Flaws in drug agency put consumer at risk

[Guest guest]

(This story was the main headline on the front page of the print edition of the

Sunday Chicago Tribune.)

 

 

http://www.chicagotribune.com/features/health/chi-0502200340feb20,1,5226641.stor\

y?coll=chi-news-hed

 

THE FDA AND DRUG SAFETY

 

Flaws in drug agency put consumer at risk

Critics of FDA cite conflicts of interest, lack of enforcement authority

 

By Judith Graham and Frank James, Chicago Tribune staff reporters. Judith Graham

reported from Denver and Frank James from Washington; Tribune staff reporters

Bruce Japsen and Ronald Kotulak also contributed

 

February 20, 2005

 

Safeguards designed to protect Americans from potentially dangerous medications

are being eroded by conflicts between federal bureaucrats who approve new drugs

and those who oversee their safety, according to former and current officials at

the U.S. Food and Drug Administration.

 

FDA regulators rush to review applications for new medicines but are slow to

address serious problems that surface with the drugs once they come on the

market, interviews with physicians, scientists, government officials and medical

school researchers suggest.

 

Defenders of the FDA say the understaffed agency is under enormous pressure to

get medications into the hands of people who need them and to balance the

potential benefits of drugs against their risks.

 

But even those who are sympathetic agree the FDA faces staggering problems that

have been building for years--and that it has a long way to go to regain the

confidence of a public worried about potentially devastating side effects of

medications.

 

" The credibility of the FDA is on the line, " said Dr. David Kessler, who headed

the agency from 1990 to 1997 and now is dean of the school of medicine at the

University of California, San Francisco.

 

The troubles at the agency come as the Bush administration struggles to contain

controversy over the popular painkiller Vioxx, which surfaced when people using

the drug suddenly learned late last year they were at higher risk of heart

attacks and strokes. Merck & Co. voluntarily recalled the drug Sept. 30.

 

An FDA advisory panel recommended Friday that Vioxx be made available to

consumers, but under restricted conditions and with strict warnings attached.

Similar drugs with similar cardiovascular side effects should also carry the

warnings, the panel advised.

 

Last week, the administration sought to defuse some of the criticism aimed at

the FDA, saying it would appoint a permanent commissioner--a position that has

been vacant for almost a year--and create a new Drug Safety Oversight Board. The

president's budget also shored up funding for the FDA's current Office of Drug

Safety.

 

But critics say those actions do not fully address deep-seated flaws plaguing

the FDA, including conflicts of interest, a lack of attention to safety issues

and a lack of authority in forcing industry to heed its recommendations.

 

" If the FDA knows there are problems with a drug, they should do something, "

said Bill Luby of Buffalo Grove, who took Vioxx for two years before having a

heart attack in October 2003. " I would rather not have gone through all this. "

 

The FDA's trials are far from over. It is being investigated by two high-profile

committees in Congress, examined by the General Accounting Office, evaluated by

the Institute of Medicine and scrutinized in several drug-safety related

lawsuits around the country.

 

Several lawmakers, including Sens. Chris Dodd (D-Conn.) and Charles Grassley

(R-Iowa) have been preparing legislation that would mandate significant reforms

for the agency.

 

The criticisms are deeply painful to staff at the FDA, including large numbers

of dedicated scientists. " All these folks have given up more lucrative types of

jobs ... because they think [that here] they'll make a difference to health, "

said the FDA's deputy commissioner, Dr. Janet Woodcock.

 

" I believe that the people [who] take drugs to prevent the risk of heart

disease, to lower their blood pressure, to treat their depression, their

arthritis, are glad they have access to these medications, " she said.

 

Roots of crisis

 

The roots of the current crisis date to an earlier time of tumult in the late

1980s when AIDS activists complained that the FDA was too slow to approve

potentially life-saving new drugs.

 

Congress took note and in 1992 passed a law imposing user fees on drug companies

to help fund expedited drug reviews. Many experts believe that was a turning

point for the agency.

 

Kessler describes it this way: " The FDA became preoccupied with rapid drug

reviews and less attention was paid to safety. "

 

Kessler was in charge at the FDA in 1992 when the Prescription Drug User Fee

Act, or PDUFA, was enacted. The goal was to expand the agency's drug review

staff, making it possible for the agency to process new drug applications

faster.

 

That process took 33 months, on average, in 1992. Today, drug company user fees

total more than $200 million a year, review times have dropped to an average of

about 13 to 14 months and the pharmaceutical industry professes to be very

satisfied with the results.

 

" We've come a long way in the last 12 years and the beneficiaries are the

millions of patients who now receive life-sustaining medicines more quickly, "

said Alan Goldhammer, associate vice president of regulatory affairs at

Pharmaceutical Research and Manufacturers of America.

 

But critics contend the drug user fee act also transformed the relationship

between the FDA and industry, making regulators financially dependent on the

regulated industry.

 

" At the very least, it created an appearance of a conflict of interest, " said

Arthur Levin, who heads the Center for Medical Consumers, an advocacy group, in

New York.

 

Kessler doesn't see it that way. " Just because you pay an application fee when

you apply to college doesn't mean you get in, " he said. " I do not believe we

lowered our standards one bit. "

 

If anything, the law has had a positive effect, according to Deputy Commissioner

Woodcock. " It really improves the premarket program. It puts a lot more science,

a lot more ability to do scrutiny, [more] people to do work-ups of drugs, " she

said.

 

What did change over time was priorities within the FDA's drug division, largely

because user fees came with strings attached, according to Kessler and several

past and current officials.

 

One stipulation was that the FDA conduct reviews within certain time

periods--most drugs had to be assessed in a year, initially--as a condition of

receiving funds. Meeting this performance standard " consumed resources and

management attention, " Kessler said, and " rapid reviews became the currency

within the agency, " distracting resources and attention from safety evaluations

of already-approved drugs.

 

Another stipulation was that the FDA's budget for new drug reviews not fall

below a certain level--a requirement that forced the agency to devote

increasingly significant resources to drug reviews and approvals.

 

More than 1,000 people now work in the FDA's Office of New Drugs, compared with

about 110 in the Office of Drug Safety, which evaluates the safety of drugs once

they are on the market.

 

" PDUFA should have had funding on the safety side from the beginning, but the

industry refused to accept that, " Kessler said, acknowledging the imbalance. " We

wanted it. The industry said no. "

 

The drug industry tells a different story.

 

" I do not recollect funding of the Office of Drug Safety being put on the

table, " said Goldhammer, who was on the industry team negotiating the

Prescription Drug User Fee Act. " The major focus of the discussions ... was to

provide the FDA with extra resources to eliminate the backlog of pending license

applications. "

 

When the FDA proposed that some user fees start to fund safety work in 2002, the

industry supported that, he said.

 

Drug safety efforts strained

 

As the process of reviewing and approving drugs has quickened, the job of the

Office of Drug Safety has become increasingly important.

 

Far more new drugs are launched in the U.S. than in the past, and Americans are

now more likely to suffer unexpected side effects of new medications. In 1980,

only 2 percent to 3 percent of all new drugs were introduced in the United

States; by 1998, it was 60 percent, according to the Journal of the American

Medical Association.

 

Yet the drug safety office, which is supposed to identify and track dangers

associated with medications after they have been approved, remains money-starved

and a " second-class citizen " within the FDA's drug division, several current and

former officials said.

 

None of the recommendations of the drug safety office are binding. If staff

members identify a potential problem with a drug, at best they can raise an

alert and serve as consultants to other agency officials who make decisions.

 

Furthermore, all negotiations over regulatory actions have to go through the

FDA's Office of New Drugs. That raises a significant potential for conflict of

interest because the staff in the office that reviews and approves drugs and is

unlikely to want to admit mistakes.

 

" The Office of New Drugs drives the bus and calls the shots and makes the

policy, " said Dr. David Graham, associate director of science in the drug safety

office, who publicly criticized the agency last November during congressional

hearings. " But they cannot remain objective and impartial. "

 

Woodcock doesn't agree. " It's important to understand that the new drug people

spend about half their time on drug safety issues, " she said. " It's still a

fundamental focus of the agency as far as review goes. "

 

Several experts believe the FDA's Office of Drug Safety needs to become an

independent, more powerful entity within the FDA. Among them is Grassley, the

powerful chairman of the Senate Finance Committee, who is drafting legislation

to ensure " that the drug safety office within the FDA be made a truly

independent entity from the Office of New Drugs. "

 

Funding seen as key

 

Dr. Frank Young, who was FDA commissioner from 1984 to 1989, supports the idea

but warns that changing the agency's structure alone won't do the job. An

independent drug safety office will only work if " provided enough resources, " he

said. If Congress is serious about reform, it will step up to the plate with

more funding, he added.

 

Woodcock says the agency is " open to any suggestions people might have " about

restructuring the Office of Drug Safety, " but we strongly feel ... you just

can't look at [drug] risks alone. "

 

Whatever changes are made, the fundamental job of the agency will remain making

sure " the benefits of [new drugs] outweigh the risks, " she notes, and that will

require constant communication between drug review and drug safety officials.

 

Most consumers assume a medication is safe if the FDA has approved it. That's

what Ronald Boros, a 6-foot-4-inch construction manager from Swartz Creek,

Mich., thought when he began taking Vioxx in September 2000 for a bad back.

 

Neither Boros nor his doctor knew about a study Merck had completed earlier that

summer that raised serious questions about Vioxx's safety.

 

In the meantime, there was no reason to suspect anything might go wrong. For 2

1/2 years, Boros watched his diet, monitored his blood pressure, worked out on

the treadmill, took pills to lower his cholesterol and took his Vioxx daily.

 

But age was catching up with Boros, who is now 55. In May 2003 he began to have

sharp, arthritis-induced pains down his arm. A family doctor recommended that he

double his Vioxx dose to 50 milligrams for about two weeks, then go back to a

25-milligram dose. When the arthritis moved into his shoulder, the doctor upped

the dose to 50 mg. again.

 

Boros had his first heart attack that July 30 followed by a second attack Aug.

14, 2003.

 

" That one they had to paddle him eight times to bring him back, " said his wife,

Diane. " It burned him real bad. "

 

Still, Boros went back on Vioxx until another heart scare a few weeks later left

him with a defibrillator in his chest and a sense that his life would never be

the same.

 

" You find yourself wondering how long are you going to live now, you know,

because the heart is damaged, " Boros, a father of six young men, said.

 

" He's depressed, " his wife said bluntly.

 

A year later, when Boros learned Vioxx was being pulled off pharmacy shelves, he

immediately wondered whether the medication that had eased his pain had also

hurt his heart. Though he'll never know, he says he wishes information about the

drug's potential dangers had come out sooner and received more attention.

 

" If the company had come out with it, or the government, then maybe my doctor

would have given me an option, " Boros said, a note of sadness in his voice.

" Maybe they would have told me, `Ron, you shouldn't be taking this.' " In exchange

for allowing drugs to be approved quickly, " We deliberately allow [medications]

on the market knowing that some side effects won't be detected for months or

years down the line, " said Dr. Brian Strom, professor of public health and

preventive medicine at the University of Pennsylvania School of Medicine.

 

" The real question is, are we doing enough once these drugs are out there in the

way of post-marketing surveillance? And the answer to that has to be no. "

 

Unknown risks

 

The history of Vioxx illustrates how much can remain unknown about drug safety

even after medications are approved, and how limited the FDA's authority is even

after safety problems do surface.

 

As with other drugs, Merck studied Vioxx extensively before asking the FDA to

review the medication on an expedited six-month schedule in 1998.

 

Most of these studies were relatively small and short-term, which is not

unusual. New drugs generally are studied in several thousand patients for

periods less than a year before the FDA decides whether to approve the

medications.

 

Of 5,435 patients who received Vioxx in clinical trials prior to approval, only

752 took what would be considered " normal " doses for more than a year.

 

Any side effects associated with long-term use of the drug wouldn't show up

under these conditions, said Dr. Curt Furberg, an expert in clinical trials and

professor of public health sciences at Wake Forest University. Nor would rare

side effects--say, those occurring once for every 5,000 or 10,000 people--be

likely to appear because of the small numbers.

 

Vioxx promotion

 

Within just a few years, Vioxx was being used by millions of Americans. Heavy

promotion and advertising pumped up sales for the drug far beyond its original

intended market--people with arthritis who couldn't take other painkillers

because of stomach complications.

 

An astute FDA medical officer noted early on that data in pre-approval clinical

trials suggested the drugs might contribute to " thromboembolic events " such as

heart attacks and strokes. To confirm this, however, a much larger study was

needed.

 

Such a study--one that specifically focused on possible cardiovascular risks

associated with Vioxx--was contemplated by Merck but never carried out.

 

There was little the FDA could do about that. Though it's easy for critics to

blame the FDA for not doing enough about dangerous drugs, the agency is

hamstrung by a lack of regulatory authority in its dealings with drug companies.

 

The FDA, for example, doesn't have the power to restrict prescriptions of drugs

for uses not approved by the agency. Once a drug is on sale, the agency's

ability to restrict marketing and promotion--or limit the drug to a particular

group of patients--is limited.

 

Perhaps most important, according to several drug safety experts, the FDA cannot

compel pharmaceutical companies to perform clinical studies to resolve safety

questions that arise about drugs on the market.

 

That means such studies almost never get done, as drug companies have little

incentive to undertake research assessing the safety of drugs they already are

selling. According to information published in the Federal Register, fewer than

half of the studies that companies agree to do after a drug is approved are

started.

 

After substantial delays, Merck agreed to examine the potential for serious

heart-related side effects in three separate clinical studies of Vioxx. But the

primary purpose of the studies was to encourage the FDA to approve new uses of

the drug so Merck could market it more broadly.

 

A study focused on safety and conducted earlier would have been far more useful

in answering questions about Vioxx's effects on the heart and ending the debates

that stalled action on the drug for years, said Furberg, a member of the FDA's

drug safety advisory committee.

 

The agency didn't find it easy, either, to change Vioxx's label to reflect the

risks of heart attacks and strokes, which were first demonstrated through Merck

research in 2000. The agency can't mandate certain language for a label or set

deadlines; it must negotiate with the drug company.

 

The FDA recently released a timeline of events surrounding the proposed Vioxx

label change that reveals the difficulties the agency encountered with Merck.

 

On Sept. 21, 2001, FDA officials recommended the Vioxx label include " balanced

information regarding safety risks of Vioxx " and de-emphasize the

gastrointestinal safety advantage of the drug.

 

Negotiations with Merck dragged on so long that it was April 2002 before the

medication's label finally was changed--nearly two years after the study

demonstrated the risks.

 

Such scenarios shouldn't happen again when the proposed new FDA Drug Safety

Oversight Board gets off the ground, government officials say. That body will

disseminate information about drug risks on a more timely basis through a new,

FDA-sponsored " Drug Watch " Web page and through easy-to-understand fliers to

patients and physicians.

 

The new board will do nothing, however, to offset the huge impact of

direct-to-consumer drug advertising, which strongly influences the way

medications are prescribed and taken. Nor will it address large gaps in the

FDA's authority, contends Dr. Bruce Psaty, professor of medicine, epidemiology

and health services at the University of Washington.

 

" It's hardly an adequate solution, " he said.

 

From a consumer's perspective, the most important thing is that people be told

when drugs are discovered to have serious side effects, said Kathi Maraffino,

who lives in the Chicago area.

 

Her husband, Michael, a healthy, active 50-year-old, died of a massive heart

attack in June after taking Vioxx for three months, leaving Maraffino wondering

if the drug was somehow involved.

 

To this day, it bothers her that her husband's doctor didn't warn him that Vioxx

could be dangerous to some people.

 

" As a consumer, shouldn't we know if there's danger with [the drugs we take] so

we can pick and choose our own fate? " Maraffino asked.

 

" I'm not opposed to drugs that are going to help people. But if there are

dangers--especially for a drug for something like pain--they should let you know

and let you decide. "

 

- - -

 

Assessing drug safety

 

The Food and Drug Administration (FDA) examines the safety of new drugs before

and after they are approved. But concerns about the effectiveness of these

reviews have mounted over the last year, fueled by a controversy over the

popular painkiller Vioxx.

 

BEFORE FDA APPROVAL

 

Drug manufacturers study hundreds to thousands of volunteers in three separate

phases.

 

PHASE 1

 

20 to 100 healthy volunteers are tested to determine the drug's safety, dosage

amount and activity in the body.

 

PHASE 2

 

100 to 500 volunteer patients with the targeted disease are tested to evaluate

the drug's effectiveness and side effects.

 

PHASE 3

 

1,000 to 5,000 volunteer patients in clinics and hospitals are monitored to

confirm the drug's effectiveness and identify adverse reactions.

 

AFTER FDA APPROVAL

 

There is no coherent system for monitoring the safety of drugs after

 

they are approved. Information is fragmented and comes from several sources.

 

CASE REPORTS

 

Physicians write up examples of adverse drug reactions in medical journals.

These accounts are anecdotal and often the first evidence of actual clinical

experience.

 

ADVERSE DRUG REACTION REPORTS

 

Physicians, pharmacists and other medical professionals can voluntarily submit

information about patients who reacted badly to drugs to the companies or to the

FDA's MedWatch system. Up to 10 percent of adverse drug reactions are actually

reported.

 

POST-MARKETING CLINICAL TRIALS

 

Companies can launch studies of drugs after they're approved, and a drug's side

effects can be documented through this research. Most companies do not undertake

post-marketing studies, however, even when they've promised to do so.

 

ACTIVE SURVEILLANCE

 

Northwestern University is part of a national group that develops theories about

which drugs might be dangerous, gathers evidence from several sources, documents

side effects and identifies circumstances under which drugs can be harmful.

 

EPIDEMIOLOGICAL STUDIES

 

Large databases can provide information about what happens with people who take

drugs in the real world. The FDA recently said it planned to examine databases

of Medicare patients to look for drug-related trends in elderly people.

 

Chicago Tribune

 

Sources: Boston Collaborative Drug Surveillance Program, Pharmaceutical Research

and Manufacturers of America, FDA and interviews

 

FDA at a glance

 

The Food and Drug Administration (FDA) regulates the safety of America's drugs,

medical devices, supplements, food and veterinary products. It is the oldest

government sponsored consumer protection agency in the nation.

 

BY THE NUMBERS

 

$200 million per year

 

Amount drug companies pay per year in user fees to have their drug's safety

reviewed by the FDA

 

$28.8 billion

 

Amount spent by drug companies* on research and development in 2004

 

16.9 months

 

Average approval time for new drugs in 2003

 

35 new medicines

 

Number approved in 2003 including six for cancer, seven for genetic disorders,

three for HIV/AIDS and three for respiratory disease

 

*Pharmaceutical Research and Manufacturers of America member companies

 

MILESTONES

 

1938 The FDA is established when Congress enacts the Food, Drug and Cosmetic Act

after 107 people are killed by elixir of sulfanilamide, a drug used to treat

strep-throat infections.

 

1962 After thousands of babies are born with defects due to their mothers' use

of thalidomide, a sleeping pill, Congress passes a law requiring that drugs must

prove to be effective according to the FDA before hitting the market.

 

1970 The FDA requires patient packages to include inserts that contain

information about specific risks and benefits of use.

 

1982 FDA issues tamperresistant packaging to prevent poisons from being placed

inside the package.

 

1992 The Prescription Drug User Fee Act requires drug manufacturers to pay fees

to the FDA for an approval application. The act also requires the FDA to use

these funds to hire more employees to review these applications.

 

1995 Restrictions are proposed on marketing and sales to reduce smoking by young

people after the FDA says that cigarettes are " drug-delivery devices. "

 

1998 The painkiller Vioxx is approved by the FDA, but is recalled in September

2004.

 

PROPOSALS FOR CHANGE

 

Here are some examples of suggested changes from medical experts who think the

FDA's monitoring system needs improving. Create an independent Center for Drug

Safety

 

- Allow the FDA to mandate clinical studies of drugs already on the market, when

needed

 

- Give the agency greater power to restrict drug use only to specific patients

 

- Boost the agency's authority to restrict drug marketing and promotion

 

- Let the FDA mandate the content and timing of product label changes and

warnings about drugs

 

- Consider a system of conditional review and re-review of drugs, similar to

Europe's system

 

- Require that all clinical studies conducted pre- and postmarketing for a drug

be publicly posted

 

- Impose penalties on drug companies if they fail to conduct agreed-upon studies

or abide by marketing restrictions

 

FDA at a glance

 

Sources: FDA, New England Journal of Medicine, Journal of American Medical

Assn., interviews, testimony of Dr. David Graham, associate director, science,

FDA Office of Drug Safety, Nov. 18, 2004, Senate Finance Committee,

Pharmaceutical Research and Manufacturers of America

2005, Chicago Tribune

 

 

 

 

Laura

 

" To announce that there must be no criticism of the president, or

that we are to stand by the president right or wrong, is not only unpatriotic

and servile, but is morally treasonable to the American public. " -

Theodore Roosevelt, 7 May 1918

 

 

[Guest guest]

In this pharmaceutical enforcement environment, our government has the nerve

to deprive us of unfettered access to nutritional supplements! These people

are nuts. They place profits above life itself; your life for certain and,

at times, even their own.

 

JP

-

" lobrien " <lobrien

 

Sunday, February 20, 2005 5:48 PM

Flaws in drug agency put consumer at

risk

 

 

 

 

(This story was the main headline on the front page of the print edition of

the Sunday Chicago Tribune.)

 

 

http://www.chicagotribune.com/features/health/chi-0502200340feb20,1,5226641.stor\

y?coll=chi-news-hed

 

THE FDA AND DRUG SAFETY

 

Flaws in drug agency put consumer at risk

Critics of FDA cite conflicts of interest, lack of enforcement authority

 

By Judith Graham and Frank James, Chicago Tribune staff reporters. Judith

Graham reported from Denver and Frank James from Washington; Tribune staff

reporters Bruce Japsen and Ronald Kotulak also contributed

 

February 20, 2005

 

Safeguards designed to protect Americans from potentially dangerous

medications are being eroded by conflicts between federal bureaucrats who

approve new drugs and those who oversee their safety, according to former

and current officials at the U.S. Food and Drug Administration.

 

FDA regulators rush to review applications for new medicines but are slow to

address serious problems that surface with the drugs once they come on the

market, interviews with physicians, scientists, government officials and

medical school researchers suggest.

 

Defenders of the FDA say the understaffed agency is under enormous pressure

to get medications into the hands of people who need them and to balance the

potential benefits of drugs against their risks.

 

But even those who are sympathetic agree the FDA faces staggering problems

that have been building for years--and that it has a long way to go to

regain the confidence of a public worried about potentially devastating side

effects of medications.

 

" The credibility of the FDA is on the line, " said Dr. David Kessler, who

headed the agency from 1990 to 1997 and now is dean of the school of

medicine at the University of California, San Francisco.

 

The troubles at the agency come as the Bush administration struggles to

contain controversy over the popular painkiller Vioxx, which surfaced when

people using the drug suddenly learned late last year they were at higher

risk of heart attacks and strokes. Merck & Co. voluntarily recalled the drug

Sept. 30.

 

An FDA advisory panel recommended Friday that Vioxx be made available to

consumers, but under restricted conditions and with strict warnings

attached. Similar drugs with similar cardiovascular side effects should also

carry the warnings, the panel advised.

 

Last week, the administration sought to defuse some of the criticism aimed

at the FDA, saying it would appoint a permanent commissioner--a position

that has been vacant for almost a year--and create a new Drug Safety

Oversight Board. The president's budget also shored up funding for the FDA's

current Office of Drug Safety.

 

But critics say those actions do not fully address deep-seated flaws

plaguing the FDA, including conflicts of interest, a lack of attention to

safety issues and a lack of authority in forcing industry to heed its

recommendations.

 

" If the FDA knows there are problems with a drug, they should do something, "

said Bill Luby of Buffalo Grove, who took Vioxx for two years before having

a heart attack in October 2003. " I would rather not have gone through all

this. "

 

The FDA's trials are far from over. It is being investigated by two

high-profile committees in Congress, examined by the General Accounting

Office, evaluated by the Institute of Medicine and scrutinized in several

drug-safety related lawsuits around the country.

 

Several lawmakers, including Sens. Chris Dodd (D-Conn.) and Charles Grassley

(R-Iowa) have been preparing legislation that would mandate significant

reforms for the agency.

 

The criticisms are deeply painful to staff at the FDA, including large

numbers of dedicated scientists. " All these folks have given up more

lucrative types of jobs ... because they think [that here] they'll make a

difference to health, " said the FDA's deputy commissioner, Dr. Janet

Woodcock.

 

" I believe that the people [who] take drugs to prevent the risk of heart

disease, to lower their blood pressure, to treat their depression, their

arthritis, are glad they have access to these medications, " she said.

 

Roots of crisis

 

The roots of the current crisis date to an earlier time of tumult in the

late 1980s when AIDS activists complained that the FDA was too slow to

approve potentially life-saving new drugs.

 

Congress took note and in 1992 passed a law imposing user fees on drug

companies to help fund expedited drug reviews. Many experts believe that was

a turning point for the agency.

 

Kessler describes it this way: " The FDA became preoccupied with rapid drug

reviews and less attention was paid to safety. "

 

Kessler was in charge at the FDA in 1992 when the Prescription Drug User Fee

Act, or PDUFA, was enacted. The goal was to expand the agency's drug review

staff, making it possible for the agency to process new drug applications

faster.

 

That process took 33 months, on average, in 1992. Today, drug company user

fees total more than $200 million a year, review times have dropped to an

average of about 13 to 14 months and the pharmaceutical industry professes

to be very satisfied with the results.

 

" We've come a long way in the last 12 years and the beneficiaries are the

millions of patients who now receive life-sustaining medicines more

quickly, " said Alan Goldhammer, associate vice president of regulatory

affairs at Pharmaceutical Research and Manufacturers of America.

 

But critics contend the drug user fee act also transformed the relationship

between the FDA and industry, making regulators financially dependent on the

regulated industry.

 

" At the very least, it created an appearance of a conflict of interest, "

said Arthur Levin, who heads the Center for Medical Consumers, an advocacy

group, in New York.

 

Kessler doesn't see it that way. " Just because you pay an application fee

when you apply to college doesn't mean you get in, " he said. " I do not

believe we lowered our standards one bit. "

 

If anything, the law has had a positive effect, according to Deputy

Commissioner Woodcock. " It really improves the premarket program. It puts a

lot more science, a lot more ability to do scrutiny, [more] people to do

work-ups of drugs, " she said.

 

What did change over time was priorities within the FDA's drug division,

largely because user fees came with strings attached, according to Kessler

and several past and current officials.

 

One stipulation was that the FDA conduct reviews within certain time

periods--most drugs had to be assessed in a year, initially--as a condition

of receiving funds. Meeting this performance standard " consumed resources

and management attention, " Kessler said, and " rapid reviews became the

currency within the agency, " distracting resources and attention from safety

evaluations of already-approved drugs.

 

Another stipulation was that the FDA's budget for new drug reviews not fall

below a certain level--a requirement that forced the agency to devote

increasingly significant resources to drug reviews and approvals.

 

More than 1,000 people now work in the FDA's Office of New Drugs, compared

with about 110 in the Office of Drug Safety, which evaluates the safety of

drugs once they are on the market.

 

" PDUFA should have had funding on the safety side from the beginning, but

the industry refused to accept that, " Kessler said, acknowledging the

imbalance. " We wanted it. The industry said no. "

 

The drug industry tells a different story.

 

" I do not recollect funding of the Office of Drug Safety being put on the

table, " said Goldhammer, who was on the industry team negotiating the

Prescription Drug User Fee Act. " The major focus of the discussions ... was

to provide the FDA with extra resources to eliminate the backlog of pending

license applications. "

 

When the FDA proposed that some user fees start to fund safety work in 2002,

the industry supported that, he said.

 

Drug safety efforts strained

 

As the process of reviewing and approving drugs has quickened, the job of

the Office of Drug Safety has become increasingly important.

 

Far more new drugs are launched in the U.S. than in the past, and Americans

are now more likely to suffer unexpected side effects of new medications. In

1980, only 2 percent to 3 percent of all new drugs were introduced in the

United States; by 1998, it was 60 percent, according to the Journal of the

American Medical Association.

 

Yet the drug safety office, which is supposed to identify and track dangers

associated with medications after they have been approved, remains

money-starved and a " second-class citizen " within the FDA's drug division,

several current and former officials said.

 

None of the recommendations of the drug safety office are binding. If staff

members identify a potential problem with a drug, at best they can raise an

alert and serve as consultants to other agency officials who make decisions.

 

Furthermore, all negotiations over regulatory actions have to go through the

FDA's Office of New Drugs. That raises a significant potential for conflict

of interest because the staff in the office that reviews and approves drugs

and is unlikely to want to admit mistakes.

 

" The Office of New Drugs drives the bus and calls the shots and makes the

policy, " said Dr. David Graham, associate director of science in the drug

safety office, who publicly criticized the agency last November during

congressional hearings. " But they cannot remain objective and impartial. "

 

Woodcock doesn't agree. " It's important to understand that the new drug

people spend about half their time on drug safety issues, " she said. " It's

still a fundamental focus of the agency as far as review goes. "

 

Several experts believe the FDA's Office of Drug Safety needs to become an

independent, more powerful entity within the FDA. Among them is Grassley,

the powerful chairman of the Senate Finance Committee, who is drafting

legislation to ensure " that the drug safety office within the FDA be made a

truly independent entity from the Office of New Drugs. "

 

Funding seen as key

 

Dr. Frank Young, who was FDA commissioner from 1984 to 1989, supports the

idea but warns that changing the agency's structure alone won't do the job.

An independent drug safety office will only work if " provided enough

resources, " he said. If Congress is serious about reform, it will step up to

the plate with more funding, he added.

 

Woodcock says the agency is " open to any suggestions people might have "

about restructuring the Office of Drug Safety, " but we strongly feel ... you

just can't look at [drug] risks alone. "

 

Whatever changes are made, the fundamental job of the agency will remain

making sure " the benefits of [new drugs] outweigh the risks, " she notes, and

that will require constant communication between drug review and drug safety

officials.

 

Most consumers assume a medication is safe if the FDA has approved it.

That's what Ronald Boros, a 6-foot-4-inch construction manager from Swartz

Creek, Mich., thought when he began taking Vioxx in September 2000 for a bad

back.

 

Neither Boros nor his doctor knew about a study Merck had completed earlier

that summer that raised serious questions about Vioxx's safety.

 

In the meantime, there was no reason to suspect anything might go wrong. For

2 1/2 years, Boros watched his diet, monitored his blood pressure, worked

out on the treadmill, took pills to lower his cholesterol and took his Vioxx

daily.

 

But age was catching up with Boros, who is now 55. In May 2003 he began to

have sharp, arthritis-induced pains down his arm. A family doctor

recommended that he double his Vioxx dose to 50 milligrams for about two

weeks, then go back to a 25-milligram dose. When the arthritis moved into

his shoulder, the doctor upped the dose to 50 mg. again.

 

Boros had his first heart attack that July 30 followed by a second attack

Aug. 14, 2003.

 

" That one they had to paddle him eight times to bring him back, " said his

wife, Diane. " It burned him real bad. "

 

Still, Boros went back on Vioxx until another heart scare a few weeks later

left him with a defibrillator in his chest and a sense that his life would

never be the same.

 

" You find yourself wondering how long are you going to live now, you know,

because the heart is damaged, " Boros, a father of six young men, said.

 

" He's depressed, " his wife said bluntly.

 

A year later, when Boros learned Vioxx was being pulled off pharmacy

shelves, he immediately wondered whether the medication that had eased his

pain had also hurt his heart. Though he'll never know, he says he wishes

information about the drug's potential dangers had come out sooner and

received more attention.

 

" If the company had come out with it, or the government, then maybe my

doctor would have given me an option, " Boros said, a note of sadness in his

voice. " Maybe they would have told me, `Ron, you shouldn't be taking

this.' " In exchange for allowing drugs to be approved quickly, " We

deliberately allow [medications] on the market knowing that some side

effects won't be detected for months or years down the line, " said Dr. Brian

Strom, professor of public health and preventive medicine at the University

of Pennsylvania School of Medicine.

 

" The real question is, are we doing enough once these drugs are out there in

the way of post-marketing surveillance? And the answer to that has to be

no. "

 

Unknown risks

 

The history of Vioxx illustrates how much can remain unknown about drug

safety even after medications are approved, and how limited the FDA's

authority is even after safety problems do surface.

 

As with other drugs, Merck studied Vioxx extensively before asking the FDA

to review the medication on an expedited six-month schedule in 1998.

 

Most of these studies were relatively small and short-term, which is not

unusual. New drugs generally are studied in several thousand patients for

periods less than a year before the FDA decides whether to approve the

medications.

 

Of 5,435 patients who received Vioxx in clinical trials prior to approval,

only 752 took what would be considered " normal " doses for more than a year.

 

Any side effects associated with long-term use of the drug wouldn't show up

under these conditions, said Dr. Curt Furberg, an expert in clinical trials

and professor of public health sciences at Wake Forest University. Nor would

rare side effects--say, those occurring once for every 5,000 or 10,000

people--be likely to appear because of the small numbers.

 

Vioxx promotion

 

Within just a few years, Vioxx was being used by millions of Americans.

Heavy promotion and advertising pumped up sales for the drug far beyond its

original intended market--people with arthritis who couldn't take other

painkillers because of stomach complications.

 

An astute FDA medical officer noted early on that data in pre-approval

clinical trials suggested the drugs might contribute to " thromboembolic

events " such as heart attacks and strokes. To confirm this, however, a much

larger study was needed.

 

Such a study--one that specifically focused on possible cardiovascular risks

associated with Vioxx--was contemplated by Merck but never carried out.

 

There was little the FDA could do about that. Though it's easy for critics

to blame the FDA for not doing enough about dangerous drugs, the agency is

hamstrung by a lack of regulatory authority in its dealings with drug

companies.

 

The FDA, for example, doesn't have the power to restrict prescriptions of

drugs for uses not approved by the agency. Once a drug is on sale, the

agency's ability to restrict marketing and promotion--or limit the drug to a

particular group of patients--is limited.

 

Perhaps most important, according to several drug safety experts, the FDA

cannot compel pharmaceutical companies to perform clinical studies to

resolve safety questions that arise about drugs on the market.

 

That means such studies almost never get done, as drug companies have little

incentive to undertake research assessing the safety of drugs they already

are selling. According to information published in the Federal Register,

fewer than half of the studies that companies agree to do after a drug is

approved are started.

 

After substantial delays, Merck agreed to examine the potential for serious

heart-related side effects in three separate clinical studies of Vioxx. But

the primary purpose of the studies was to encourage the FDA to approve new

uses of the drug so Merck could market it more broadly.

 

A study focused on safety and conducted earlier would have been far more

useful in answering questions about Vioxx's effects on the heart and ending

the debates that stalled action on the drug for years, said Furberg, a

member of the FDA's drug safety advisory committee.

 

The agency didn't find it easy, either, to change Vioxx's label to reflect

the risks of heart attacks and strokes, which were first demonstrated

through Merck research in 2000. The agency can't mandate certain language

for a label or set deadlines; it must negotiate with the drug company.

 

The FDA recently released a timeline of events surrounding the proposed

Vioxx label change that reveals the difficulties the agency encountered with

Merck.

 

On Sept. 21, 2001, FDA officials recommended the Vioxx label include

" balanced information regarding safety risks of Vioxx " and de-emphasize the

gastrointestinal safety advantage of the drug.

 

Negotiations with Merck dragged on so long that it was April 2002 before the

medication's label finally was changed--nearly two years after the study

demonstrated the risks.

 

Such scenarios shouldn't happen again when the proposed new FDA Drug Safety

Oversight Board gets off the ground, government officials say. That body

will disseminate information about drug risks on a more timely basis through

a new, FDA-sponsored " Drug Watch " Web page and through easy-to-understand

fliers to patients and physicians.

 

The new board will do nothing, however, to offset the huge impact of

direct-to-consumer drug advertising, which strongly influences the way

medications are prescribed and taken. Nor will it address large gaps in the

FDA's authority, contends Dr. Bruce Psaty, professor of medicine,

epidemiology and health services at the University of Washington.

 

" It's hardly an adequate solution, " he said.

 

From a consumer's perspective, the most important thing is that people be

told when drugs are discovered to have serious side effects, said Kathi

Maraffino, who lives in the Chicago area.

 

Her husband, Michael, a healthy, active 50-year-old, died of a massive heart

attack in June after taking Vioxx for three months, leaving Maraffino

wondering if the drug was somehow involved.

 

To this day, it bothers her that her husband's doctor didn't warn him that

Vioxx could be dangerous to some people.

 

" As a consumer, shouldn't we know if there's danger with [the drugs we take]

so we can pick and choose our own fate? " Maraffino asked.

 

" I'm not opposed to drugs that are going to help people. But if there are

dangers--especially for a drug for something like pain--they should let you

know and let you decide. "

 

- - -

 

Assessing drug safety

 

The Food and Drug Administration (FDA) examines the safety of new drugs

before and after they are approved. But concerns about the effectiveness of

these reviews have mounted over the last year, fueled by a controversy over

the popular painkiller Vioxx.

 

BEFORE FDA APPROVAL

 

Drug manufacturers study hundreds to thousands of volunteers in three

separate phases.

 

PHASE 1

 

20 to 100 healthy volunteers are tested to determine the drug's safety,

dosage amount and activity in the body.

 

PHASE 2

 

100 to 500 volunteer patients with the targeted disease are tested to

evaluate the drug's effectiveness and side effects.

 

PHASE 3

 

1,000 to 5,000 volunteer patients in clinics and hospitals are monitored to

confirm the drug's effectiveness and identify adverse reactions.

 

AFTER FDA APPROVAL

 

There is no coherent system for monitoring the safety of drugs after

 

they are approved. Information is fragmented and comes from several sources.

 

CASE REPORTS

 

Physicians write up examples of adverse drug reactions in medical journals.

These accounts are anecdotal and often the first evidence of actual clinical

experience.

 

ADVERSE DRUG REACTION REPORTS

 

Physicians, pharmacists and other medical professionals can voluntarily

submit information about patients who reacted badly to drugs to the

companies or to the FDA's MedWatch system. Up to 10 percent of adverse drug

reactions are actually reported.

 

POST-MARKETING CLINICAL TRIALS

 

Companies can launch studies of drugs after they're approved, and a drug's

side effects can be documented through this research. Most companies do not

undertake post-marketing studies, however, even when they've promised to do

so.

 

ACTIVE SURVEILLANCE

 

Northwestern University is part of a national group that develops theories

about which drugs might be dangerous, gathers evidence from several sources,

documents side effects and identifies circumstances under which drugs can be

harmful.

 

EPIDEMIOLOGICAL STUDIES

 

Large databases can provide information about what happens with people who

take drugs in the real world. The FDA recently said it planned to examine

databases of Medicare patients to look for drug-related trends in elderly

people.

 

Chicago Tribune

 

Sources: Boston Collaborative Drug Surveillance Program, Pharmaceutical

Research and Manufacturers of America, FDA and interviews

 

FDA at a glance

 

The Food and Drug Administration (FDA) regulates the safety of America's

drugs, medical devices, supplements, food and veterinary products. It is the

oldest government sponsored consumer protection agency in the nation.

 

BY THE NUMBERS

 

$200 million per year

 

Amount drug companies pay per year in user fees to have their drug's safety

reviewed by the FDA

 

$28.8 billion

 

Amount spent by drug companies* on research and development in 2004

 

16.9 months

 

Average approval time for new drugs in 2003

 

35 new medicines

 

Number approved in 2003 including six for cancer, seven for genetic

disorders, three for HIV/AIDS and three for respiratory disease

 

*Pharmaceutical Research and Manufacturers of America member companies

 

MILESTONES

 

1938 The FDA is established when Congress enacts the Food, Drug and Cosmetic

Act after 107 people are killed by elixir of sulfanilamide, a drug used to

treat strep-throat infections.

 

1962 After thousands of babies are born with defects due to their mothers'

use of thalidomide, a sleeping pill, Congress passes a law requiring that

drugs must prove to be effective according to the FDA before hitting the

market.

 

1970 The FDA requires patient packages to include inserts that contain

information about specific risks and benefits of use.

 

1982 FDA issues tamperresistant packaging to prevent poisons from being

placed inside the package.

 

1992 The Prescription Drug User Fee Act requires drug manufacturers to pay

fees to the FDA for an approval application. The act also requires the FDA

to use these funds to hire more employees to review these applications.

 

1995 Restrictions are proposed on marketing and sales to reduce smoking by

young people after the FDA says that cigarettes are " drug-delivery devices. "

 

1998 The painkiller Vioxx is approved by the FDA, but is recalled in

September 2004.

 

PROPOSALS FOR CHANGE

 

Here are some examples of suggested changes from medical experts who think

the FDA's monitoring system needs improving. Create an independent Center

for Drug Safety

 

- Allow the FDA to mandate clinical studies of drugs already on the market,

when needed

 

- Give the agency greater power to restrict drug use only to specific

patients

 

- Boost the agency's authority to restrict drug marketing and promotion

 

- Let the FDA mandate the content and timing of product label changes and

warnings about drugs

 

- Consider a system of conditional review and re-review of drugs, similar to

Europe's system

 

- Require that all clinical studies conducted pre- and postmarketing for a

drug be publicly posted

 

- Impose penalties on drug companies if they fail to conduct agreed-upon

studies or abide by marketing restrictions

 

FDA at a glance

 

Sources: FDA, New England Journal of Medicine, Journal of American Medical

Assn., interviews, testimony of Dr. David Graham, associate director,

science, FDA Office of Drug Safety, Nov. 18, 2004, Senate Finance Committee,

Pharmaceutical Research and Manufacturers of America

2005, Chicago Tribune

 

 

 

 

Laura

 

" To announce that there must be no criticism of the president, or

that we are to stand by the president right or wrong, is not only

unpatriotic

and servile, but is morally treasonable to the American public. " -

Theodore Roosevelt, 7 May 1918