In short drug tests, fatal flaws

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In short drug tests, fatal flaws

 

A narrow focus on effectiveness is a prescription for harm

 

 

By Thomas J. Moore, 7/14/2002

 

 

It is a major medical debacle when hormone replacement

therapy - a drug treatment that doctors recommended to millions of

women - is discovered to be harmful despite 60 years of widespread

use. Yet because of weaknesses in the entire system that tests and

promotes drugs for long-term use, this major surprise surely will

not to be the last.

 

 

The Women's Health Initiative trial provides an object lesson

about how easily some inadequately-tested drug treatments can cause

harm. These findings speak with unusual authority because they come

from one of the largest, longest, and best-designed clinical trials

reported in many years.

 

 

So what was the magnitude of the hormone replacement debacle?

Estrogen and progestin significantly harmed about 1 percent of the

women tested over the 5.2 years they took the hormones, but caused

no additional deaths. The harmful events included breast cancer,

stroke, heart attack, or blood clots in the lungs. In addition,

about a third of treated women had gynecological

symptoms requiring a doctor's care.

 

 

How could this happen with one of the most extensively

researched, high-visibility treatments in all of medicine? It

occurred, and will happen

again, for three reasons. First, our society settles for short-term

studies about drugs taken for long-term effects. Second, the health

professionals

tend to see drugs with tunnel vision, focusing narrowly on a

particular benefit while forgetting that drugs have many effects.

Finally, many popular

long-term treatments provide very small benefits to people with an

already low risk of death or serious injury. In such circumstances,

only a small,

unintended effect tips the balance from good to harm.

 

 

To get new drugs more quickly, drug testing worldwide is often

extensive, but lasts only for short periods. Antidepressants are

usually tested for six weeks, new blood pressure drugs for a matter

of months, and drugs for adult-onset diabetes from six months to a

year. To limit development costs, an individual trial for Food and

Drug Administration approval seldom has more than a few hundred

participants.

 

 

The harm of hormone replacement therapy was detected only

because taxpayers paid for a much larger, longer trial with 16,608

participants who

were going to be observed for 81/2 years.

 

 

This is hardly the first time that long-term trials conducted

at government expense have produced findings of harm. A heart drug

called Tambocor, effective in the short term in suppressing mild

irregular heartbeats, was discovered in a longer government trial to

cause people to drop dead with cardiac arrest. Cardura, a blood

pressure drug, was found inferior to other drugs in another large,

long-term study conducted by the National Institutes of Health. In

other long studies, two

cholesterol-lowering drugs were found to be harmful overall, even

though they lowered cholesterol.

 

 

However, no system is in place to ensure that drugs intended

for long-term treatment ever receive long-term testing. The legal

structure of

our drug-approval laws has been built around simpler drugs such as

painkillers and antibiotics - which are taken for short periods of

time with

effects that are more immediately apparent.

 

 

As a result, we know little about the long-term effects of

many important drugs. For example, millions of schoolchildren take

Ritalin and

other powerful stimulants for years without long-term trials to

establish safety, and despite evidence they cause brain damage in

some children. The long-term benefits of some best-selling drugs to

lower cholesterol or blood

pressure are similarly unknown. Although many popular drugs caused

cancer in animals, few have been tested for the five years or longer

needed to document excess cancer risks in humans.

 

 

Until the hormone trial results were published, the scientific

case for estrogen replacement therapy seemed persuasive, so long as

focus was limited to just part of the evidence. Estrogen does

preserve bone density, and the Women's Health Initiative confirmed

its ability to reduce bone fractures. Estrogen also lowered ''bad''

(or low-density) cholesterol, so it seemed reasonable to presume it

would prevent heart attacks.

 

 

But drugs have many effects, and these were only two. Estrogen

is also a powerful growth promoter, and it is also reasonable to

assume it might accelerate the growth of some cancers. It also

increases blood clotting, and therefore might cause heart attacks

and dangerous blood clots in the lungs and legs. These effects were

well documented in scientific literature, along

with the benefits, but many doctors ignored them. Only a large, long-

term clinical trial such as the Women's Health Initiative was

capable of providing a conclusive, balanced perspective on all the

risks and benefits.

 

 

Examples abound of this medical tunnel vision. Many clinicians

have embraced two heavily marketed drugs for adult-onset diabetes

called Actos and Avandia. These drugs had a small effect in lowering

blood sugar (the benefit

the doctors saw) but also increased stress on the heart and induced

weight gain (the drawbacks that get little attention).

 

 

Without a long-term trial of about 10 years, no one knows

whether the net effects on health are harmful or beneficial. Doctors

and patients alike

embraced an arthritis drug called Vioxx, impressed by evidence that

people had fewer stomach ulcers of microscopic size compared to

ibuprofen and naproxen. But few noted that Vioxx lacked the

cardioprotective effects of naproxen until hard evidence emerged in

another large clinical trial. For many people, a greater risk of a

heart attack or stroke with Vioxx might outweigh any benefits from

fewer injuries to the digestive tract. In each of these cases, the

lesson is that drugs have many effects, not just the benefits used

for marketing and promotion.

 

 

The hormone replacement debacle also illustrates why

relatively small adverse effects can render a drug treatment harmful

overall. The reason is that the participants - two-thirds from 60 to

75 years old - were remarkably healthy regardless of whether they

took a placebo or the hormone replacement therapy. Over five years

only 52 of 8,102 older women taking the placebo died

of breast cancer, colorectal cancer, heart attack, or stroke - less

than 1 percent. Among people so healthy it is extremely difficult

for a drug to have

a beneficial effect because there is so little room for improvement.

 

 

That fact also doomed the most important benefit of hormone

replacement

therapy - prevention of hip fractures. Despite an avalanche of

medical advertising about the dangers of osteoporosis, hip fractures

were rare. Just 62 hip fractures occurred in the placebo group,

compared with 44 among those on hormone replacement. Helping just 18

women avoid a hip fracture among more than 8,000 treated was a

benefit so tiny it was outstripped by very modest increases in

strokes, breast cancer, and heart disease.

 

 

How many drugs are so completely free of adverse effects that

fewer than 1 person per 1,000 per year is injured? Yet an adverse

effect of that

rarity nullifies the protection against hip fractures provided by

hormone replacement therapy. One has to wonder whether many drugs

targeted at a

population with such an excellent health status are destined to fail

in a large clinical trial capable of detecting risks and benefits

that are this

small. Yet the pharmaceutical industry loves to market drugs to the

healthiest people because there are so many of them, and the largest

market

yields the most money.

 

 

It is also noteworthy that the important but unwelcome

findings of the Women's Health Initiative came in an NIH study

conducted by medical investigators without a financial stake in the

outcome. What if this study had been sponsored by a pharmaceutical

company whose stock would plummet, and if the investigators were

bound by secrecy agreements not to reveal the

findings? Furthermore, the companies have no legal obligation to

make public such findings.

 

 

Every large complex clinical study raises questions capable of

triggering a technical debate over the validity of its findings.

Scientists

can find just as many technicalities to debate as a skilled lawyer

with a guilty client. It does not even take the assumption that

companies would

deliberately fudge the numbers - as so many large corporations now

stand accused of doing. A fat consulting fee to a specialist with

sterling

credentials who is willing to advance one side of a technically-

arguable issue is all it would take to mire important findings in an

endless technical

debate. For this reason, drug companies with a financial stake in

the outcome should not be allowed to control these large, long-term

studies.

 

 

We need new laws, a national scientific program, and money to

assure that every important drug intended for long-term use receives

the same long-term testing as was provided for hormone replacement

therapy. The funds

should come from a new tax on the pharmaceutical companies that

profit from the sale of such drugs.

 

 

It now remains to be seen whether Congress and the Bush

administration will respond to this clear public need - or to the

millions of dollars spent on pharmaceutical lobbying. But the fact

remains that drugs intended for long-term use require long-term

testing. And under our present system they don't get it.

 

 

 

This story ran on page C1 of the Boston Globe on 7/14/2002.

 

© Copyright 2002 Globe Newspaper Company.