Risky RX, PART 3 of 3

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Risky RX

 

 

 

 

 

 

Posted on Tue, Nov. 04, 2003PART 3 of 3

FDA oversight of 'off-label' drug use wanes

By CHRIS ADAMS and ALISON YOUNG

Knight Ridder Newspapers

 

 

WASHINGTON — In 1962, a Congress horrified that thousands of European babies had

been deformed by the medication thalidomide ordered the Food and Drug

Administration to make sure the same thing never happened in America.

 

Congress gave the FDA the power to assess the safety and effectiveness of all

drugs before they could be sold on the U.S. market.

 

Forty years later, however, an ever-growing segment of the American

pharmaceutical business is eluding that rigorous scrutiny. Millions of patients

are being given drugs by their doctors that the FDA hasn't approved for treating

their particular illnesses. Off-label prescribing, as it's called, puts patients

at risk while offering no assurance the drugs will work.

 

And while the FDA has argued in court that the " risk to the public from unproven

uses of drugs and devices is both real and substantial, " the agency rarely has

tried to curb it. When it attempted to do so in the 1990s, its efforts fizzled.

Now as the phenomenon soars — Knight Ridder found that off-label prescribing for

a sample of top-selling drugs has nearly doubled in the last five years — the

Bush administration has opened the door to doing even less to stop it.

 

 

Saying recent court rulings have eroded its power, the FDA has sought public

comment on whether drug makers should have more leeway to market the unapproved

uses of their profitable drugs. Overseeing the effort is a Bush appointee who,

before coming to the FDA, helped sue the agency over its marketing and

advertising restrictions.

 

" They certainly are backing off, " said Michael Wilkes, the vice dean at the

School of Medicine at the University of California, Davis. He studied off-label

promotions for the FDA in the 1990s.

 

In part, the agency is handcuffed by a conflicted mandate from Congress. The FDA

is trying to do many things: Get powerful drugs to market while protecting the

public, respect the First Amendment while regulating drug advertising and let

doctors practice as they see fit — except when they make dumb errors. Given the

rapidly growing number of drugs in the marketplace, prescribing is far more

complicated for doctors today.

 

" There's some limit to what the federal government should do, I think, because

it's not going to be effective, " said Dr. Janet Woodcock, the director of the

FDA's drug division. " You can't just Band-Aid and patch something that has

systemic, underlying problems. "

 

But it's also clear that the agency hasn't followed through on its limited

efforts to reduce the risks of off-label drug sales:

 

 

Under FDA rules, if a drug maker knows a drug is being used for off-label

purposes, it's required to come forward with evidence supporting those

unapproved uses. FDA officials said in a court deposition that the rule had not

been enforced.

 

 

 

 

After the FDA took a major drug company to court in 1993 and won a hefty payment

for overt off-label sales pitches, its commissioner vowed to use such sanctions

again to control illicit marketing. But FDA officials could point to no other

case since then when they have.

 

 

 

 

Last year, the FDA issued 28 violation letters for improper drug marketing, down

from 158 in 1998. The agency said it would need nearly twice as many people to

adequately police the industry's 37,000 advertisements and other promotions each

year.

 

 

 

 

Twenty-four years ago, the FDA said it wanted to ensure that patients got

useful, easy-to-understand information about the drugs they took. Most still

don't.

 

 

The bottom line for consumers: Beware.

 

" We as patients have got to raise the questions ourselves and take care of our

own selves, " said Jere Goyan, who was FDA commissioner from 1979 to 1981.

 

MISUSE OFTEN ENCOURAGED

 

 

The drug Kristen Pettijohn took was called Avelox. It's part of a family of

antibiotics called fluoroquinolones.

 

Those powerful but risky drugs are intended for patients who are fighting

particular bacterial bugs. But they're widely prescribed off-label for less

serious illnesses, sometimes even to treat viruses, which can't be killed by

antibiotics.

 

A study this year funded by the National Institutes of Health reviewed 100

emergency room prescriptions for fluoroquinolones and found that only 19 were

written for appropriate conditions and only one was given in the correct dose

and for the proper duration.

 

The FDA long has been aware of the possibility that Avelox could be misused.

 

Just before it approved Avelox in 1999, a member of the agency's expert review

panel — Robert Danner, a critical care expert at the NIH — offered a warning:

" This is exactly the kind of place that you get into trouble. … I am absolutely

convinced that the drug will be used differently once it's marketed frequently. "

 

Avelox was approved, however, and marketed hard by Bayer Corp. In 1999 and 2001,

the FDA admonished company officials for encouraging unapproved uses.

 

This past May, Pettijohn, a gregarious 23-year-old nursing student from

Batesville, Ind., who recently had gotten engaged, picked up the persistent cold

that had been running through her family. " Her version was a little worse than

ours, " said her father, Gary Pettijohn. " I would say it was moderate at best. "

 

Early in the morning of May 15, Pettijohn's mother took her to an emergency

room. Going there, Pettijohn told her mom, would be quicker than waiting for an

appointment with their family physician.

 

Forty-two minutes later, Pettijohn was on her way to the drugstore. The doctor

had diagnosed her with acute bronchitis and prescribed Avelox. The potent

antibiotic's label says it's approved for cases of chronic, or long-term,

bronchitis, and only after blood tests have been taken to identify the bacteria

causing the problem. Her medical records show no blood work was done.

 

That was a Thursday. By Sunday, Pettijohn was nauseated and suffering abdominal

pain. Her mother packed a plastic bag with the remaining Avelox pills and took

her to the hospital.

 

Over the next five days, Pettijohn was incoherent. She had a burning rash and

her skin began peeling off. She slipped into a coma, resting on an air bed,

totally wrapped as though she were a severe burn patient.

 

By Wednesday, a doctor approached Gary and Ruth Pettijohn.

 

" Our problem just got twice as difficult, " he said. " She has two

life-threatening conditions simultaneously. "

 

Pettijohn's liver was in full failure, and she was experiencing a form of

Stevens-Johnson syndrome, a rare and extreme drug reaction mentioned on the

Avelox label.

 

She had a liver transplant on Friday. The doctors reported that her old liver

had turned to mush and fallen apart in their hands.

 

Soon after the operation, Pettijohn had a heart attack, then another. Her death

certificate cited Avelox as the prime contributing factor in her death.

 

The hospital had no comment about her death. Bayer had no comment beyond saying

the death " was promptly and accurately reported to the FDA, " and that it thinks

its antibiotic should be prescribed only for approved conditions.

 

FIXES FALL SHORT

 

As Congress reworked the nation's drug-safety laws after thalidomide, it sought

to create a regulatory system that guaranteed that the drugs Americans used were

safe and effective.

 

Lawmakers in 1962 worried that drug makers might be tempted to get a medication

approved for one use and then promote it for others. " The initial claim would

tend to be quite limited, " said a group of senators led by the late Tennessee

Democrat Estes Kefauver. " Thereafter, the sky would be the limit. … Extreme

claims of any kind could be made. "

 

Congress told the FDA to require stringent tests before a drug could get to

market. Once a drug passed, a company could advertise it only for the approved

uses.

 

The FDA began reviewing all the drugs that had been on the market as of 1962,

when the new approval rules kicked in. Of 3,443 drugs commonly prescribed,

1,124, or one-third, were deemed useless and taken off the market, FDA records

show.

 

Even though that shows that doctors often can't judge drugs' effectiveness, the

FDA largely has stayed out of the doctor's office.

 

The agency's rules say it can require a drug company to prove that an off-label

use is safe and effective. The FDA has said that a drug's " actual use " by

doctors can show a drug maker's " intent " in selling it.

 

However, asked in a lawsuit deposition in 1996 if the FDA had ever considered

using the option of requiring proof of off-label effectiveness, the agency's Dr.

Robert Temple replied: " We think about this all the time. … We just don't know

quite how to do it. "

 

Knight Ridder found that the off-label use for some drugs is as high as 90

percent of all prescriptions sold for it.

 

 

Off-label uses became a concern in the 1990s, under the activist tenure of

then-Commissioner David A. Kessler, who noted that " medical history is replete

with examples of products and procedures that were based on medical anecdote,

not evidence, and were thought for years by most clinicians to be effective, but

later turned out to be useless and sometimes even dangerous. "

 

In 1991, the FDA established a task force to examine off-label uses of drugs and

medical devices.

 

The agency also found that drug companies often had no incentive to evaluate the

merits of off-label prescribing because they might discover that their drugs

didn't work when prescribed off-label and sales would suffer, according to a

review of FDA records.

 

The drug makers, which are among the most profitable industries in the United

States, know they can continue to get off-label sales without going through the

expense of proving a drug's effectiveness for the off-label use to the FDA.

 

Also interfering is the patent protection process. Once a drug's patent lapses,

there's little financial interest in taking on the added costs of new FDA

application.

 

Based in part on the work of the off-label task force, the FDA attempted a host

of fixes. But a decade later, those efforts largely have fallen short:

 

 

 

One push was to have companies apply for FDA approval for popular off-label

treatments. While the effort initially produced more applications, the numbers

have been dropping. From 1998 to 2002, the number of approvals for new uses of

existing drugs went from 74 to 39, according to the FDA.

 

 

 

 

An attempt to revise the prescribing labels for doctors has dragged on for more

than 10 years. The agency says its labels are confusing even for doctors, and

that fixing them could reduce medication errors.

 

 

 

 

Proposals to give patients more meaningful drug information have been stalled

even longer. The FDA repeatedly backed away from plans, dating to 1979, to

ensure that all patients get basic information about the drugs they buy.

Opposition has been fierce. Doctors have argued that the information would

frighten patients unnecessarily. Today, most of the leaflets patients get about

drugs are part of an industry-run voluntary program. The quality of the

information they provide varies widely, with only about half of the leaflets

studied meeting FDA goals for usefulness, according to an FDA-commissioned study

announced last year.

 

 

 

 

Proposals to restrict drug makers' efforts to get around the ban on promoting

off-label drug uses ran into a blizzard of legal challenges by the Washington

Legal Foundation, a free-market advocacy group. On free-speech grounds, the

courts turned away many of the FDA's arguments; U.S. District Judge Royce

Lamberth said the " FDA exaggerates its overall place in the universe. "

 

 

Helping the Washington Legal Foundation make its case was Daniel Troy, a

prominent First Amendment and corporate lawyer. Today, Troy is chief counsel of

the FDA, a Bush administration appointee who has started a process that could

substantially rewrite the FDA's rules on commercial speech, including those

regulating off-label drug promotions.

 

The pharmaceutical industry has jumped on the opportunity, pushing the agency to

relax some of its restrictions on promoting off-label uses. Consumer groups,

such as Public Citizen Health Research Group, and many congressional Democrats

say to do so would invite disaster.

 

FDA Commissioner Mark B. McClellan, a physician, said the agency would like to

see more evidence submitted about off-label uses, stressing that it was

important for such treatments to meet the " gold standard " of FDA approval.

 

To help curb risky off-label prescribing, he wants to improve the FDA's system

for reporting drugs' side effects, and he wants better information in the hands

of doctors and consumers. The effort to rewrite the labels doctors read will be

finished " in a matter of months, " he said. " I think we can do much better than

we have. "

 

The FDA has had some success using its authority to get the pharmaceutical

industry to study drugs' affects on children and put that information on the

label. Those efforts, begun in the 1990s and involving congressional and agency

action, have produced some results, although they recently have been set back in

court.

 

'INTOLERABLE RECORD OF COMPLIANCE'

 

 

In many ways, the FDA's 1962 mandate to determine whether drugs are safe and

effective is irrelevant in today's market, in which some off-label treatments

have become so widespread that they're now considered the standard of care.

 

Amiodarone — under the brand name Pacerone — was the drug taken by George Cox, a

Buckner, Mo., man who lost nearly all his sight, and by Martha Andreasen of

Bowie, Texas, who's struggling with lung damage.

 

Amiodarone can have a devastating effect on the lungs: As many as 17 percent of

patients in some studies experienced lung damage, and about 10 percent of them

died. Patients taking the drug have suffered thyroid, liver and eye problems,

including blindness. The FDA approved it only as a drug of last resort for

patients with a life-threatening heart condition called ventricular tachycardia.

 

In 1999, Cox, now 75, was given amiodarone for atrial flutter, a heart condition

that isn't life-threatening. He got the prescription a full decade after the FDA

began telling the drug's makers to stop promoting it as something other than a

last-resort drug.

 

Andreasen also was given amiodarone off-label. She had atrial fibrillation, a

common heart problem similar to atrial flutter. Like many patients, she said she

was never warned of the drug's risks or that her prescription was off-label. Her

pharmacy leaflet mentioned nausea and dizziness, but not death from lung

problems.

 

Today, Andreasen is tethered to an oxygen tank each night, and at age 54 she's

already made her funeral arrangements. She's homebound and doesn't have the

strength to clean her house, a humiliating letdown for a woman who's been a

member of her town's Young Homemakers club for 30 years. Since she was dropped

by her husband's health insurance, the Andreasens now pay $800 a month for

high-risk insurance and co-payments. Their dining room table sits atop plywood

because they can't afford to finish a repair to the floor.

 

" The FDA is supposed to protect the general public from situations such as this

— or so I thought, " Andreasen said.

 

Since at least 1988, the FDA has warned two drug companies to stop false and

misleading promotions that downplayed amiodarone's risks while suggesting it as

a first-line therapy. The agency sent letters to amiodarone makers in 1989, 1992

and 1998. " Your firm has an intolerable record of compliance with the law, " read

the 1989 letter to Wyeth, one of the amiodarone makers.

 

Wyeth's promotions continued. From 1999 to 2002, a slick magazine-style brochure

that Wyeth paid for proclaimed " Amiodarone From Last to First-Line

Antiarrhythmic Therapy " on its glossy purple cover.

 

Wyeth spokesman Doug Petkus said the brochure was educational, not promotional.

Regardless, Wyeth no longer is doing any promotion of its amiodarone drug,

Cordarone, because its patent protection has expired.

 

After Cox lost most of his sight, his Missouri pharmacist gave him Wyeth's

" First-Line " brochure, and he passed it on to the FDA in 2001.

 

The agency wrote back, saying it can " take action when unapproved (off-label)

uses become widespread or endanger the public health, " but until last month it

had done little to try to curb the widespread off-label prescribing of

amiodarone.

 

In the last year, doctors wrote nearly 2.3 million off-label amiodarone

prescriptions, according to Knight Ridder's analysis. That's 82 percent of all

the prescriptions for the drug.

 

In response to Knight Ridder's findings, the FDA's Woodcock said the agency

would require that all amiodarone prescriptions be accompanied by an

FDA-approved patient guide to ensure that consumers know exactly what the drug

is approved for and what its dangers are. Patients will get the guides starting

early next year.

 

" What you brought to the table was the extent of off-label use and some specific

patient experiences of not getting all of the information about this drug, "

Woodcock said.

 

" Obviously this drug is a very risky drug, " she said.

 

While many cardiologists defend amiodarone's off-label use for atrial

fibrillation, a recent NIH study challenged their long-held beliefs.

 

Called AFFIRM, the study concluded that patients taking drugs such as amiodarone

to control their hearts' rhythm experienced more side effects and

hospitalizations than those given safer drugs to control how fast their hearts

beat. For all its extra risks, amiodarone was no more effective.

 

Dr. Claude Lenfant, the recently retired director of NIH's National Heart, Lung

and Blood Institute, said amiodarone didn't appear to be the best treatment for

many patients with atrial fibrillation. But changing a doctor's practice " takes

place very, very slowly. "

 

" I personally feel there's a system failure, " he said.

 

OFF-LABEL USE SOARS

 

Even when it's aggressive, the FDA has been unable to stem off-label

prescribing.

 

For more than a decade, the FDA has tried to corral the use of Accutane — a drug

for severe forms of acne — which can cause birth defects.

 

As early as 1990, a frustrated FDA official wrote that " intensive regulation has

not, cannot and will not achieve the Agency's goal of eliminating pregnancy

exposure to Accutane. " At the time, the official estimated that 90 percent of

Accutane's use by women was off-label, typically for mild acne that can be

treated with safer drugs.

 

Even tough new warnings on the drug's label about suicide, psychosis and

depression didn't stop sales.

 

According to an internal company sales plan for 2001, drug maker Roche concluded

that despite extensive media coverage about those new dangers, " prescribers were

apparently unmoved by this information. "

 

In 2002, the same FDA official made another estimate that 90 percent of Accutane

use was off-label. The company disputes the FDA estimate.

 

FDA IRRELEVANT?

 

Thalidomide's entry into the U.S. market shows how physicians and the drug

industry consider the FDA irrelevant.

 

The drug was approved in 1998 for a leprosy-related skin condition that's

virtually nonexistent in the United States.

 

After studies showed that the drug might be useful for treating multiple

myeloma, a form of cancer, Celgene Corp. aggressively sold that idea to doctors.

 

One company sales representative went further, telling an oncologist that the

drug, marketed as Thalomid, is " good for weight loss, " could be used " as an

appetite stimulant " and is a " great drug for feelings of general well-being, "

according to an FDA document describing the sales pitch.

 

When the doctor asked whether the FDA had approved Thalomid for those uses, the

sales rep said, " No, but do you want some material anyway? "

 

In 2002, the FDA told Celgene that its existing data on multiple myeloma

wouldn't be enough to win the agency's approval. The earliest the company says

it might seek authorization as a treatment for that form of cancer is 2005.

 

Today, 70 percent of Thalomid uses are for multiple myeloma, while only 1

percent are for its approved leprosy condition. Celgene, in filings with the

Securities and Exchange Commission, declared: " We may not be able to attain or

maintain profitability " if physicians prescribe Thalomid only for patients who

are diagnosed with leprosy.

 

(Knight Ridder Newspapers Researcher Tish Wells contributed to this report.)

 

 

 

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