2nd FDA
STAFFER: But this drug has a safety
problem. And to the best of our
knowledge, we don't think that that problem exists with similar drugs of this
class.
NARRATOR: The question was, What action should
the FDA take in light of the drug's association with liver damage?
2nd FDA
STAFFER: The safety problem is real. And at the very least, we should inform
clinicians that this is what we see and this is what they expect because this
is lifetime therapy we're talking about.
1st FDA
STAFFER: Right. Well, there are different kinds of remedies that we can
imagine to apply, such as try to reduce the usage, but not necessarily removing
the drug from the market.
NARRATOR: The leader of the meeting, who used to
work in the approval part of the FDA, proposed letting the company kept its
drug on the market, provided it conducted more studies.
3rd FDA
STAFFER: My concern will be, I think, the time
of the action. I certainly
wouldn't want to wait for five years and hear much more reports of this kind of
severity.
1st FDA
STAFFER: Do you favor that we should give strong
consideration to asking the company to consider withdrawing this drug?
3rd FDA
STAFFER: This is what I would suggest, yes.
1st FDA
STAFFER: And your reasoning is that there are
potentially other alternatives?
3rd FDA
STAFFER: Yes.
1st FDA
STAFFER: I frankly don't agree with you. And the reason I don't agree with you
is that I agree that there is a bad outcome in a very small percentage of
users, but from the clinician's perspective, there is some merit to saying that
clinicians should have some freedom of action in dealing with patients and
choosing-
NARRATOR: Over the next few months, the arguments
that took place here became a contentious issue inside the FDA, as reports of
liver damage continued to arrive. The safety staff wrote up a 37-page document detailing all the cases,
including nine deaths. And then in
March, 2003, a public advisory committee meeting was called to review the
safety of the product. Here we
learned the drug's identity. It
was a medication to treat rheumatoid arthritis called Arava.
The
scientists who had argued at the internal meeting that the drug should be taken
off the market were here, along with a senior epidemiologist and physician,
David Graham, who's been with the FDA for two decades and who helped write that
37-page report.
For
months, FRONTLINE had
requested an interview with Graham, but FDA administrators would not let us
talk to him on camera.
The
first thing committee members found out was that they weren't going to hear
from the authors of the safety report, a message delivered by Dr. Sidney Wolfe,
who had petitioned the FDA to stop sales of Arava.
Dr.
SIDNEY WOLFE: Despite this 37-page evaluation, which
concluded the drug should be withdrawn from the market, none of the authors of
this review were allowed to present their work to the advisory committee and to
be questioned by you, in terms of what you agree with, what you disagree with.
NARRATOR: Making the FDA's presentation was a
scientist not from the safety division but from the division that originally
approved the drug.
LAWRENCE
GOLDKIND, MD, FDA: There was extensive confounding-
NARRATOR: He downplayed the significance of the
Medwatch reports.
Dr.
LAWRENCE GOLDKIND: -other likely causes for liver toxicity
in the majority of those cases.
NARRATOR: Then he pointed to other databases
where there were no cases, concluding his one-hour presentation saying the
liver problem must be very rare.
Dr.
LAWRENCE GOLDKIND: Cases did not occur in these large
databases, so we can't really quantitate what the rate would be.
NARRATOR: While Graham and the other safety staff
members watched in silence, the pharmaceutical company, with its army of
scientists surrounded by stock market analysts, got to make a one-hour
presentation, too.
WILLIAM
HOLDEN, PhD, Aventis Pharmaceuticals: The first study we did was a
retrospective cohort study using Aetna claims data-
NARRATOR: The company pointed to databases where
they could compare the rate of liver problems associated with Arava, also known
as leflunomide, to other rheumatoid arthritis drugs.
WILLIAM
HOLDEN: What we are claiming, based on the
analyses presented here, is that leflunomide is just as safe.
NARRATOR: Towards the end of the meeting, a
special consultant to the committee expressed concern that the FDA was ignoring
its Medwatch reports.
LEONARD
B. SEEFF, MD, FDA Consultant: While the database that I heard was so
compelling, and all of this seems so wonderful that there is really nothing to
show acute liver failure, these were sent to me. I mean, I didn't make them up. They were sent to me, and they were actually listed as
either "serious liver disease" or "liver failure." And going through them, I was unable to be absolutely certain
that there was not.
NARRATOR: As the discussion continued, suddenly,
one of the committee members surprised everyone at the meeting.
ALLAN
GIBOFSKY, MD, JD, FDA Consultant: The suggestion that the proceedings
here are somehow tainted by the absence of individuals who wrote a report, and
the absence of our opportunity to have a colloquy with officers of the agency
who may have differing viewpoints, is a concern.
NARRATOR: With just a little time left - it was
almost 5:00 P.M., and the meeting was supposed to be over - the discussion was
opened up to anybody who wanted to speak.
MEETING
CHAIRMAN: If there is somebody who would like to
comment, address Dr. Gibofsky's comment, I think we would be open to that.
NARRATOR: Dr. Graham, who had been told by his
bosses that he could not speak here, decided not to volunteer.
In
the end, the committee recommended keeping Arava on the market, despite the
safety concerns raised by the Medwatch reports.
After
the meeting, we caught up with David Graham in the hallway. Now he decided to speak to us without
the FDA's permission.
DAVID
GRAHAM, MD, FDA Epidemiologist: We
had a different perspective, and we really weren't given an opportunity to
present our side of the story. And
the people who did present, the reviewing division and the company, you know,
they didn't see a problem and they presented. We found a problem, and we weren't permitted to present.
INTERVIEWER: You were invited to go up and
speak. I mean, why didn't you get
up and speak when you were invited?
Dr.
DAVID GRAHAM: Dr. Goldkind had about an hour to
present his analyses, the company had another hour to present theirs, and they
were basically each presenting the same thing. I didn't think that much would be accomplished in a
30-second sound bite. This was a
very hostile process. And let's
just leave it at that. [Editor's Note (12/6/04): One year after this FRONTLINE report, Dr. Graham became a FDA whistleblower, testifying before a Congressional panel in Nov. 2004 about the failed FDA policies that had led to the recall of the arthritis drug Vioxx.]
NARRATOR: Critics suggest what went on at this
meeting, and what's been happening inside the agency for many years, has a
simple explanation.
LEO
LUTWAK, MD, Former FDA Drug Reviewer: He
who pays the piper calls the tune. I think that a regulatory agency should be independent of the industry
it's regulating.
NARRATOR: Top administrators at the FDA insist
that industry money isn't a problem.
STEVEN
GALSON, MD, Dpty Dir, FDA's Drug Division: We don't really feel pressure to please the industry. We feel quite independent. In among the scientists, we have a large
number of mechanisms for assuring high quality of the reports that we do do to
make decisions about new drugs. So
we just reject that we're actually influenced by that.
NARRATOR: In fact, thanks to recent congressional
legislation, the FDA's approval division will get more industry money than ever
this year. And for the first time,
the Office of Drug Safety will also get industry money to increase its staff
for monitoring drugs after they go on the market.
JOHN
KELLY, MD, PhD, Drug industry spokesman, PhRMA: The Congress has repeatedly looked at
how it wants to fund the FDA. And
so once, twice, and again last year, the Congress decided the best way to fund
the FDA was to look to the pharmaceutical industry to provide a portion of the
funds to help support review. That's the decision of the Congress.
DANGEROUS
PRESCRIPTION
WRITTEN,
PRODUCED AND DIRECTED BY
Andrew
Liebman
EDITED
BY
Mark
Chesak
PHOTOGRAPHED
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Hoving
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Meistrich Gidal
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ORIGINAL
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Li
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EDITOR
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ONLINE
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H. Amundson
SOUND
MIX
Jim
Sullivan
SPECIAL
THANKS
Marcia
Angell
Curt
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Johnson
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2003
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ANNOUNCER: This report continues on our Web site,
where you'll find additional reporting by the producer on drug safety issues
beyond the FDA, a summary of the dozen drugs pulled off the market since 1997,
more on the politics of drug safety, including an interview with veteran
reporter Philip Hilts, author of a new book on the FDA's history, plus FRONTLINE's extended interviews
with FDA officials, scientists, critics and more. And watch the full program again on line, then join the
discussion at pbs.org.
Next
time on FRONTLINE: He was a lost
soul.
-He
believed violence was the only effective tool.
ANNOUNCER: On a political mission.
-He wanted
to bring about a new world order.
NEWSCASTER: President Kennedy's been cut down by an assassin's bullets.
NARRATOR: Did Lee Harvey Oswald act alone, or was
he part of a vast conspiracy? Forty years later, review the evidence and decide for yourself next time
on FRONTLINE.
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