WSJ.com - As Drug-Safety Worries Grow, Looking Overseas for Solutions

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>Date: Fri, 31 Dec 2004 13:38:06 -0800

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The Wall Street Journal

December 31, 2004

PAGE ONE

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By ANNA WILDE MATHEWS

Staff Reporter of THE WALL STREET JOURNAL

December 31, 2004; Page A1

The U.S. spends more on pharmaceuticals, devotes more resources to

medical research and discovers more new drugs than any other country.

But its system for monitoring and responding to safety issues after

drugs are approved isn't state-of-the-art, and in some ways falls short

of what's done elsewhere in the world.

The abrupt withdrawal of Merck & Co.'s Vioxx after about 20 million

Americans had taken it, and warnings about Pfizer Inc.'s similar

painkillers Celebrex and Bextra, draw attention to shortcomings of the

U.S. approach to tracking approved drugs. It largely relies on doctors

voluntarily alerting drug manufacturers, which then have a duty to tell

regulators.

Now there's new interest in the ways other developed nations do it. In

France, for instance, a network of " pharmaco-vigilance centers " serves

as a sentinel and a resource for doctors. In Britain, concerns about a

particular drug spur researchers to send out " green cards " seeking

information from doctors who've prescribed it. In Australia, independent

drug-safety experts meet regularly to ponder new information about drugs

on the market.

There's also new attention to ways that wider use of information

technology -- much more pervasive elsewhere in the economy than in

health care -- could spot problems more rapidly and reliably. " We

shouldn't be depending on spontaneous reports from overworked doctors

and other health-care professionals for detecting adverse events, " says

Mark McClellan, who recently left the helm of the Food and Drug

Administration to run the Medicare and Medicaid programs.

The FDA's drug-safety office, which leads efforts to detect adverse

effects of drugs already on the market, has a budget of about $27

million a year. That has risen gradually but is a small part of the $327

million the agency spends on drug regulation overall. A 2000 FDA

proposal to spend $150 million on new surveillance and research never

won backing in Congress.

The FDA is likely to advance another proposal early next year. In the

wake of the withdrawal of Vioxx, which was linked to higher

cardiovascular risk when taken for 18 months or more, Congress will

certainly consider legislation. One proposal that has resurfaced:

splitting the responsibility for approving new drugs from that for

monitoring those already on the market.

Here's a look at ideas the U.S. might pick up from other countries and

from innovators within its borders.

Stronger Surveillance

Some 66% of FDA drug reviewers are " not at all " or only " somewhat "

confident the agency adequately monitors approved drugs' safety,

according to a survey for a 2003 report by the Health and Human Services

Department inspector general.

The agency receives about 300,000 reports a year of possible bad

reactions to approved drugs. About 94% come from drug makers, which are

obligated to disclose them. The companies, in turn, depend largely on

doctors and other medical people to alert them.

But those medical professionals have no duty to report adverse reactions

either to drug makers or the FDA and frequently don't, perhaps because

of lack of time, liability concerns or simply a physician culture that

doesn't make this a priority.

In Sweden, by contrast, health professionals " regard this

as...mandatory, ethical, " says Ulf Bergman, a professor of clinical

pharmacology at the Karolinska University Hospital in Stockholm.

In France, doctors often turn to 31 government-funded pharmaco-vigilance

centers with questions about how best to use drugs. The center in

Bordeaux, for instance, recently heard from a doctor who said a

patient's face swelled after the person took a blood-pressure

medication. The doctor asked if a different drug would have the same

effect. The center said there was a 50% chance it would. " Doctors cannot

possibly collect as much information as we have on drugs, " says

Francoise Haramburu, director of the Bordeaux center.

The big payoff comes when such an inquiry unearths a new side effect. In

one case, a psychiatrist and a general practitioner separately told the

Bordeaux center of finding hyperglycemia -- high blood sugar -- in

patients taking an antipsychotic known as olanzapine.

[Check That]

In such cases, the center works with the doctor to figure out if the

event is tied to the drug. The center partially writes a report, which

the doctor completes and signs, and then it's entered in a central

tracking system. The concern about olanzapine -- sold as Zyprexa in the

U.S. by Eli Lilly & Co. -- was later added to its label and those of

similar antipsychotics.

The centers give French regulators early and first-hand information.

That's in contrast to the FDA, which often hears of events weeks later

via drug companies. Says , a professor at University

Victor Segalen in Bordeaux: " We're right there when the information is

still warm. "

In some corners of the U.S., hospitals are deploying technology to

better detect drug reactions. At Intermountain Health Care's 520-bed LDS

Hospital in Salt Lake City, an advanced system automatically informs

pharmacists of events that may signal problems with a drug.

One trigger is a prescription for a drug that's often prescribed to

counter problems caused by other drugs. An example is naloxone, which is

used to counter the effect of opioid painkillers. In other cases, an

order for a lab test for bacteria known to cause serious diarrhea will

trigger an alert, because diarrhea is sometimes a sign of a drug reaction.

Each alert brings a pharmacist to the patient's bedside to look for

signs of a possible bad drug reaction. Often, the patient is quickly

taken off the suspect drug, stopping the problem before it becomes

serious. Intermountain also uses its database of patient records to look

for links between drugs and side effects, or to impose tight

surveillance on a new drug to scan for unforeseen problems.

According to Brent , vice president for medical research at the

nonprofit Intermountain, the result of all the efforts is a decline of

as much as 60% in the rate of serious adverse reactions.

He says when his father went into LDS with congestive heart failure, he

was given a commonly used diuretic, which caused a severe pancreatic

reaction. " I didn't have a clue " that this could be an effect of the

drug, Dr. says. But, he says, one of the hospital's drug-safety

experts saw the connection, the drug was stopped, and " it may have saved

his life. "

Early Warnings

The FDA has long acknowledged the limits of its voluntary reporting

system. It has sought to commission studies to pursue hints of trouble,

but its funds are limited. " We would like to be able to perform

independent studies more frequently, " says Janet Woodcock, deputy FDA

commissioner. " We don't really have a robust program that can do that. "

The agency can't always force companies to complete promised follow-up

studies of approved drugs. As of September 2003, drug makers had agreed

to do 1,338 such follow-up studies. A recent FDA tally found that around

two-thirds of them hadn't even started.

" I would like to see the FDA have the authority to guarantee that

post-marketing commitments made by a company are met, " says Carl Peck, a

former director of the FDA's drug center and now head of the Center for

Drug Development Science, affiliated with the University of California,

San Francisco.

In the United Kingdom, labels of recently approved drugs are marked with

a black triangle, signaling to doctors a need for extra vigilance. When

there is a concern about a particular drug, British regulators have

other options. Turning to a database of doctors who have prescribed the

drug, researchers can send them inquiries printed on green paper --

called " green cards " -- about possible bad reactions.

Physicians respond to green cards at a robust rate of 50% to 60%,

possibly because the research center sending them, the Drug Safety

Research Unit, makes sure no doctor gets more than four a month. The

green cards give researchers at the safety center an early glimpse of

potential problems. " Understanding the safety of medicines is like a

jigsaw puzzle, " says Saad Shakir, head of the center. " Various pieces

need to be put together. "

Pharmacists can play a bigger role in dispensing medicines in some

European countries, which offer certain drugs " behind the counter, " a

status between prescription and over-the-counter. Monitoring systems

like the U.K.'s accept reports from pharmacists as well.

Some British general practitioners also voluntarily feed computerized

patient records into a large database. It now covers three million

patients, who've been in the system for an average of seven or eight

years. It permits study of long-term effects, such as a possible link

between the antibiotic flucloxacillin and liver disease, says

Jick, co-director of Boston University's Boston Collaborative Drug

Surveillance Program. The FDA itself plans to acquire access to this

database.

In the U.S., rising numbers of health plans and hospitals are creating

databases that could develop into resources for drug-safety research.

Ultimately, the Medicare drug benefit, which will put the government in

the role of paying for drugs for millions, may create the most extensive

U.S. pool of drug-use information ever. The Centers for Medicare and

Medicaid Services plans to require more data on drugs as a condition of

payment for some " off label " cancer treatments, that is, uses beyond

those the item is approved for.

Regulatory Responses

The FDA has a limited toolbox. It can pull a clearly hazardous drug off

the market. But in the more-common case where risks and benefits are

closely matched, the agency hasn't many options besides pressing

companies to change a drug's label.

Altering the label -- which is actually a long, difficult-to-read

document that physicians don't always study -- has limited effect.

" They've got an atomic bomb or a powder puff, " says Woosley,

vice president for health sciences at the University of Arizona.

New technology at the hospital level could give FDA's warnings more

potency. At Wishard Memorial Hospital in Indianapolis, doctors prescribe

by computer, not a pad. Prescribing a drug pulls up four or five lines

of text telling the doctor the drug's significant side effects. The

system includes patient records, and it integrates all new FDA cautions.

So it can create a digital bulletin -- as when a drug is being

prescribed for a patient who might be allergic to it -- or it can tell a

doctor the patient needs a test to be sure a drug isn't inducing a side

effect.

The FDA is trying to go beyond label warnings and press drug makers to

restrict marketing and distribution of certain medicines it believes

present serious risks. But once a drug is approved, the agency must rely

mainly on jaw-boning and the implied threat of a recall.

And it has sway only with the manufacturer, not with physicians. Doctors

routinely (and legally) prescribe drugs for uses not approved by the agency.

The European Medicines Agency, by contrast, can suspend a drug license

for a year while the manufacturer seeks answers to regulators' safety

questions. In 1998, European Union regulators suspended the license of

Tasmar, a Parkinson's Disease treatment that appeared linked to liver

problems; the license was reinstated in 2004 after additional company

research.

In addition, drug licenses granted by the European agency face a renewal

process after five years, allowing regulators to reassess the

risk-benefit balance.

In 1999 the FDA raised the idea of getting " suspension " authority for

approved drugs, but didn't press for it. Another idea that's been

floated is to give some drugs conditional approval.

Strom, a University of Pennsylvania drug-safety researcher, has

suggested such a system, with the maker not allowed to do consumer

advertising until a drug wins full approval. The maker would have an

incentive to generate additional safety data quickly, he says. " Right

now you get full approval and it's drastic to remove a drug. "

Another longstanding idea is an independent agency looking at the safety

of already-approved drugs. In Britain and Australia, independent groups

of safety experts meet regularly to consider information that emerges

about drugs on the market. The FDA's advisory committees, including one

on safety, tend to meet only a few times a year and focus on a few

high-profile scientific questions, rather than hold regular sessions

weighing a variety of issues.

Forming a new committee to advise the FDA might not satisfy critics who

call for a split in regulatory authority. They argue that the officials

who approve drugs shouldn't be the same ones who check whether approval

was a good idea.

One model that's been floated comes from the transportation sector. The

National Transportation Safety Board studies major plane crashes and

then makes recommendations to regulators, airlines, pilots and plane

manufacturers.

" Should there be a post-mortem by an independent group with an analysis?

That's worth talking about, " says J. Crout, former director of

the FDA's bureau of drugs, referring to cases like Vioxx. " How to make

that be constructive and improve decision-making without it just being

Monday-morning quarterbacking, that's the problem. "

Write to Wilde Mathews at anna.mathews@...

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