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#632 - Another Kind of Drug Problem, 06-Jan-1999

A medical report in 1998 estimated that adverse reactions to
prescription drugs are killing about 106,000 Americans each year --
roughly three times as many as are killed by automobiles.[1] This makes
prescription drugs the fourth leading killer in the U.S., after heart
disease, cancer, and stroke. The report included only drugs that were
given properly and under normal circumstances, excluding drugs that
were administered in error or taken in attempted suicides. (When errors
of administration are included, the death toll may be as high as
140,000 per year.[2] Such errors include prescribing the wrong drug or
the wrong dosage; giving medications to the wrong person; giving
medications to the right person but in the wrong quantities or the
wrong frequencies, and so forth.)

According to the 1998 report, which analyzed the data from 39 separate
studies conducted over the last 32 years in U.S. hospitals, 3.2 out of
every 1000 (or 3200 per million) hospital patients die from adverse
reactions to prescription drugs. Of the 106,000 people killed each year
by prescription drugs in the U.S., 41% (43,000) were admitted to the
hospital because of an adverse drug reaction; the other 59% (63,000
people) were hospitalized for some other cause but developed a fatal
reaction to prescription drugs they received while hospitalized. In the
U.S. in 1994, there were 33,125,492 hospital admissions.

The sale of prescription drugs has more than doubled in the U.S. during
the past 8 years. In 1990, Americans spent $37.7 billion on
prescriptions; in 1997, national spending on prescriptions reached 78.9
billion.[3] Prescription drugs are the fastest-growing portion of
health-care costs, having risen at the rate of 17% per year for the
past few years.[3]

Urging physicians to prescribe particular drugs -- especially new drugs
-- is a huge business. According to the NEW YORK TIMES, the sales force
of the largest 40 drug companies has "exploded" in recent years.[3] In
1994, there were 35,000 full-time "detail people" employed by drug
companies to visit doctors and describe pharmaceutical products; by
1998, the number had grown to 56,000 -- one sales person for every 11
physicians.[3] Drug companies spent $5.3 billion in the first 11 months
of 1998 sending their "detail people" into doctors' offices and
hospitals, plus another $1 billion putting on "marketing events" for
doctors.

Not all adverse reactions to new drugs can be anticipated or avoided
under the present system, according to medical experts. "It is simply
not possible to identify all the adverse effects of drugs before they
are marketed," say three physicians writing in the NEW ENGLAND JOURNAL
OF MEDICINE.[4] In fact, "Overall, 51% of approved drugs have serious
side effects not detected prior to approval."[5]

Side effects from new drugs cannot be anticipated for 2 main reasons:
(1) Individuals vary greatly in their reactions to chemical substances;
and (2) drugs are tested on only 3000 or 4000 people before they are
marketed, so rare side effects may not appear in such a small group but
may become painfully obvious when millions of people start taking the
drug. Even a few years ago, drugs reached a mass audience slowly,
providing time for unexpected side effects to show up in relatively
small numbers of people. But today drugs are marketed directly to
consumers via TV, so a huge market for a new product can be created
quickly and side effects can appear in large numbers of people. The
sexual potency drug, Viagra, provides an example of this phenomenon.
Within a few months of its introduction, several million people began
taking Viagra, and many serious side effects, including fatalities,
suddenly appeared.

Despite the widespread knowledge that half of all new drugs will cause
serious side effects in some people, neither the government nor the
drug companies systematically collect information on adverse reactions
to new drugs. "Even when it is recognized that a new drug will be given
to many patients for many years, rarely are systematic post-marketing
studies carried out."[4]

In the U.S., there is no formal procedure for monitoring drug safety.
If physicians became aware that a new drug has killed or maimed one of
their patients, or caused an allergic reaction, they may report it but
they also may not. As reports filter into the U.S. Food and Drug
Administration (FDA) in hit-or-miss fashion, FDA can revoke the
approval of a drug, and sometimes does, but almost never quickly. In
December, 1997, the popular nonsedating antihistamine terfenadine was
withdrawn from the market because a safer alternative existed without
terfenadine's danger of a potentially fatal heart arrhythmia (irregular
heart beat). However, by that time terfenadine had been on the market
12 years. Last September the FDA took the diet drugs fenfluramine and
dexfenluramine off the market because of heart valve damage to 31% of
those who took the drugs in combination with another diet pill,
phentermine (a combination known as fen/- phen) Fenfluramine could also
damage heart valves when taken alone. By the time fenfluramine was
banned, it had been on the market for 24 years.

A recent commentary by three doctors, published in the NEW ENGLAND
JOURNAL OF MEDICINE, contrasted prescription drug safety with airline
safety.

Airplanes are built, licensed and flown according to standards set by
the Federal Aviation Administration (FAA). But whenever a plane crash
occurs, a different agency (the National Transportation Safety Board,
or NTSB) steps in to establish the facts and make recommendations for
avoiding future crashes. The assumption is that a second, independent
agency is needed because the FAA would have a conflict of interest
investigating crashes of planes it had approved and licensed.

In drug safety, on the other hand, there is only one agency. The Food
and Drug Administration (FDA) approves pharmaceuticals and it also has
responsibility for investigating injuries and deaths caused by those
pharmaceuticals. As we have seen, FDA has a very limited capacity to
conduct surveillance studies so, in fact, they rely on the drug
companies to provide data on deaths and illnesses caused by their own
products.

As mentioned above, the diet drug dexfenfluramine was taken off the
market in 1997 because, combined with phentermine (the fen/- phen diet-
pill combination), it damaged heart valves.[4] When the FDA learned
that dexfenfluramine was dangerous, the agency had no good data on the
total number of people harmed. At the time, the director of FDA's
Office of Epidemiology and Biostatistics said, defensively, "We've done
what is necessary to determine there is a problem. Other information is
up to American Home Products [which marketed dexfenfluramine] to find
out." Of course American Home Products had little incentive to
investigate the number of problems caused by its product.

The three doctors comment, "Given the litigious climate surrounding
issues of drug safety, information from investigations conducted by
parties with vested interests is unlikely to be impartial and is seldom
publicly available to improve future decision making."

The three doctors say an independent drug safety board -- analogous to
the National Transportation Safety Board -- is needed to study deaths
and illnesses from drugs. They point out that FDA officials spend up to
a year of their lives evaluating a drug before approving it for
marketing "and it is unlikely that those who recommended a drug for
approval could later conduct a dispassionate evaluation of possible
harm due to that drug."

According to a recent commentary in the JOURNAL OF THE AMERICAN MEDICAL
ASSOCIATION, a competent drug safety program would have four parts:

(1) A program to monitor all adverse effects from prescription drugs
and annually report the number of injuries and deaths and their likely
causes. Currently no one keeps such statistics.

(2) A program to monitor side effects from new drugs. Presently, the
FDA's Division of Pharmacovigilance and Epidemiology (DPE) has a staff
of 52 people, but only 8 of those have MD degrees and only one has a
Ph.D. in epidemiology. This small group collects anecdotal information
about side effects of new drugs, but hasn't the resources to be
systematic or thorough.

The problem with anecdotal information is that only about 1% of adverse
drug reactions get reported in this way. For example, the FDA received
an average of 82 reports each year about adverse reactions caused by
the drug digoxin. This relatively small number of reports seemed to
indicate that digoxin was not a big problem. However a systematic
survey of Medicare records revealed 202,211 hospitalizations for
adverse reactions to digoxin during a seven-year period.

When FDA's DPE identifies a drug problem, they can only pass the
information along to the division of FDA that approved the drug. That
division can require the manufacturer to develop additional
information. However, "The most common corrective action is a change in
the product disclosure label or package insert."[5] The question then
becomes, are such warnings effective?

(3) The third part of a competent drug safety program would make sure
that safety information is being disseminated and heeded by physicians.
FDA currently has no such program. "The limited information available,
however, suggests that some important safety information--such as boxed
warnings on drug disclosure labels--either was not received or had
little effect. For example, one outcome of the protracted debate over
the safety of the sedative triazolam was a new drug label warning that
it should be prescribed for only 7 to 10 days. Several years later an
FDA task force reported that 85% of the prescriptions were being
written for longer periods.... Neither the FDA nor any other agency has
an organized program to find out whether the important warning messages
are achieving their intended purpose of protecting the public and, if
not, discovering the cause."[5]

(4) The fourth part of a competent drug safety program would
aggressively seek out information about unsuspected adverse reactions
to drugs. Instead of waiting passively for anecdotal information to
filter in, the government needs to aggressively look for drug
involvement in reported birth defects, heart problems and other common
disorders that are frequently caused by prescription drugs. In the same
way that the world's public health specialists aggressively seek out
new strains of influenza, FDA needs to be aggressively seeking out new
side effects of drugs.

Rather than strengthening the U.S. government's drug safety programs,
the present Congress has recently diminished the powers of the FDA to
monitor drug safety. Congress now allows drug companies to pay fees
which FDA uses to speed up the approval process for new drugs. As a
result, during 1996-1997, FDA approved 92 new drugs for market -- twice
the previous rate. However, Congress specifically prohibited FDA from
using any of the new money for monitoring drug safety.[4]

--Peter Montague (National Writers Union, UAW Local 1981/AFL-CIO)

=====

[1] Jason Lazarou and others, "Incidence of Adverse Drug Reactions in
Hospitalized Patients," JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
Vol. 279, No. 15 (April 15, 1998), pgs. 1200-1205. And see: David W.
Bates, "Drugs and Adverse Drug Reactions; How Worried Should We Be?
[editorial]" JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Vol. 279, No.
15 (April 15, 1998), pgs. 1216-1217.

[2] David C. Classen and others, "Adverse Drug Events in Hospitalized
Patients," JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Vol. 277, No. 4
(January 22/29, 1997), pgs. 301-306.

[3] Abigail Zuger, "Fever Pitch: Getting Doctors To Prescribe Is Big
Business," NEW YORK TIMES January 11, 1999, pgs. A1, A13.

[4] Alastair J.J. Wood and others, "Making Medicines Safer -- The Need
for an Independent Drug Safety Board," NEW ENGLAND JOURNAL OF MEDICINE
Vol. 339, No. 25 (December 17, 1998), pgs. 1851-1854.

[5] Thomas J. Moore and others, "Time to Act on Drug Safety," JOURNAL
OF THE AMERICAN MEDICAL ASSOCIATION Vol. 279, No. 19 (May 20, 1998),
pgs. 1571-1573.

Descriptor terms: pharmaceutical drugs; hospitals; drug industry;
fenfluramine; dexfenfluramine; airline safety; phentermine; fda; faa;
ntsb; fen/phen; fen-phen; drug safety;