Strong Medicine: What's Ailing the FDA?

[Guest guest]

A Reader's Digest special report takes a look at pharmaceutical

manufacturing and how new drugs receive FDA approval.

Key Problems With the FDA

• Problem: Pressure From the Industry

There's pressure to speed decisions, and there's pressure to soft-

pedal problems. That means drugs may go on the market without

adequate vetting -- or follow-up. Critics of the FDA like to say it's

the best agency the pharmaceutical industry can buy. That's a

political jab, and agency advocates say it's unfair. " The

extraordinary efforts of these committed staff members are the very

reason further catastrophic food-and-drug events have been averted, "

an otherwise scathing review by the FDA's Science Board concluded

last November.

But most agree that there's at least a problem of perception, and

perhaps more than that, caused by the growing chunk of the agency's

budget that comes directly from drug companies. Industry dollars now

pay for more than half of the FDA's drug-review budget; in five

years, that proportion is expected to jump to 70 percent.

Called user fees, this $400 million a year is designed to speed

decisions on applications for new drugs. " User fees seem to save

taxpayers money, " says Wood, PhD, the former assistant

commissioner for women's health at the FDA and now a professor of

public health at Washington University. " But they undermine

public confidence in the FDA's independence and impose time pressures

that could end up costing lives. "

Faster approval of drugs, of course, is a very good thing if you need

a lifesaving medicine. Many patients are clamoring for that speed.

Review times have been cut from 27 months to less than a year. Vioxx

was fast-tracked in just six months. But some argue that the pendulum

has swung too far. " A lifesaving drug should be sped along, " says

Nissen, MD, chair of the department of cardiovascular medicine

at the Cleveland Clinic and a frequent advisor to the FDA. " But with

user fees, we've pressed the accelerator on all drugs, and that's a

mistake. "

Here's the danger: " The easiest way to make those deadlines is not

raise too many questions and just accept what the drug companies say

about safety, " says former FDA drug reviewer Ross, MD. Too

often, Dr. Ross says, reviewers tell their FDA supervisors that a

drug doesn't work or has a major safety problem and " managers come up

with contrived reasons to approve the drug anyway. " He says the

standards of safety and efficacy have slipped to the point that the

drug reviewers " can end up approving almost anything. "

No one can say that moving drugs more quickly from the laboratory to

the pharmacy always puts Americans at risk. But there is a smoking

gun: an alarming spike in adverse drug reactions reported to the FDA

recently, from 267,000 in 2000 to over 471,000 in 2006. And the

number of reported deaths has nearly tripled, from 5,519 to 15,107.

That's only part of the story: The agency estimates that it learns of

fewer than one in ten drug reactions.

Janet Woodcock, MD, the FDA's deputy commissioner and chief medical

officer, flatly denies that user fees and sped-up approvals

compromise safety. " The FDA is legendarily tough -- our requirements

are viewed as a really tough bar to get over. "

" The review standards have not changed one bit since the introduction

of user fees, " says Alan Goldhammer, PhD, deputy vice president for

the Pharmaceutical Research and Manufacturers of America, the drug

industry lobby. " We've been careful never to compromise the

independence of the FDA. Congress would not permit it. "

Nevertheless, says Dr. Woodcock, " I understand that there's a

perception problem. "

What's Being Done

Congress slightly increased the FDA's drug safety budget last year

but accomplished that mostly by boosting user fees once again. To

help offset that influence, and enable the FDA to tackle all its

other responsibilities, reformers say Americans should pay 3 cents a

day to fund the agency, rather than the 1.5 cents we now pay. The

agency's Science Board argues, " That's a great price to pay for the

assurance that our food and drug supply is, indeed, the best and

safest in the world. "

• Problem: Safety of New Drugs

When the FDA approves a drug or medical device, staff scientists

must, in effect, make a judgment call about its safety. They're

relying on industry studies that usually follow between 600 and 3,000

people, often for just a few months. Those small clinical trials are

designed to measure a drug's safety and effectiveness in a targeted

group of patients -- not the dangers the drug might pose when it's

taken by people with a wide variety of backgrounds and health

conditions. " If it kills one in 2,000 people, or makes one go blind,

you may not see that in the trial, " says Drummond Rennie, MD, a

deputy editor of The Journal of the American Medical Association

(JAMA) and a professor of medicine at the University of California,

San Francisco. " You start adding that up, and that's ten in 20,000

going blind, and that's a lot of people. "

Those risks are revealed only after a medicine goes on sale and has

been used for months or years by hundreds of thousands or even

millions of people. Keeping track of those reactions is called post-

market surveillance, and experts say it's one of the most important

phases of drug testing. Historically, user fees were not allowed to

go toward checking the safety of drugs once they were on the market.

And until now, those follow-up reports haven't been mandatory. A 2006

report found that 65 percent of the studies that drug firms promised

to conduct in recent years hadn't even begun.

What's Being Done

Congress authorized the FDA to spend $25 million from user fees this

year to improve drug safety. But agency insiders say that's not

nearly enough. " You've still got a mismatch, " says Hubbard, who is

now a senior advisor for the Alliance for a Stronger FDA, a group

that includes seven former agency commissioners and three former

Secretaries of Health and Human Services. " You still have all this

effort going into getting the drugs on the market, and not much going

into making sure they're safe once they're out there. "

On that issue, Congress got tough last year. The FDA can now require

companies to trace the long-term effects of their drugs. If firms

renege, they face stiff fines, up to $10 million for repeat offenses.

Another crucial reform: Companies can no longer treat the results of

clinical trials as trade secrets. Until this year, a manufacturer

could cherry-pick what it revealed -- publishing a favorable study in

a medical journal and sticking less rosy findings in a drawer. A

report in the January New England Journal of Medicine revealed that

one-third of antidepressant drug trials are not published, which can

mislead doctors into thinking the drugs are more effective than they

really are.

Here, too, Congress has drawn the line: Companies must post results

of clinical trials on a public database, ClinicalTrials.gov, within

one year of their completion. Independent experts should soon be able

to evaluate the findings and better inform doctors and consumers

about what the studies mean. Unfortunately, companies can wait three

years to post summaries written for the general public.

That new measure of openness draws kudos from Dr. Woodcock, the FDA

deputy commissioner. " People volunteered for those trials, and their

lives may have been altered as a result, " she says. " They deserve to

know that their information has contributed to society. " Having such

full disclosure about a treatment or device is the only way to know

what medical research means for all of us.

• Problem: Sloppy Record Keeping

For an organization whose core function is gathering and analyzing

crucial facts quickly, the FDA's partially computerized database " is

like something that came off the ark, " says Dr. FitzGerald, the Penn

pharmacologist and agency advisor.

Companies are required to tell the FDA about any severe reactions

they learn of, and do so within 15 days if the injuries are life-

threatening. And the agency operates a website called MedWatch

(www.fda.gov/medwatch), where doctors (and patients) can download a

form to report problems. But few physicians bother to use it. The

result: Only a small fraction of adverse reactions get passed on.

Even more important, the FDA doesn't have the time or money to make

sense of the information it does receive.

The agency is notified of half a million problems each year, a third

of them serious, says Dr. Woodcock. Most of those reports arrive via

paper fax and have to be sorted by hand. More worrisome, the FDA's

skeleton staff of 35 report analysts have only eight minutes to read

even the most serious case, says Hubbard, who tracked such things as

associate commissioner.

" We've never had enough resources to really do the job and hire the

staff, " says Dr. Woodcock, who has been at the FDA for two

decades. " And it's not that we didn't try. "

What's Being Done

Congress has responded, telling the agency to invest several million

dollars to connect to large medical-records databases run by the

Veterans Health Administration, Medicare and HMOs. Using these

databases will allow the FDA to better track and analyze adverse drug

side effects. That means the FDA will know much sooner if a newly

marketed drug needs to be relabeled or pulled off the market, even

whether one medication works better than another. And thanks to

Congressional intervention, the agency will now be able to make label

changes quickly, without prolonged negotiations with the drug

companies.

Problem: Conflicts of Interest

The FDA's advisory boards, which vote on drugs and devices, are

intended to represent a broad spectrum of physicians, researchers and

patient advocates -- not stockholders. But a study published in JAMA

in 2006 found that in 22 percent of advisory board meetings, more

than half the members had direct financial interests in the companies

whose medical products they evaluated, or their rivals.

The agency says it's doing the best it can. Because drug companies

underwrite most clinical research, even at universities and

hospitals, some say it's difficult to find top medical experts with

no ties to industry.

What's Being Done

Congress has decided to roll up the red carpet. Over the next five

years, the FDA will have to cut by 25 percent the number of advisory

committee members with financial ties to a product under review.

Consumer groups had hoped for an outright ban but say this is a step

in the right direction.

• Problem: Muzzled Experts

Dr. Graham, in the FDA's drug safety office, says that a few years

ago he was ordered to soften his assessment of a drug he thought

should be withdrawn because it could cause liver failure and

death. " Industry is our client, " a supervisor told him.

" It may be your client, " Dr. Graham says he replied, " but it will

never be mine. "

When told this story, FDA spokeswoman Zawisza said, " Our client

is really the public. "

Still, other agency scientists share Dr. Graham's concerns. Drug

reviewer Rosemary Johann-Liang, MD, suggested two years ago that the

diabetes drug Avandia carry a black box on its label (the agency's

strongest warning), alerting patients and doctors to its cardiac

risks. Instead, Dr. Johann-Liang says, her supervisors reprimanded

her and deep-sixed her report.

Last August the agency did finally issue an urgent warning about the

drug and placed a black box on its label. But by then Dr. Johann-

Liang had resigned -- and millions of Avandia prescriptions had

already been filled.

Many agency staffers say they've felt similar pressure to soft-pedal

product dangers. In a poll of 1,000 FDA scientists, conducted in 2006

by the Union of Concerned Scientists, 20 percent said agency decision

makers had asked them explicitly " to provide incomplete, inaccurate

or misleading information to the public, regulated industry, media or

elected/senior government officials. " And 40 percent said they could

not publicly express concerns about public health " without fear of

retaliation. "

The tone has been set from the top. Last year von Eschenbach,

MD, the FDA commissioner, told a roomful of staffers to stop making

their gripes public. " If they don't follow the team, " he said, " the

first time, they'll be spoken to; the second time, they'll be

benched; and the third time, they'll be traded. " (FDA spokeswoman

Zawisza says Dr. von Eschenbach has no desire to limit dissent.)

The tangled story of Ketek, a once-promising new antibiotic,

illustrates what can happen when the agency's scientists feel

marginalized.

What's Being Done

Last year Congress created the Office of Chief Scientist of the FDA,

to give staff members a forum for debates and improve the quality of

research. The new law also gives in-house staffers the right to

publish their critiques in medical journals and makes sure their

assessments, even if overruled, are made part of the public record.

Money alone won't solve the FDA's morale problem. In recent years,

dozens of career scientists and senior managers have left the agency,

a much higher turnover than that of the National Institutes of Health

or the Centers for Disease Control and Prevention. Public trust in

the agency has slid from 67 percent in 2001 to 36 percent in 2006.

Without change at the top, longtime agency watchers say, there's no

assurance that officials will get tough on industry scofflaws. In

fact, from 2000 to 2005, FDA enforcement against drug, vaccine and

medical device manufacturers dropped by more than 50 percent,

according to a recent investigation by California Congressman Henry

Waxman.

A discouraging sign: One of the first regulations the agency proposed

this year is intended as a shield, according to some Congressional

leaders, designed to protect drug companies from lawsuits brought by

people who believe they've been injured by drugs or medical devices.

But having stronger tools and the right leadership could gradually

restore the FDA to what it once was -- a highly respected band of

medical detectives, apolitical and immune to corporate pressure.

There is one bright spot on the horizon, says Jerry Avorn, MD, a

professor of medicine at Harvard Medical School and an expert on the

drug-approval process. " There is more public awareness of this issue

than I've seen in 30 years, " he says. " And that can help put the

agency's many smart, dedicated people back into the driver's seat.

Because a lot of this is really not about very arcane science. It's

about common sense. And that's what's been missing, until now. "

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