Drug
Makers Say FDA Safety Focus
Is Slowing New-Medicine Pipeline
By
AVERY JOHNSON and RON WINSLOW
June
30, 2008; Page A1
Nearly
four years after Merck
& Co. yanked the painkiller
Vioxx off the market, beleaguered
pharmaceutical-industry executives
say they are facing a tough new
regulatory climate that is altering
the landscape of drug development.
Over
the past 16 months, Schering-Plough
Corp. Chief Executive Fred Hassan
and his top scientists have pulled
the plug on two drug-development
projects -- one for obesity and the
other for cholesterol -- that had
the potential to produce big
sellers. And they're considering
scrapping a third.
SHIFTING
CLIMATE
•
What's New: Some
drug-industry executives think the
FDA has become more conservative
about approving new drugs.
•
The Background: Merck's
withdrawal of Vioxx in 2004 prompted
criticism that the FDA wasn't
vigilant enough about safety.
•
What It Means: Some
companies are changing their
drug-development plans because of
the regulatory climate.
The
reason: Mr. Hassan believes an
intensifying focus on safety and a
diminished tolerance for side
effects at the Food and Drug
Administration have dramatically
lowered the odds that the drugs
would make it to market -- at least
not without a lot of extra time and
money.
"What
will it take to get new drugs
approved?" Mr. Hassan asks.
"The point is, we don't
know."
Just
last week, Eli
Lilly & Co. and Japan's Daiichi
Sankyo Co. said the FDA wants an
additional three months to decide
whether to approve their highly
anticipated new heart drug called
prasugrel. Days earlier, Merck said
the FDA wanted to wait for the
results of a huge clinical trial
before ruling on its cholesterol
drug Cordaptive, which could delay a
decision on the medicine until 2013.
On Tuesday, an FDA panel is set to
consider whether to recommend that
the agency adopt tougher standards
for diabetes drugs, which could
lengthen the development process for
many other types of medicines.
Last
year, the FDA approved just 19 new
medicines, the fewest in 24 years,
and announced about 75 new or
revised "black-box"
warnings about potential side
effects -- the agency's strongest --
twice the number in 2004. The number
of so-called approvable letters,
which typically postpone FDA
decisions pending more data,
increased by 40% last year,
according to a unit of Sagient
Research Systems Inc., which tracks
the regulatory paths of drugs.
Janet
Woodcock, director of the FDA's
Center for Drug Evaluation and
Research, denies that the agency has
become "more conservative"
about drug safety. Rather, she says,
the industry's faltering research
efforts are mostly to blame for the
fewer product approvals. She says
the agency continues to base its
decisions on science, not outside
pressures. New methods, she adds,
have helped it become more vigilant
about side effects. She attributed
the increase in black-box warnings
primarily to a few large groups of
medicines that were relabeled.
Some
outside observers disagree.
"There is no question that the
FDA is more safety-oriented than it
has been in years," says Ira
Loss, senior health-care analyst at
Washington Analysis, a research
firm. "Regulation tends to be a
pendulum, and a series of things,
the most dramatic of which was Vioxx,
has sent the pendulum back in the
direction of safety."
Grousing
by drug-industry executives about
the FDA is nothing new. It's a
product of the perennial tension
between regulators and the companies
they oversee.
But
the Vioxx debacle, which sparked
harsh criticism of both drug
companies and their chief regulator,
appears to have led to a climate
shift. The drug industry largely has
itself to blame for allegedly
manipulating clinical data,
concealing dangerous side effects
and aggressively promoting risky
products, which created widespread
mistrust. The FDA, for its part, was
harshly criticized for its decisions
on Vioxx and in a litany of
subsequent drug scares.
Outspoken
scientists, watchdog groups,
medical-journal editors and
politicians have fanned worries
about safety. The wave of post-Vioxx
drug scares included concerns that GlaxoSmithKline
PLC's widely used diabetes drug,
Avandia, could raise heart-attack
risk, and that Pfizer
Inc.'s smoking-cessation drug,
Chantix, may be connected to
suicides. More than 80
U.S.
deaths linked to contaminated
heparin from
China
have further ratcheted up public
anxiety. The FDA has been battered
by criticism that it wasn't vigilant
enough, including from Cleveland
Clinic cardiologist Steven Nissen,
Sen. Chuck Grassley of
Iowa
and Rep. John Dingell of
Michigan
.
Serious
Dangers
Now,
the agency is considering such
measures as adding warnings about
cancer risk to arthritis drugs for
children, and warnings about suicide
risk to epilepsy drugs. For most
drugs, such side effects strike only
tiny percentages of users. But when
millions take the medicines, the
numbers can add up.
Consumer
advocates have welcomed many of the
agency's recent warnings and some
drug withdrawals, arguing that they
have brought serious dangers to the
attention of patients and doctors.
Industry
executives acknowledge some
excesses. Dan Vasella, Novartis
AG's chief executive officer, says
direct-to-consumer advertising
lulled many Americans into thinking
that taking prescription drugs was
as safe as eating candy, leading
some doctors to feel pressure to
prescribe.
New
medicines fall out of development
pipelines all the time when they
raise safety flags, underperform in
studies, or when marketing prospects
dim in the face of rival compounds.
But worries about a costly and
uncertain regulatory road are now
prompting drug makers to withdraw
applications for some medicines and
to remove some once-promising
compounds from their pipelines.
Novartis
has stopped trying to get
U.S.
approval for its diabetes drug
Galvus and its painkiller Prexige,
even though Galvus is on the market
in
Europe
and Prexige has been approved in
about 50 countries. Sanofi-Aventis
SA, which markets the weight-loss
drug Acomplia in Europe, withdrew
its application in the
U.S.
after an FDA panel recommended
additional studies to address
concerns about psychiatric side
effects. On Friday, Merck and
Schering-Plough said they were
withdrawing their FDA application
for a combination asthma and allergy
medicine after the agency turned
down the drug earlier this year.
"There
are no drugs that are 100%
safe," says Novartis's Dr.
Vasella, who thinks the FDA has
become inconsistent. "Look at
Tylenol. It's over-the-counter, but
if you take doses of it that are too
high, you're dead."
Growing
Discrepancy
The
industry points to the growing
discrepancy between drug approvals
in the
U.S.
and
Europe
as evidence that the FDA has become
too cautious. Europe's drug
regulator, the European Medicines
Agency, has greenlighted a number of
drugs recently that haven't received
the nod in the
U.S.
, including Galvus, Prexige and
Acomplia. The FDA has delayed
approval of Glaxo's cancer vaccine,
Cervarix, and Schering-Plough's
sugammadex, a drug designed to be
used after surgeries to quickly undo
the effects of muscle relaxants, and
rejected Merck's pain medicine
Arcoxia. Cervarix and Arcoxia are on
the market in
Europe
, while sugammadex has been
recommended for approval there.
The
FDA's Dr. Woodcock responds that
"it's long been true that
different countries looking at the
same facts and data arrive at
different conclusions."
Over
the years, the FDA's approach to
drug safety -- the way it balances
the risks and benefits posed by new
drugs -- has swung like a pendulum.
In
the early 1960s, thousands of birth
defects in the
U.K.
linked to the morning-sickness drug
thalidomide triggered an overhaul of
drug evaluation in the
U.S.
The FDA began demanding more
extensive evidence from drug
companies that their products were
effective and safe.
In
the 1970s, a report showed that
approval of drugs for high blood
pressure and other ailments had all
but stopped in the
U.S.
, while several new medicines for
the conditions were introduced in
the
U.K.
That fueled a debate, complete with
congressional hearings, about
whether the FDA was keeping
life-saving drugs off the
U.S.
market. Several classes of heart
drugs were subsequently approved,
benefiting the public and generating
enormous profits for the industry.
In
the 1980s, several painkillers known
as nonsteroidal anti-inflammatory
drugs, or NSAIDs, which had been
approved by the FDA, were pulled off
the market because of safety
problems. Critics questioned the
FDA's attention to safety. But by
the end of that decade, the AIDS
crisis prompted patient activists to
demand faster access to experimental
drugs. That led to sweeping changes
aimed at speeding FDA approval of
drugs that could save lives.
A
new law required drug companies to
pay for the FDA to review products,
and set time limits for the FDA to
deliver its verdicts. In the 1990s,
the agency began conferring
"fast track" status to
drugs that address unmet medical
needs. It also began granting
"accelerated approval" to
drugs for cancer and other
life-threatening conditions, based
on promising preliminary data, not
proof, that they extended survival.
The
changes paved the way for new drugs
for cancer and AIDS. But a new
string of safety problems emerged.
In 1998, Wyeth's analgesic Duract
was pulled off the market due to
possible links to liver failure. In
2000, one of the first fast-tracked
medicines, the diabetes drug Rezulin,
was also pulled because of potential
liver toxicity. In 2001, Bayer AG
had to withdraw its cholesterol drug
Baycol because of a rare but
potentially lethal muscle-wasting
effect.
When
Merck withdrew Vioxx in 2004 after
the painkiller was linked to heart
attacks and strokes, it triggered an
uproar over drug safety. Critics
charged that drug companies snared
customers with clever marketing
campaigns that overstated drug
benefits and underplayed risks.
Plaintiffs lawyers filed some 28,000
lawsuits against Merck. They accused
the industry of putting profits
ahead of safety, and the FDA of
allowing unsafe products to reach
the market.
Merck
spokeswoman Amy Rose says the
company's "voluntary withdrawal
of Vioxx, whether pivotal or not,
was taken in the interests of
patients."
Kenneth
Kaitin, director of the
Tufts
Center
for the Study of Drug Development,
says: "Everything pointed to
the notion that the FDA and the
industry had lost their compass, and
that the FDA needed a course
correction." With the ensuing
changes, he says, the FDA is now
"viewed as an agency that is
supposed to keep unsafe drugs off
the market, not to speed access to
life-saving drugs."
The
FDA's Dr. Woodcock says that the
quality of research coming out of
the pharmaceutical industry is
slowing the number of drug
approvals. New drug applications
submitted by the industry, she says,
dropped 33% in 2006, which helps
explain the decline in 2007
approvals. "You can't approve
drugs you don't get applications
for," she says.
The
constant criticism of the FDA, she
says, has hurt employee morale and
depleted staffing. Since last
October, her group has been working
to fill 500 vacancies among its
staff of 2,700 reviewers. That
process, as well as training the new
hires, is contributing to delays in
reviewing drug applications, Dr.
Woodcock acknowledges.
Over
at Schering-Plough, Mr. Hassan
remains convinced there's been a
paradigm shift, and he's been taking
a hard look at medicines in the
company's pipeline. In the spring of
2007, Schering-Plough canceled a
program studying good cholesterol
and abandoned plans to license a
cholesterol drug. Later in the year,
it scrapped an obesity medicine
after Sanofi-Aventis's Acomplia,
which worked in a similar way, ran
into regulatory trouble. Although
Schering-Plough's researchers
believed its version might have less
pronounced psychiatric side effects,
Mr. Hassan and his team killed the
effort because they may have had to
mount large and expensive clinical
trials, with little certainty that
the studies would resolve the safety
question.
Voluminous
Testing
Now
Schering-Plough is weighing the
future of a novel pill for multiple
sclerosis, called a VLA4 antatonist.
It's a concept that Mr. Hassan and
his researchers still believe in.
But a related medicine made by
Biogen Idec Inc. and Elan Corp.,
called Tysabri, was temporarily
withdrawn after it was linked to
several cases of a rare brain
infection. Now the Schering-Plough
team is unsure about whether to
invest in the voluminous testing the
FDA could require in the wake of the
scare.
Schering-Plough's
version of the medicine would be
taken orally, unlike Tysabri, which
requires a once-a-month intravenous
infusion, typically in a doctor's
office. Stephen Lore, a 51-year-old
retired lawyer from
Atlanta
with multiple sclerosis, says he had
heard the drug industry was working
on an oral version, and that he
"absolutely" wants to try
it. He says he had tried almost
every therapy on the market before
finding relief in 2005 with Tysabri.
When
Tysabri was pulled from the market
later that year, Mr. Lore says, he
was emotionally and physically
devastated by the return of his
symptoms, including stumbling,
slurred speech and vision problems.
He blames an overreaction at the FDA
for his relapse.
Mr.
Lore says he was one of the first
patients to go back on Tysabri in
2006, when it returned to the market
with the FDA's strongest warning.
Taking the medicine again made him
feel like he'd "walked through
a fountain of youth," he says.
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