Fw: Calculating Safety in Risky World of Drugs ~ NYTIMES

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From: Ilena Rose <ilena@...>

Sent: Friday, March 09, 2001 1:12 PM

Subject: Calculating Safety in Risky World of Drugs ~ NYTIMES

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http://www.nytimes.com/2001/03/06/health/06CONV.html?searchpv=site03

March 6, 2001

Calculating Safety in Risky World of Drugs

By DENISE GRADY

When Dr. Fenichel left his emergency medicine job in Arizona to join

his future wife in Washington in 1988, he took the first job he found,

evaluating new drug applications for the Food and Drug Administration. He

did not expect to stay long with the drug agency.

" It seemed in prospect to be sort of Dickensian work, not challenging in

any interesting way, " he said. " But in fact it is as intellectually

demanding as anything I've ever done. "

The F.D.A. was his third career. His first had been in computer science:

after earning a Ph.D. in applied mathematics from Harvard in 1967, he

worked for five years as an assistant professor of electrical engineering

at the Massachusetts Institute of Technology. Then, at 30, he returned to

Harvard to study medicine, expecting to work in a hospital computer lab

after graduation.

But instead, he said, " I was seduced by medicine. " He spent the next 12

years as an emergency room doctor.

At the F.D.A., the brief stay he anticipated turned into 12 years. He

retired last year as deputy director of a major drug-evaluating branch of

the F.D.A., the division of cardiorenal drug products, having reviewed

applications for about 100 new drugs for disorders like high blood

pressure, congestive heart failure and kidney diseases.

" It's a job in weighing evidence, " he said.

Now, acting as a consultant to various drug companies, Dr. Fenichel works

for the industry he once helped regulate.

In an interview at his home in Washington last month, he discussed the

risks and benefits weighed in decisions on new drugs and an abiding truth

that many would rather ignore: no drug is without risk. Any medicine

strong enough to have good effects on the body is strong enough to have

bad effects as well.

Q. When a drug is said to be safe, does that mean 100 percent safe?

A. Everything has some adverse ef- fects. When people need medications,

that's fine. For instance, you need penicillin for bacterial endocarditis,

which has 100 percent mortality if you don't treat it. True, you might die

from an allergic reaction to the antibiotic, but it doesn't matter. The

calculation has already been done. You're still better off taking the

thing, and if you decline you're just stupid.

Q. You make a distinction between drugs that are truly needed for serious

illnesses and what you call " symptomatic therapy, " the medicines that many

people take without thinking twice, just to relieve annoying symptoms like

runny noses or headaches. How does the risk-benefit decision compare?

A. It's very different. With endocarditis, one expects that the net effect

on mortality will be favorable. Some people will die from the therapy, but

more lives will be saved than lost. In purely symptomatic conditions, the

therapy will also kill people. Not a lot of people, but some people. There

are no lives to save, so any loss is a net loss. It may not be a large

loss, but it will be a loss.

It can't be anything else. People are taking something for their common

headache or for menstrual cramps, or they're getting cosmetic surgery. The

problem they have is not one that causes any mortality. So if they take

some nontrivial therapy it can't make mortality better. It has to make it

worse. If they take acetaminophen for a headache, it may cause their

livers to rot out. If they get cosmetic surgery they may have an

anesthetic death. And so on.

People need appendectomies. They don't need cosmetic surgery or

antihistamines.

Q. Given the risks, should people tough it out and avoid drugs and

operations that treat only symptoms?

A. Those decisions have to be made like other life decisions. There are

downsides. People go sky diving. Presumably it makes them feel better. If

someone is appropriately informed of the hazards, it's not illegal to go

sky diving.

Certainly in a surgical setting we say everybody should know the risks. If

you go in to get a nose job, you might die. There's an informed consent

and risks and benefits and the patient is the only one who could possibly

know whether this nose is so oppressive that the risk is acceptable.

That's not different from the medical context. Your symptom is your own. I

do not feel your pain.

Q. Do you think most people know how to put medication risks in perspective?

A. Of course not. With drugs, it's not obvious what the risk is. People

may feel, `I didn't really grasp this,' and that's probably true often.

Does that mean an inadequate effort was made to transmit the information?

Maybe, and maybe not.

Do I really understand a one-in-a- million risk of hepatitis from taking

something? I'm not sure I do. These numbers when they're very small are

very hard to comprehend. They don't correspond to human experience. People

don't even know that 25 percent means 1 in 4. They worry much more about

safety in airplanes than in cars. They worry more about mad cow disease

than about smoking. Go to France and see what people worry about. They're

all smoking, and they've given up beef.

Q. Are symptoms ever bad enough to justify taking a drug with considerable

risks?

A. The most dramatic case, I think, was a drug called flosequinan, made by

Boots Pharmaceuticals in the United Kingdom, for congestive heart failure.

People with severe congestive heart failure are terribly disabled. Some

cannot even walk across a room without becoming desperately short of

breath, and their median survival from diagnosis is only two or three

years. Flosequinan really made patients feel lots better. They stayed out

of the hospital and they could move around.

And the drug increased mortality, by about 50 percent. I mean really a

lot. They died of their congestive failure sooner than people who weren't

taking the drug.

Well, we thought about this, and the results with respect to feeling

better were so impressive that people in the division thought, Gee, if I

had that disease, I would want that drug. Now not everyone said that. But

many people in the division thought, I would want that drug.

And so it was approved. And the company finally lost its nerve, and they

never marketed it.

Q. Why do some bad effects not turn up before marketing, even though drugs

are tested in thousands of people?

A. If you have 3,000 patients, which is a typical number of patients

exposed to a drug before marketing, and something on average will occur 1

in 1,000 times in people using the drug, it's 95 percent likely that you

will see such a thing in those 3,000 patients. Five percent of the time

you won't see this thing. But if something is happening 1 in every 5,000,

your chance of seeing it is pretty small.

The only real hope you have is if it's something that is so distinctive,

like the thalidomide babies, even if it's happening one in a million, you

say, " My God, what's that? " and then if you see another one you say, " This

can't be a fluke. "

But most things are very difficult to detect. And that means plenty of

small effects will never be detected. Q. Can we expect to identify

additional side effects once a drug is marketed and more people are taking

it than during the test period?

A. Subtle things are very hard to see without a control group. To the

extent that a new drug is causing truly bizarre adverse reactions, then,

yes, you'd see that postmarketing.

But there have been many postmarketing blips, suspicions that have been

raised from time to time, which took endless amounts of time to dispatch,

and which turned out to be completely wrong.

The F.D.A.'s worst hour of recent times was the breast implant fiasco.

Someone claimed that leaking silicone caused systemic illness, and F.D.A.

ã instead of pointing out that the epidemiological evidence was

essentially absent ã triggered what turned out to be a multibillion-dollar

transfer from publicly held companies to the tort lawyers and destroyed

the scientific credibility of the agency in many minds. That's the easiest

example. But there have been many others.

Q. When the blood pressure drug Posicor, also known as mibefradil, turned

out after marketing to have dangerous interactions with other drugs, the

labeling was changed several times to warn patients and doctors. But the

drug was finally taken off the market anyway. Why?

A. The company made a huge effort, with all sorts of new detailing efforts

where they tried to train physicians. And it was very demoralizing because

it didn't do the trick. People were still using the drug inappropriately.

They were doing it a lot. My old boss always used to say that labeling

doesn't make a difference. The real thing was, Are you going to approve

the drug or not? After that you've got no control over it, it's out there.

Q. Do you think a drug that mixed badly with other medicines could stay on

the market if the bad interactions were discovered before it was approved

and listed on the label from Day 1?

A. I think what came out of mibefradil really was a novel realization,

that a drug can be as safe when used according to instructions as the next

drug for the same thing when used according to its instructions. And

nevertheless, if the instructions for the first drug are more complex,

more difficult to comply with, that's sufficient reason for thinking that

it either is a second-line drug, to be used only if other drugs are

ineffective or not tolerated, or is not to be approved.

You can go back to thalidomide, which caused birth defects. What could be

a worse drug than that in its original incarnation? You could say, Well,

that was just a labeling problem, wasn't it? Just don't give it to women.

They didn't adopt that solution. It would have been ridiculous. Because

you know people won't do that.

Q. But thalidomide is on the market now. And Accutane, which also causes

birth defects, is prescribed for acne even in young women, who are warned

not to get pregnant. Don't these drug raise the same problem all over

again?

A. Accutane is without peer. If you have big cystic acne, then you've got

to take Accutane. That's just the way it is. It's not idiot-proof. I think

women who receive it have to, on each cycle, have a pregnancy test. And

they've got an icon developed just for it, with this pregnant lady with a

slash through it.

But I'm sure Accutane is causing grossly deformed babies even now; not

very many, because of all these things they're doing. But I'm sure that's

happening. And I'm sure it's going to happen with thalidomide when they

bring it out for some of these AIDS complications and leprosy and a few

other things. But the drugs are filling unique niches.

Right now, I think it is absolutely appropriate that Accutane be on the

market. It is a symptomatic treatment that causes horrible, irreversible

stuff. If something came along that were similar in every way except that

it was nonteratogenic, down it goes. It's out. That wouldn't mean it had

been a mistake to have it around all this time. It just means, O.K., it's

been superseded.

Q. Is the F.D.A. doing enough to track adverse effects from drugs that are

already on the market?

A. We have many, many more drugs than we used to that are out there, and

the same budget is being used to follow them all. It's being done less

well.

Q. Critics of the F.D.A. have said that pressure from Congress to speed up

the approval process may result in having dangerous drugs on the market.

Do you agree?

A. There is pressure on reviewers, and I think it may happen that some

sort of disaster will sooner or later come of it. There certainly have

been cases where very late-breaking information has been crucial, where

we've said, " Oh, I see, well there's a real problem there, " and things

have not been.The fact that it can come close means that sooner or later

it's not going to be close. It's going to be on the other side of the

line, and the mistakes will be made.