United States General Accounting Office

GAO Report to Congressional Requesters

January 2000 ADVERSE DRUG

EVENTS

The Magnitude of

Health Risk Is

Uncertain Because of

Limited Incidence Data

GAO/HEHS-00-21

GAO United States

General Accounting Office

Washington, D.C. 20548

Health, Education, and

Human Services Division

B-281822 

January 18, 2000

Congressional Requesters

In 1998, about 2.7 billion prescriptions were filled in the United States.

Prescription drugs have great clinical benefits, but they also have risks.

Although most health problems associated with the use of

pharmaceuticals are relatively minor, serious adverse drug events (ADE)

that lead to hospitalization, disability, or death do occur. Because

exposure to prescription drugs is so high, even a very low ADE rate can

lead to a large number of serious injuries and deaths. The Food and Drug

Administration (FDA), the federal agency that approves drugs for

marketing; the pharmaceutical industry; physician groups; consumer

advocates; and health care researchers all agree that every medicine has

risks as well as benefits. However, they disagree substantially about the

extent of the risk, how to categorize ADEs, and what, if anything, should be

done to reduce their number.

In light of this debate, you asked us to summarize from available research

what is known about ADEs. In this report, we (1) describe the different

types and causes of ADEs, (2) examine the evidence on the overall

incidence and cost of ADEs in the United States, and (3) describe measures

that have been proposed to reduce the number and severity of ADEs. To

conduct our work, we reviewed the relevant scientific literature published

since 1980, organized a symposium of experts, and spoke with experts in

government, academia, and industry. Our methodology is described in

appendix I. We conducted our work between November 1998 and

December 1999 in accordance with generally accepted government

auditing standards. At your request, we plan to examine next the adequacy

of the U.S. system for monitoring the safety of prescription drugs that FDA

has approved for marketing.

Results in Brief Adverse drug events arise either from adverse drug reactions (ADR), which

are previously known or newly detected side effects of drugs, or from

medication errors committed by health care professionals or the patients

themselves. Many types of drugs can cause ADRs; the drugs reported as

associated with ADRs vary among different studies, depending on the

patients and settings examined. Two factors that can increase the risk of a

patient’s suffering from an ADR are illness severity and intensity of

treatment, including taking several drugs simultaneously. Studies of

several hospital populations found that most medication errors did not

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cause ADEs, but because so many drug doses were given, an estimated

quarter to half of all ADEs among the hospital patients resulted from

medication errors. Other studies found that medication errors were most

often the result of physicians’ prescribing errors and nurses’ errors in

administering drugs. Certain classes of drugs have consistently been

associated with medication errors, including analgesics, antibiotics,

psychotropics, and cardiovascular drugs.

Although it is clear that a wide range of commonly used drugs cause ADEs

with potentially serious consequences for patients, relatively little is

known about their frequency. Data routinely collected on ADEs during

clinical trials or after drugs are marketed are intended to identify the ADEs

that are associated with particular drugs and do not focus on their

frequency. Information on the overall incidence of ADEs from all drugs is

limited to a few research studies that typically examined the experience of

patients in one or two specific institutions—generally hospitals or

sometimes nursing homes—leaving the overall incidence of ADEs in

outpatient care largely unexplored. The most broadly based information

on ADE incidence comes from two studies drawing on statewide samples of

hospital patients. These studies applied a particularly restrictive definition

of ADE in finding that ADEs occurred at a rate of 0.56 for every 100 patients

admitted in Colorado and Utah, 0.72 in New York. Other studies that used

broader definitions found a range of 2 to 30 ADEs per 100 hospital

admissions. Two studies of ADEs in individual nursing homes reported an

incidence of 0.44 to 0.71 ADEs per patient month. Although studies have

estimated the overall rate of fatalities from ADEs and the total costs of

treating ADEs, their estimates are open to question because of the limited

underlying data on overall incidence available to support them.

Greater understanding of certain factors that affect the likelihood of ADEs

has led researchers and patient safety advocates to suggest a range of

measures to decrease their number and severity. Proposals for reducing

ADRs include improving communication between patients and physicians

about the risks and benefits of medications and expanding and

accelerating research on the safety of marketed drugs to more quickly

detect previously unknown ADRs and determine the risk factors that

increase their likelihood. Suggestions for reducing medication errors

include developing computerized prescribing and dispensing systems to

detect possible errors, avoiding confusing names and packaging for

medications, increasing the role of pharmacists as advisers to physicians

prescribing drugs and in monitoring drug therapy, and improving health

care providers’ pharmaceutical education.

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Background Each year, nearly half of all Americans take prescription drugs, spending

about $100 billion. For many medical conditions, pharmaceuticals are the

treatment of choice. Pharmaceuticals have contributed to lengthening life

expectancy by virtually eliminating the risk from some formerly deadly

infectious diseases and, more recently, by providing tools for more

effective management of chronic conditions such as heart disease,

hypertension, diabetes, and asthma.

Like all medical interventions, pharmaceuticals have risks as well as

benefits. Serious ADEs—those that cause hospitalization, significant

disability, or death—are relatively rare. Most ADEs involve transient and

less severe side effects from drugs, such as nausea or rash. Many ADEs

reflect the inherent risks, both known and unknown, of drugs that are

prescribed and administered correctly; these are what we call ADRs in this

report. Other ADEs stem from errors in prescribing, dispensing, or

administering prescription drugs. Common examples include physicians’

prescribing antibiotics to patients who have documented allergies to them,

nurses’ not properly diluting intravenous solutions, and patients’ failing to

take medications as directed.1

FDA within the Department of Health and Human Services decides which

drugs are approved for use by the general public. It assesses the

information that pharmaceutical companies provide when they seek

approval to market a drug to determine whether the drug is both safe and

effective in treating one or more specified medical conditions. In making

this assessment, FDA considers safety not in absolute terms but as a

balance of risks and benefits. For example, a new drug may have serious

adverse effects on some patients but still win FDA’s approval because of its

overall effectiveness in treating certain conditions relative to alternative

therapies. FDA also considers drugs in relation to the illness they are meant

to cure or relieve. Patients with life-threatening conditions may be willing

to assume more risk than other patients.

FDA continues to assess the risks and benefits of drugs after they are

initially approved, primarily on the basis of reports health professionals

and patients make about their experience with them. These reports are

voluntarily submitted to either FDA itself or, more commonly, a drug’s

manufacturer, which is required to pass them on to FDA. As FDA and the

medical community learn more about a particular drug, FDA may require

1

The distinction between medication errors and an ADE associated with the inherent risks of drugs is

sometimes ambiguous. For example, some drugs are difficult to use safely because toxic doses are

only slightly larger than those required for treatment, or appropriate dosing levels may vary over time,

requiring frequent adjustments. These factors provide abundant opportunities for medication errors.

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manufacturers to change its labeling. Such changes may restrict the

conditions for which the drug is approved or require certain safety

precautions. However, new information can also point to expanded uses

for a drug. For example, it was recently discovered that the diuretic

spironolactone, which has been marketed for 30 years, may substantially

reduce the risk of death in patients with congestive heart failure (Pitt,

1999).2

 In other cases, new applications of a drug have revealed previously

unsuspected risks. After more than 20 years on the market, the drug

fenfluramine was linked to damaged heart valves when used in

combination with phentermine, another weight-loss medication. This was

one of the rare instances in which FDA requested that the manufacturer

withdraw its drug from the market rather than change the label.

The Risk of ADEs Has

Multiple Factors

Some ADRs are the predictable result of a drug’s known pharmacological

properties, some become predictable as experience with using a drug

expands, and others are not predictable because they are caused by

individual sensitivities or allergies in particular patients. Many types of

drugs cause ADRs: Different studies vary in the drugs they report as

associated with ADRs, depending on the patients and settings they examine.

Two clinical factors known to increase the risk of a patient’s suffering an

ADR are the severity of illness and intensity of treatment, including taking

several drugs simultaneously (polypharmacy). Several studies of hospital

patients found that most medication errors did not cause an ADE but that

the few that did were still so numerous that they accounted for a quarter

to half of all ADEs. Other studies found that medication errors were most

often the result of physicians’ prescribing errors and nurses’

administration errors. Analgesics, antibiotics, psychotropics, and

cardiovascular drugs are among the drug classes that have been

consistently associated with a greater proportion of medication errors.

Inherent Properties of

Medications Lead to Many

ADEs

Many ADRs are the predictable result of a drug’s known pharmacological

properties and are often listed in a medication’s label. For example,

hemorrhaging is the most common ADR for warfarin, a drug that reduces

the risk of heart attack, stroke, and other conditions by decreasing the

clotting ability of blood. Nonsteroidal anti-inflammatory drugs (NSAID),

prescribed over long periods for rheumatoid arthritis, suppress enzymes

that protect the lining of the stomach and intestines, which causes serious

gastrointestinal complications in a small percentage of patients.

2

Interlinear bibliographic citations refer to the bibliography at the end of this report.

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Other ADRs, including allergic reactions, are unpredictable, caused by

sensitivities in particular patients who have neither a known risk factor

nor a history of adverse reactions to a specific drug. An unpredictable ADR

is more likely to cause disability or death than one that is predictable. Still

other ADRs are related to previously undetected inherent risks, including

drug-drug and drug-food interactions, that become evident as a drug is

used by many types of patients, having many kinds of comorbidities and

taking many other medications, including over-the-counter drugs and

dietary supplements. FDA’s system for collecting voluntary reports on

adverse experiences with marketed drugs is designed specifically to

uncover these kinds of previously unknown risks.

Many types of drugs can cause ADRs. Therefore, the drugs associated with

ADRs in particular studies vary, depending on the patients and clinical

settings studied. In addition, some drug classes are associated with a

substantial number of ADRs simply because they are prescribed to many

patients. These include antibiotics, narcotic analgesics, drugs to control

hyperglycemia in type II diabetics, psychotropic drugs such as

antidepressants and tranquilizers, and NSAIDs.3

 However, some classes of

drugs have notably lower ADR rates despite high rates of use. In the studies

we reviewed, antihistamines and the statin drugs prescribed to lower

cholesterol levels were rarely associated with serious ADRs.

Some Patients Have a

Greater Risk of ADRs Than

Others

Patients who are very ill, including those with several concurrent

diagnoses, have a greater ADR risk than others. Not only are they more

fragile but their illnesses may require several simultaneous treatments. In

addition, they may be receiving more aggressive treatments that are

known to entail significant risks. One study found that pediatric cancer

patients undergoing chemotherapy had suffered ADRs at a rate 10 times

that of other children admitted for inpatient treatment (Mitchell and

others, 1988). Another study found that hospital patients in intensive care

units (ICU) had 80 percent more ADRs than patients in general medical

wards and that most of this difference was accounted for by the greater

number of medications given the ICU patients (Bates and others, 1995a).

(Controlling for the number of medications reduced the adverse event rate

for ICU patients to 20 percent more than that for general medical patients.)

Some reports have found that elderly persons and women have more ADRs

than younger persons and men. However, it is possible that age and gender

3

Wolfe and others (1999) estimated 16,500 NSAID-related deaths annually among arthritis patients in the

United States.

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are merely related to other known risk factors instead of representing

additional, independent risks of ADRs.4

 In some studies, controlling for the

number of medications being taken substantially diminishes any

relationship between age and ADRs (Gurwitz and Avorn, 1991). Although

other studies have shown that women both use more drugs and have more

ADRs than men overall, these studies did not control for illness severity and

the number of different medications the patients took.

Medication Errors Are

Common and Have

Numerous Causes

Very few medication errors cause ADEs, either because errors are caught

before the drugs are administered or because specific errors created no ill

effects.5

 Nonetheless, because so many drug doses are given, an estimated

quarter to half of all ADEs among hospital patients result from medication

errors (Bates and others, 1995a; Classen and others, 1997).6

 For example, a

6-month hospital study found that the ADE rate was 1 for every 10,000

doses; 700,000 drug doses were given, and there were 70 injuries.7

Although estimates of the actual effect of medication errors vary, they

have led to hospital admissions, emergency department visits, and the

death of hospitalized patients (Nelson and Talbert, 1996; Classen and

others, 1991; Schneitman-McIntire and others, 1996).

Most medication errors in hospitals involve the prescriptions ordered by

physicians and nurses’ administration of drugs. Pharmacists make

relatively few medication errors when they transcribe, verify, and dispense

hospital prescriptions. Physicians’ errors include overdosing and

underdosing, prescribing drugs the patients have documented allergies to,

and prescribing drugs known to interact adversely with other medications

patients take. Administration errors include giving drugs other than those

prescribed, giving drugs at the incorrect time, and giving patients the

incorrect form of a drug, such as an injection rather than a tablet.

4

Changes in the metabolism of drugs with age mean that dosing requirements for older persons differ

from those for younger adults, complicating the determination of a proper dose. At the same time,

elderly persons frequently have other concurrent illnesses and, as a result, usually take several drugs.

One study of hospital admissions found that elderly patients took an average of 3.5 prescription drugs

before their hospitalization (Grymonpre and others, 1988).

5

Bates and others (1995b) found that 1 percent of medication errors lead to ADEs. If missed doses

(approximately half of the errors) are excluded, then 2 percent lead to ADEs.

6

A 1994 review by Pearson and others indicated that 30 to 80 percent of ADRs are preventable.

However, the majority of the studies they cited were published before 1980, and therefore we did not

include them in our review.

7

Comments of Lucian Leape, “The Safety of Pharmaceuticals: Monitoring and Regulation,” American

Enterprise Institute conference, Washington, D.C., Mar. 26, 1999.

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Patients’ noncompliance is also a major ADE source. Outside the hospital

and other health care institutions, patients are responsible for complying

with their drug regimen rather than relying on health care professionals.

They may underuse or overuse drugs, run out of a medication, or take

medications inconsistently. Their noncompliance is an important cause of

emergency department visits and hospital admissions. For example,

researchers reported that 58 percent of ADEs in patients visiting one

hospital’s emergency department were caused by noncompliance

(Dennehy and others, 1996). Another study found that 11 percent of all

elderly patients admitted to a hospital were related to noncompliance (Col

and others, 1990).

Sometimes, consistent patterns of medication error have resulted in the

withdrawal of certain drugs from the market. Recently, for example, the

manufacturer of bromfenac withdrew the drug when physicians continued

to prescribe it for more than 10 days, even after FDA had warned against

long-term administration. Similarly, the antihistamine terfenadine was

withdrawn from the market after warnings and new labels failed to stop its

use with certain other medications that could cause serious heart

problems.

Some Drugs Lead to

Medication Errors More

Often Than Others Do

Analgesics, antibiotics, and cardiovascular and psychotropic drugs are

among the classes of drugs consistently associated with medication errors.

The number of errors for a drug class is a function of the error rate for the

class and how often drugs in the class are used. The error rate for

cardiovascular drugs is lower than that for many other drug classes; the

large number of errors for this class primarily reflects the large number of

patients taking these drugs. Not only are analgesics and antibiotics used

frequently but their error rates are among the highest (Bates and others,

1998).

Some drugs have high medication error rates because their

pharmacological properties make them difficult to use, even when

administered in generally recommended doses. For instance, both the

anticoagulant warfarin and the cardiac stimulant digoxin have narrow

therapeutic indexes, meaning that the dosage levels for therapeutic

effectiveness are close to toxic, and both require careful adjustment of

dosage levels in individual patients. Known drug interactions pose

additional risks, since some drugs interact in potentially dangerous ways

with many other pharmaceuticals. For example, the label for warfarin

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indicates clinically significant interactions with approximately a hundred

other drugs.

Drugs with similar names can also lead to medication errors. Physicians

may confuse names when prescribing drugs and pharmacists may do the

same when dispensing them. Recently, concern has been raised about

possible confusion between Celebrex, Celexa, and Cerbyx, names that

look and sound alike but that represent very different drugs—a pain

medication used to treat arthritis, an antidepressant, and an antiseizure

drug, respectively.

Certain medications have been identified with a greater incidence of

patient noncompliance, including insulin, phenytoin, and drugs in

metered-dose inhalers (Dennehy and others, 1996; Prince and others,

1992).8

 Each of these medications requires careful monitoring by the

patient or physician to determine when it should be given and in what

dose. Consequently, the potential for noncompliance is quite high.

Little Is Known About

the Incidence and

Cost of ADEs

Although it is clear that a wide range of commonly used drugs cause ADEs

with potentially serious consequences for patients, relatively little is

known about the frequency of the ADEs. Data routinely collected on ADEs

before and after drugs are marketed focus more on identifying which ADEs

are associated with which drugs. Information on the overall incidence of

ADEs from all drugs is limited to a few research studies that have typically

examined the experience of patients in one or two specific

institutions—generally hospitals or sometimes nursing homes—leaving the

overall incidence of ADEs in outpatient care largely unexplored. The most

broadly based information on ADE incidence comes from two studies

drawing on statewide samples of hospital patients. These studies applied a

particularly restrictive definition of ADE in finding a rate of 0.56 for every

100 patients admitted in Colorado and Utah and 0.72 in New York. This

compares with a range of 2 to 30 ADEs per 100 admissions found in other

studies with increasingly expansive definitions of ADE. Two studies of ADEs

in individual nursing homes reported an incidence of 0.44 to 0.71 per

patient month. Other studies have estimated the overall rate of fatalities

from ADEs and the total costs of treating them, but both estimates are

questionable because of gaps in the underlying data on ADE incidence

rates.

8

Phenytoin is an anticonvulsant used to control seizures in certain types of epilepsy and other

conditions.

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ADEs Are Often Difficult

to Identify

Linking a particular symptom to a specific drug is difficult, primarily

because ADEs are relatively rare for most drugs marketed in the United

States and because drugs are often given to seriously ill patients whose

underlying conditions manifest many symptoms. The best chance of

identifying ADEs is when they show distinct effects shortly after a drug is

administered.

Other ADEs can be extraordinarily difficult to detect. For example,

symptoms that develop with the prolonged use of a drug require studies

with long follow-up periods to determine whether ADEs have occurred.

Similarly, rare adverse events require studies with very large numbers of

patients to accumulate a sufficient number of problematic cases, and

adverse symptoms that mimic those of a patient’s underlying condition

require carefully controlled clinical trials.9

Data on ADE Incidence

Collected Routinely Before

and After Drug Approval

Are Not Comprehensive

Safety is a prominent concern throughout drug development, and many

dangerous substances are identified and their testing is halted in the

process. Nonetheless, by themselves, the results of clinical trials submitted

with an application to FDA to market a drug cannot provide comprehensive

information on possible adverse events (Faich, 1986). First, the number of

patients typically included in preapproval clinical trials is too small to

detect less frequent adverse events. According to the pharmaceutical

industry, the total number of patients in such trials averages roughly 4,000

per drug. Consequently, adverse events that occur in 1 of 10,000 patients,

for example, often do not appear at all in any clinical trials. In addition, the

patients who are included in clinical trials are selected to obtain a clear

picture of a drug’s safety and efficacy and are therefore unlikely to reflect

the full range of consumers who will actually use the drug. For example,

participants in clinical trials usually include few elderly patients, few

patients with serious illnesses other than the one the drug targets, and few

patients taking many other medications. Clinical trials also usually last for

a relatively short time, so that adverse events that occur with long-term

treatment are not likely to be detected.

The limitations of the data on adverse events derived from clinical trials

can be especially critical during a drug’s initial marketing period. When a

9

One well-known example comes from the Cardiac Arrhythmia Suppression Trial, which found that

antiarrhythmia medications doubled the risk of cardiac arrest and death in heart attack survivors. This

relationship was not detected in clinical practice because patients with heart disease regularly have

arrhythmias and heart attacks, providing a ready alternative explanation that masked the causal role of

the drugs. It has been estimated that these medications caused up to 50,000 premature deaths (see

Echt and others, 1991).

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drug is first available to consumers, it can be quickly prescribed to

hundreds of thousands of patients who are far more heterogeneous than

the patients studied in the clinical trials. Further, physicians often

prescribe new drugs to patients who have not responded to older

medications; thus, the initial recipients of a drug are more likely to be

especially ill and unlike the patients studied in the clinical trials.

FDA’s current postmarketing data collection systems for approved drugs

are intended to compensate for the limitations of information from clinical

trials by detecting the existence of previously unidentified ADEs. However,

because FDA’s Adverse Event Reporting System (AERS) relies on voluntary

reports from physicians, pharmacists, patients, and others, it can uncover

instances of problems but it cannot determine their incidence.10 The same

intrinsic limitation applies to the incident reporting systems that many

hospitals have established to monitor adverse events, including ADEs. All

such systems based on spontaneous reporting detect only a fraction of the

total number of adverse events (Cullen and others, 1995). FDA’s AERS

includes an estimated 1 to 10 percent of adverse events (Goldman and

others, 1996). In addition, the adverse events that are reported are unlikely

to be representative of the much larger number of unreported events. For

example, there is evidence that ADEs are reported more often to FDA if they

involve a newly released drug or one sold by a company that has a

relatively large postmarketing surveillance program (Baum and others,

1994). Consequently, any estimate of ADE incidence based on a

spontaneous reporting system such as AERS would necessarily incorporate

the biases of the data, undercounting some types of adverse events and

overcounting others.

FDA, recognizing the limitations of its spontaneous reporting system,

augments the data in AERS with information from other sources. If

“signals” from AERS reports suggest new adverse events or an

unexpectedly large number of known ADEs, FDA can gather additional

information from several health maintenance organizations that have

cooperative agreements with the agency to use their databases of member

medical and pharmacy records to investigate issues of ADE causation and

incidence. However, these databases sometimes do not have enough

10Health care providers and patients are not obligated to report suspected ADEs to FDA. However,

they are encouraged to report events either directly to AERS or to the drug’s manufacturer, and the

manufacturers are required to forward all adverse event reports they receive to FDA.

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patients taking a particular drug for a given medical condition to provide

definitive answers to the questions that have arisen.11

Knowledge of Overall ADE

Incidence Is Fragmentary

There is relatively little information on ADE frequency overall for all types

of drugs. The data collected routinely before and after drug approval and

through studies of ADEs associated with specific medications do not

answer this question.12 Appendix II describes the relatively few studies

that we identified that were designed specifically to examine the overall

incidence of ADEs.

One potential reason for the paucity of research in this area is the

methodological challenge it presents. Determining that an adverse event

occurred and that it was caused by a drug and not some other factor, such

as the patient’s underlying disease, is necessarily more complex when the

scope of the investigation includes all possible adverse events and every

drug the patient took. Researchers have to consider much more

information from each patient’s medical record on symptoms, diagnostic

tests, and treatments.

Researchers conducting these studies have typically responded to this

challenge by focusing on a narrowly defined patient population. For

example, the large majority of the studies deal exclusively with patients

treated in one or two specific institutions. On a practical level, this enables

researchers to examine the complete medical record for hundreds of cases

without having to go to multiple institutions to first obtain permission and

then copy and ship the often voluminous patient records from diverse

locations.

The disadvantage of focusing on institutions is that the extent to which

ADEs in different treatment settings are studied is quite uneven.

Researchers tend to study the type of institutions that have the most

complete and detailed records, which is usually hospitals. Consequently,

ADEs in other settings are examined either less often or not at all. We found

11Without information on the incidence of ADEs, it can be difficult for FDA to assess the level of risk a

drug poses. For example, in March 1999, an FDA advisory committee considering the safety of

troglitazone, a drug for type II diabetes, was unable to determine the number of patients who suffered

liver failure while taking the drug. Estimates of the number of deaths and liver transplants presented

by an FDA epidemiologist and the drug’s manufacturer differed by tenfold.

12Much of the substantial literature on ADEs consists of published studies that focused on a specific

drug or class of drugs. See, for example, the 239 abstracts of studies conducted by the Boston

Collaborative Drug Surveillance Program listed in Jick (1992). Such studies may indicate the incidence

of adverse events with a given medication or drug class, but there is no direct way to aggregate

specific drugs and types of ADEs to arrive at an overall incidence rate.

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only a few studies of ADEs among nursing home residents and only one

small study of ADEs that occurred in the community and were treated in

physicians’ offices.13 The general lack of information about the incidence

of ADEs that occur and are treated outside hospitals and nursing homes

means that our basing our estimates of overall ADE incidence on current

knowledge necessarily limits us to institutional settings.

A related problem arises in attempting to extrapolate from the studies of

overall ADE incidence in selected hospitals and nursing homes to other

comparable institutions. Without evidence that the studied institutions are

representative of others, it is not appropriate to project the results to

patients treated in other facilities. The one or two institutions studied may

differ substantially from other institutions of the same type with respect to

the characteristics of the patients served or services provided, which in

turn could affect the overall rate of ADEs.

ADEs Differ for Hospital

Patients and Nursing Home

Residents

With two exceptions, the existing studies of ADEs among hospital patients

each reported data from a different individual hospital (or, in one case,

two hospitals) and they frequently differed substantially in the way they

defined and counted ADEs. Some studies examined how many hospital

admissions stemmed from ADEs, others tracked ADEs that occurred during

the course of a hospital stay, and a few did both. One study focused solely

on ADRs (thereby excluding medication errors), another identified any

injury caused by a drug, and several others counted any adverse

experience associated with the use of a medication. Some included events

that were possibly, but not definitely, caused by a drug, while others did

not. All these variations help explain the range in ADE incidence reported

by different studies.

The two studies with an unusually broad, statewide sample of patients but

a highly restrictive definition of ADEs found rates of 0.56 and 0.72 ADEs for

every 100 hospital admissions. The higher figure emerged from the

Harvard Medical Practice Study (HMPS), which examined a representative

sample of all nonpsychiatric patients treated in acute care hospitals in

New York in 1984 (Brennan and others, 1991; Leape and others, 1991). It

therefore included a proportionate mix of patients from teaching and

nonteaching, urban and rural, and large and small hospitals. More recently,

13Klein and others (1984) was a study of 299 mostly chronically ill patients treated in outpatient clinics

run by Johns Hopkins University and is therefore unlikely to reflect community-based care as a whole.

There are several studies from periods before our 1980 cutoff date and from foreign countries, but this

is the only one we found that examined overall ADE incidence in outpatient care that met our

selection criteria—U.S. patient data from 1980 or later. However, several new studies of ADE incidence

in noninstitutionalized populations are now under way.

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the same methodology was applied to statewide samples of 1992 hospital

discharges in Colorado and Utah (Thomas and others, forthcoming). Even

though a sample of patients in one or two states is vulnerable to certain

biases—such as those deriving from regional variation in clinical practice

patterns—the databases for the studies that used them are far more

diversified and representative than those of the other studies we

examined. Moreover, the fact that the rates found in these two studies are

relatively close, despite the studies’ variation in time and place, suggests

that regional and temporal variation in ADE incidence may not be very

large. However, by counting only those ADEs that resulted in disability,

prolongation of a patient’s hospital stay, or death, these two studies

identified just a fraction of the patients injured by drugs.14

Four other studies examined adverse drug events among hospital

inpatients, reporting ADE incidence rates ranging from 2.0 to 30 ADEs per

100 admissions (see table II.1 in appendix II).15 The higher rates came from

the studies with more expansive definitions of ADEs. There was less

variation among the studies in their reported incidence of moderate to

severe ADEs, which ranged from 1.9 to 19 per 100 admissions.

Compared with hospital patients, nursing home residents are generally

more frail and functionally impaired. While nursing homes are designed to

provide less intensive care than hospitals, their residents still receive many

medications. These factors probably increase the vulnerability of nursing

home residents to ADEs. Patients also tend to stay longer in nursing homes

than in hospitals, so ADE rates for nursing home residents are often

reported per unit of time, such as patient months, to adjust for risk

differences attributable to longer and shorter stays.

We found fewer studies of ADE incidence in nursing homes than in

hospitals, and none examined more than one or two institutions.16 As with

the hospital studies, the definition of what constituted an ADE varied

substantially. One study with a more narrow definition reported an

incidence of 0.44 ADEs for every month that a patient spent in that

institution, compared with 0.71 ADEs reported in a second study with a

14Bates and others (1995a), conducting a study in two Boston-area teaching hospitals, applied both the

ADE definition that HMPS used and a broader ADE definition that included any injury related to a

prescribed drug. The ADE incidence rate was 0.5 percent under the HMPS definition and 6.5 percent

under the broader definition.

15It is not possible to calculate an incidence rate for studies focusing on ADE-caused admissions to a

particular hospital, because there is no defined population at risk for admission to that hospital, and

only that hospital, if an ADE occurs. See appendix II.

16A study of 18 nursing homes in eastern and central Massachusetts is under way.

Page 13 GAO/HEHS-00-21 Adverse Drug Events
B-281822 

much broader definition (see table II.2 in appendix II).17 These rates are

roughly comparable with the rates reported by the one study of hospital

ADEs that presented ADE incidence in terms of time spent in the hospital.18

Estimates of Deaths Are

Uncertain

Adverse drug events are sometimes so severe that patients die from them.

There is little certainty about the frequency of fatal ADEs, because the data

on fatalities stemming from ADEs are even more sparse than the data on

overall ADE incidence. Recently, Lazarou, Pomeranz, and Corey (1998a)

attempted to synthesize available data on ADR fatalities.19 To derive their

estimate of 106,000 fatal ADRs in the United States in 1994, they drew on

data from 16 ADR studies published between 1964 and 1995. The studies

cumulatively looked at 78 deaths, but only two of the studies had more

than 10 deaths, and more than 40 percent of the deaths were reported in

one 1973 study. Consequently, there were too few deaths to arrive at a

stable estimate of total ADR fatalities—as even a small change in the

number of deaths reported in the studies would lead to substantial

changes in the number of deaths extrapolated to the national population.

In addition to the small number of deaths on which this estimate was

based, there is a major question about relying on data from studies more

than 20 years old. Since the 1960s and 1970s, drug therapies have shifted

markedly for many conditions, with a generally more intensive use of

pharmaceuticals now than in the past. Of the 16 studies that Lazarou and

colleagues included in their analysis of ADE fatalities, only 4 were

published after 1976. Collectively, these 4 studies accounted for a total of 5

deaths, compared with 73 in the 12 earlier studies. Thus, the projection

17The first study (Gerety and others, 1993) basically looked for ADRs. The second (Cooper,

1986) looked for a much larger category of drug-related problems, including any unwanted

consequence of using or not using drug therapy.

18This study (Bates and others, 1995a) reported an overall incidence of 0.345 ADEs per patient month,

ranging from 0.267 in surgical general care wards to 0.582 in medical intensive care wards. The figures

were converted from events per 1,000 patient days to events per patient month.

19Their estimates are for fatal adverse drug reactions; they did not address fatalities caused by

medication errors.

Page 14 GAO/HEHS-00-21 Adverse Drug Events
B-281822 

Lazarou and his colleagues made for the incidence of fatal ADEs for 1994

was actually based on the experience of patients 20 or more years earlier.20

Data on the Cost of

Treating ADEs Are Limited

The lack of overall incidence data for ADEs in the United States impedes

making a reliable estimate of the nationwide costs of adverse drug events,

although several studies have reported similar costs for treating ADEs in

hospitals. Researchers have followed different approaches in attempting

to generate information about the direct costs of treating adverse drug

events, but we found only one study that attempted to calculate indirect

costs such as lost income.

Most studies of ADE costs have focused on one or two individual

institutions. (See appendix III.) Three of the four studies that specifically

analyzed the average excess hospital costs resulting from ADEs reported

estimates ranging from $1,939 to $2,595 (Bates and others, 1997; Classen

and others, 1997; Evans and others, 1994b). The outlier study reported

average ADE costs of only $783 (Schneider and others, 1995). Two of these

studies also extrapolated their findings on ADE incidence and costs in these

particular hospitals to all hospital patients in the United States, producing

estimates of $1.56 billion and $4 billion in additional hospital costs per

year nationwide from ADEs (Bates and others, 1997; Classen and others,

1997). While these estimates may help indicate the general scope of ADE

costs, because each is based on just one or two hospitals, their precision

for estimating costs on a national level is limited.

Three other studies used expert panels to generate ADE cost estimates

(Bootman, Harrison, and Cox, 1997; Johnson and others, 1995, 1997). The

experts came to a collective judgment as to the likely probability of

specified negative outcomes arising from drug therapy, which translated

into an incidence rate for the patient population as a whole.21 The total

20When Kenneth Fremont-Smith (1998) criticized Lazarou and his colleagues on this point, they

responded (1998b) that they had since analyzed unpublished data from 32 additional studies of fatal

ADEs in industrialized countries other than the United States. They stated that these data, when

combined with the U.S. data, showed no trend in rates of fatal ADRs, either up or down over time.

They also found no statistically significant difference between the U.S. and non-U.S. studies. They

maintained that this demonstrated that the rate of fatal ADRs had not changed in the United States,

thereby validating their original estimate. They took this approach because, in their view, the data

from recent studies of fatal ADRs among U.S. hospital patients were not sufficient to derive a

statistically reliable estimate of the incidence of fatal ADRs in the United States.

21The panel members in one of these studies were pharmacists who were selected because of their

extensive clinical practice in ambulatory settings and recognition as leaders in pharmacy practice in

the United States (Johnson and others, 1995). In a later study, the panel members were physicians and

consultant pharmacists with practice experience in nursing facilities and geriatric care (Bootman,

Harrison, and Cox, 1997).

Page 15 GAO/HEHS-00-21 Adverse Drug Events
B-281822 

cost of ADEs was then calculated by multiplying the estimated number of

ADEs by the unit cost of treating them.22 For one study in 1995, this process

produced an estimate for the costs of drug-related morbidity and mortality

in the ambulatory setting of $76.6 billion annually, primarily because of the

resulting admissions to hospitals, costing $47.4 billion, and long-term-care

facilities, costing $14.4 billion.23 A later study in 1997 estimated the cost of

drug-related morbidity and mortality in nursing facilities to be around

$7.6 billion annually (Bootman, Harrison, and Cox, 1997). The probability

statements developed by an expert panel are inherently subjective and

would be likely to change if the composition of the panel changed. Since

the cost estimates are based on these estimated incidence rates, the cost

estimates are also open to question.

Finally, the 1999 study conducted in Colorado and Utah also collected

information about the costs of adverse events, including those that were

drug-related (Thomas and others, 1999). Distinguishing this study are its

broad-based sample of 14,732 randomly sampled discharges from hospitals

in two states and its inclusion of indirect as well as direct treatment costs

for ADEs. From data extracted from the patients’ medical records,

physicians and malpractice claims adjusters estimated the patient’s degree

of disability and likely use of health care in the future. Projected inpatient

and outpatient health care costs, lost wages, and lost household

production were then estimated, and the total was reported as an

aggregate national figure. The $5.2 billion estimate for hospital costs alone

exceeded the costs reported in both of the earlier studies from individual

institutions. Adding in the estimated cost of outpatient care, lost income,

and lost household production brought the total of direct and indirect

costs to an estimated $12.2 billion in 1996 dollars. This result is based on a

much broader sample than in the earlier studies, although still limited to

Colorado and Utah. In extrapolating the results to an aggregate national

estimate, the authors did not attempt to adjust for the likely variation in

hospital costs and personal incomes in other parts of the country.

22The expert panels also estimated the proportion of patients with negative outcomes who would

receive various types of treatment in response, such as additional physician visits, new prescriptions,

emergency department visits, nursing home admissions, and hospitalizations. The cost of each

scenario was calculated as “monetary values”—obtained from published statistical series and

research reports—for each type of treatment employed in that scenario, and then an aggregate cost

figure was computed from the estimated total cost of each separate scenario and multiplied by its

estimated probability across all patients (Johnson and others, 1995).

23With adjustments in the assumptions of the model, the estimates of total ADE costs ranged from

$30.1 billion to $136.8 billion. (See Johnson and others, 1995.)

Page 16 GAO/HEHS-00-21 Adverse Drug Events
B-281822 

Measures Intended to

Reduce the Number

and Severity of

Adverse Drug Events

Increased understanding of what makes ADEs likely has led researchers

and patient safety advocates to develop a variety of measures intended to

decrease their number and severity. The approaches they have suggested

to reduce ADRs include improving communication between patients and

physicians about the risks and benefits of medications, as well as

expanding and accelerating research on the safety of marketed drugs to

reduce the time it takes to detect previously unknown ADRs and determine

the risk factors that identify the patients who are most likely to experience

them. Measures designed to reduce the number of medication errors

include developing computerized prescribing and dispensing systems to

detect errors, avoiding confusing names and packaging, increasing the role

of pharmacists as advisers to physicians in prescribing drugs and in

monitoring drug therapy, and improving physicians’ pharmaceutical

education.

Drug Development and

Better Information to

Reduce ADRs

Some have suggested that the process of drug research and development

could help reduce ADRs as pharmaceutical companies respond to market

incentives by developing new medications with fewer risks than the ones

they replace. For example, a new generation of NSAIDs called cox-2

inhibitors has recently reached the market; these drugs were designed

specifically to lower the risk of gastrointestinal injury compared with

traditional anti-inflammatory drugs such as aspirin or ibuprofen. Similarly,

while the first in a new class of diabetes drugs, troglitazone, approved for

marketing in 1997, has been associated with rare cases of deadly liver

failure, FDA has since approved other drugs with similar clinical benefits

but less liver toxicity (although they may have other serious side effects).

Others have suggested that physician’s education—and communication

between physicians and patients—about the benefits and risks of

particular drugs be improved in order to promote informed

decisionmaking about pharmaceuticals and thereby help reduce the

incidence of ADRs. Given the large number of drugs on the market and the

voluminous information about each one, some observers have suggested

that computerized systems could be designed to help remind physicians

when they submit prescriptions about important therapeutic

considerations, including comparative benefits, risks, and

contraindications for several similar drugs.

Expanded surveillance programs to gather information about marketed

drugs might also help prevent ADRs by more quickly accumulating

information about them for particular drugs. For example, FDA has

Page 17 GAO/HEHS-00-21 Adverse Drug Events
B-281822 

proposed for discussion several methods of rapidly gathering information

during the crucial period following a drug’s approval for marketing. These

ideas include establishing a network of health care facilities to serve as

“sentinel sites” for closely monitoring the experiences of the first patients

to take a new drug and slowing down the introduction of new drugs until

sufficient information has been collected about their risks once they are

on the market.24 Quantified risk data about new drugs could assist

physicians and patients to make more informed treatment choices.

Data collection efforts that document patient risk factors for adverse

events have the effect of moving some ADRs into the category of

preventable medication errors. For example, reports of cardiovascular

complications from using sildenafil surfaced after its approval in 1998,

ultimately causing a change in the product’s label to warn physicians

about its dangers for patients with certain preexisting conditions. Patients

with these conditions who took sildenafil and suffered an adverse

cardiovascular event when the drug was first marketed might have been

then classified as suffering an ADR but today would probably be considered

victims of medication error.

Measures to Reduce

Medication Errors

Numerous measures to reduce medication errors have been taken, and

experts have proposed others for drug manufacturers and health care

providers—many aiming to make errors more difficult across a range of

specific circumstances. For instance, computer systems can screen

prescriptions to detect errors in dosage levels or known allergies. Some

proposed measures, such as eliminating look-alike packaging, would make

it physically harder to dispense or administer the wrong drug. Table 1,

which is meant to be illustrative rather than comprehensive or evaluative,

describes a number of general approaches.

24The benefits of slowing down the marketing of new drugs must be weighed against the health costs

of potentially restricting patients’ access to them.

Page 18 GAO/HEHS-00-21 Adverse Drug Events
B-281822 

Table 1: Current and Proposed Approaches to Reduce Medication Errors

Approach Intended benefit

Dispensing change

Physicians’ direct computer entry of

prescriptions

Physicians’ entering prescriptions on a computer rather than writing them reduces

transcription errors and indicates potentially problematic prescriptions. For instance, it

can indicate an improper dose that is being prescribed or a drug that might interact with

another medication the patient is taking.

Unit dosing Dispensing drugs from the pharmacy in single-unit or unit-dose packages (for instance,

blister packs) makes them ready to administer.

Automated hospital dispensing systems Such systems notify nurses when a drug is to be administered and allow access only to

it. The systems also record what has been given and when as well as reducing delays in

giving patients their medications and decreasing other administration errors.

Bar coding hospital medications Machine-readable labels can facilitate matching patients with their prescribed

medications and documenting drug dispensing and administration.

Focus on high-alert drugs Specific systems and educational initiatives minimize errors with the drugs that have the

greatest potential to cause serious harm when used incorrectly, such as insulin, opiates

and narcotics, potassium chloride concentrate, and intravenous anticoagulants.

Packaging and physical change

Differentiated drug names Giving drugs whose names sound alike (for example, Celebrex, Celexa, and Cerbyx)

different names could reduce the likelihood of their being confused.

Differentiated packaging Packaging different drugs differently would make them easily distinguished.

Standardized packaging Uniform labels with standards for print size and color would help practitioners and

patients know where to look for particular information.

One name and one look for each drug Drugs would be less easily confused if each one had only one name, not a generic and a

brand name, and two or more manufacturers who made the same drug gave the pills the

same design, packaging, and labeling.

Change in sensitivity to ADEs

Physicians’ education Educating physicians about pharmaceuticals more, both during and after medical

school, would improve their prescribing practices.

Greater pharmacist involvement Including pharmacists in hospital rounds helps physicians make prescribing decisions,

and increasing the role of community pharmacists in monitoring drug therapies improves

patients’ compliance.

Timely communication Timely feed back on ongoing ADEs could help physicians in hospitals prevent the

progression of ADEs to more severe forms.

Computerized ADE monitoring Computer programs designed to screen for potential ADEs, using data from electronic

inpatient or outpatient medical records, such as orders for known antidotes or specific

laboratory test abnormalities, cut their number and frequency.

Culture change

Encouraged reporting Changing an institution’s culture so that errors are seen as an indication of where

systemic improvements are needed rather than simply assigning blame to individuals

would make it more likely that mistakes would be reported.

Page 19 GAO/HEHS-00-21 Adverse Drug Events
B-281822 

Agency Comments We provided a draft of this report to the Commissioner of FDA and five

outside experts, including physicians, pharmacists, and epidemiologists

who are actively involved in analyzing ADEs. FDA responded that the report

accurately describes the current status of adverse event reporting. The

agency also provided technical comments that we incorporated as

appropriate. The outside experts generally found that our characterization

of currently available information on ADEs is accurate and thorough.

However, several of them expressed concern that our critical assessment

of existing studies might create the misperception that there is little

evidence that ADEs pose a substantial health risk to patients. We revised

sections of the report and its title to make clear that while the magnitude

of the health risk is uncertain its existence is not. Other comments from

the experts led us to make additional corrections and clarifications to the

text.

As we arranged with your office, unless you publicly announce the

contents of this report earlier, we plan no further distribution of it until 30

days after its issue date. We will then send copies to the Secretary of the

Department of Health and Human Services, the Commissioner of FDA, and

others who are interested. We will also make copies of the report available

to others on request.

If you or your staff have any questions, please contact me at

(202) 512-7114. Robert M. Copeland, Martin T. Gahart, Michele Orza, Eric

A. Peterson, and Helene F. Toiv were the major contributors to this report.

Janet Heinrich

Associate Director, Health Financing

 and Public Health Issues

Page 20 GAO/HEHS-00-21 Adverse Drug Events
B-281822 

List of Requesters

The Honorable James M. Jeffords

Chairman

The Honorable Edward M. Kennedy

Ranking Minority Member

Committee on Health, Education, Labor, and Pensions

United States Senate

The Honorable Bill Frist

Chairman

Subcommittee on Public Health

Committee on Health, Education, Labor, and Pensions

United States Senate

The Honorable Richard J. Durbin

The Honorable Jack Reed

United States Senate

The Honorable Thomas J. Bliley, Jr.

Chairman

The Honorable John D. Dingell

Ranking Minority Member

Committee on Commerce

House of Representatives

The Honorable Henry A. Waxman

Ranking Minority Member

Committee on Government Reform

House of Representatives

Page 21 GAO/HEHS-00-21 Adverse Drug Events
Contents

Letter 1

Appendix I 

Objectives, Scope,

and Methodology

24

Appendix II 

Estimating the Overall

Incidence of Adverse

Drug Events

26

The Few Studies That Estimate ADE Incidence Measure It in

Specific Settings

26

Studies of Hospitals Vary Substantially 27

Studies of Nursing Homes Suggest That ADEs Are Common

Among Residents

29

The Data on Emergency Department Visits and Hospital

Admissions Are Insufficient for Estimating Overall ADE

Frequency

30

Appendix III 

Sixteen Studies

Estimating ADE Costs

in the United States

35

Appendix IV 

Experts We Consulted

37

Bibliography 39

Tables Table 1: Current and Proposed Approaches to Reduce

Medication Errors

19

 Table II.1: Six Studies of Hospital Inpatient ADEs 28

 Table II.2: Three Studies of ADEs in Long-Term-Care Facilities 30

 Table II.3: Four Studies of Emergency Department Visits for

ADEs

32

 Table II.4: Four Studies of Hospital Admissions for ADEs 33

Page 22 GAO/HEHS-00-21 Adverse Drug Events
Contents

Abbreviations

ADE Adverse drug event

ADR Adverse drug reaction

AERS Adverse Event Reporting System

FDA Food and Drug Administration

HMPS Harvard Medical Practice Study

ICU Intensive care unit

NSAID Nonsteroidal anti-inflammatory drug

WHO World Health Organization

Page 23 GAO/HEHS-00-21 Adverse Drug Events
Appendix I 

Objectives, Scope, and Methodology

The objectives of this report were to (1) describe the different types and

causes of adverse drug events (ADE), (2) examine the evidence on the

overall incidence and cost of ADEs in the United States, and (3) describe

measures that have been proposed to reduce the number and severity of

ADEs.

This study concerns only prescription medicines. We did not examine

vaccines or other biologics, medical devices, procedures, or

nonprescription or illicit drugs. The study encompasses both adverse

events that result from the intrinsic pharmacological characteristics of

drugs and those that stem from mistakes that physicians, nurses,

pharmacists, other health professionals, and patients make in using

pharmaceuticals. We focused on obtaining information about the use of

prescription drugs in the United States since 1980 across the full range of

treatment settings, including hospitals, long-term care institutions, and

outpatient facilities. We chose 1980 as the cutoff because many drugs in

use now were not available before then and, for many major clinical

conditions, the main classes of drugs relied on now did not exist before

1980. The results obtained in studies conducted before 1980 may have little

applicability for current clinical practice. In describing proposed measures

to reduce ADEs, we did not attempt to evaluate their potential

effectiveness.

To identify published studies that were relevant to our study questions, we

pursued three primary strategies. First, we searched computerized

bibliographic databases, including Medline and Embase, for citations

related to ADEs or reactions and medication error. Second, we consulted

with academic researchers specializing in this area and obtained their

recommendations for useful studies (see appendix IV for a list of the

outside experts we consulted). Third, we examined the footnotes of the

studies thus identified for leads to additional relevant studies. We then

selected studies for more intensive analysis. They consist of the studies

that presented primary data on the incidence of and factors related to ADEs

in the United States after 1980.

We used a standardized data abstraction form to collect categories of

information: how ADE (or some other corresponding term) was defined in

the study, the types and severity of events observed; the relative frequency

of events for different classes of drugs; the demographic and clinical

characteristics of the patients experiencing the ADEs; the characteristics of

the overall study population, including the number of subjects and

institutions (for example, hospitals or nursing homes); how the subjects

Page 24 GAO/HEHS-00-21 Adverse Drug Events
Appendix I 

Objectives, Scope, and Methodology

and institutions were selected; data sources; completeness of the data; and

the procedures used to attribute an adverse event to a drug and to identify

medication errors. We selected these data elements to address two

questions. First, what did the study have to say about the frequency and

characteristics of ADEs? Second, what limitations applied to that

information in terms of the population groups and institution types to

which its results applied, as well as any uncertainties about the results that

could derive from the way the study was conducted? Having made these

assessments, we drew on the most appropriate studies to address each of

our three objectives.

We obtained additional data for this study in meetings and interviews with

Food and Drug Administration (FDA) officials and academic,

industry-based, and other experts in the field. We initiated this process

with a public forum on postmarketing surveillance, which we organized in

conjunction with the Drug Information Association’s Conference on

Adverse Event Reporting in Washington, D.C., on February 24, 1999.

Invited participants included ADE experts with a range of institutional

affiliations (see appendix IV). The conference and interviews provided us

with background information on the drug approval and postmarketing

surveillance processes, information on proposals to reduce the incidence

of and research on ADEs that had not yet been published, and clarification

on several methodological issues.

Page 25 GAO/HEHS-00-21 Adverse Drug Events
Appendix II 

Estimating the Overall Incidence of Adverse

Drug Events

This appendix examines the strengths and limitations of available data on

the overall incidence of ADEs. It explains why much of the information

currently collected on ADEs does not pertain to the question of overall

incidence. It describes the few research studies that have addressed ADE

incidence in various treatment settings: hospitals, nursing homes, and

emergency departments. The characteristics of these studies, in particular

their nearly universal focus on one or two individual institutions,

determine the limitations of current knowledge on the overall frequency of

ADEs.

The Few Studies That

Estimate ADE

Incidence Measure It

in Specific Settings

Most of the studies on ADEs assess the risks associated with individual

drugs or classes of drugs—they do not estimate overall incidence. In

particular, a large number of studies have involved checking whether

specific events such as liver failure or allergic reactions that appeared in

case reports about a drug are in fact linked to the use of that drug among

larger numbers of patients. Much of the work sponsored by

pharmaceutical companies and FDA falls into this category.

Other studies that have examined ADEs more broadly have used data that

are not appropriate for incidence calculations. For example, some

researchers have examined ADEs by using data from the incident reporting

systems that virtually all hospitals maintain. These systems compile

reports of adverse events submitted by hospital staff members, including

those involved in drug therapy. The key limitation of all such spontaneous

reporting systems with regard to estimating ADE incidence is that the cases

that any one person chooses to report probably differ substantially from

the much larger number of unreported events.

This leaves a relative handful of studies that attempted to collect primary

data on the full range of ADEs experienced by a defined patient population.

Their small number reflects the complexity of the task. It can often be

difficult to distinguish adverse events caused by a drug from those caused

by the medical conditions that the drugs are intended to treat. To do this

requires either a careful review of the medical record for each case

included in the study or, preferably, a means of monitoring a patient’s care

as it is provided in order to identify and verify ADEs when they occur. As a

practical matter, it is most feasible to do this in specific institutional

settings. Therefore, the studies that have produced data on the incidence

of ADEs are restricted by having focused on a particular treatment

setting—for example, hospitals and nursing homes—and in most cases to

one or two specific providers.

Page 26 GAO/HEHS-00-21 Adverse Drug Events
Appendix II 

Estimating the Overall Incidence of Adverse

Drug Events

Studies of Hospitals

Vary Substantially

The six studies we found that systematically collected primary data on

ADEs occurring during a hospital stay vary substantially along multiple

dimensions.25 (See table II.1.) First, they define ADEs very differently. The

Harvard Medical Practice Study (Brennan and others, 1991) and its

replication in Colorado and Utah (Thomas and others, forthcoming)

counted only quite severe adverse events, whereas several others had no

severity threshold. The Brennan and Thomas studies and, to a lesser

extent, Classen (Classen and others, 1991) included some cases in which

an ADE was present on admission rather than just cases that developed

during the hospital stay under study. Classen used the World Health

Organization (WHO) definition of an adverse drug reaction (ADR), which

excludes adverse effects produced by doses outside the normal

therapeutic range.26 The other studies focused on events caused by drug

therapy, whatever the dosage.

25These studies attempted, within their given institutional focus, to capture the experience of a broad

range of patients in terms of demographics and clinical conditions. Numerous other studies focus

exclusively on various patient subgroups—such as children, the elderly, patients with psychiatric

conditions, and patients receiving specific drugs or experiencing specific types of ADEs—that we

judged to be less useful for assessing the overall incidence of ADEs.

26WHO defines ADR as the noxious and unintended effects of a drug that occur at doses used in

humans for prophylaxis, diagnosis, or therapy. This definition excludes some medication errors (such

as accidental overdoses) but includes others (such as prescribing the wrong drug).

Page 27 GAO/HEHS-00-21 Adverse Drug Events
Appendix II 

Estimating the Overall Incidence of Adverse

Drug Events

Table II.1: Six Studies of Hospital Inpatient ADEs

ADE definition ADE type

ADEs per 100

admissions Study size Site studied

Thomas and others, forthcoming

Injury caused by medical

management resulting in prolonged

hospitalization or disability at

dischargea

Inpatient and

admission

0.56 14,700 All wards except psychiatric

in a stratified sample of acute

care hospitals in Colorado

and Utah

Brennan and others, 1991

Unintended injury caused by

medical management resulting in

measurable disability or prolonged

hospitalizationa

Inpatient and

admission

0.72 31,429 All wards except psychiatric

in a representative sample of

New York State acute care

hospitals

Classen and others, 1991

Any noxious, unintended, and

undesired effect of a drug that

occurs at doses used in humans

for prophylaxis, diagnosis, or

therapy

Inpatientb 1.99

(1.91 moderate or

severe)

36,653 All wards in one acute care

referral center and teaching

hospital in Utah

Bates and others, 1995a

An injury resulting from

administering a drug

Inpatient 6.5

(2.8 serious, 

life-threatening, or

fatal)

4,031 Medical, surgical, and

intensive care units (ICU) in

two tertiary care hospitals in

the Boston area

Steel and others, 1981

Any illness resulting from a

diagnostic procedure or from any

form of therapya

Inpatient 25.5

(4.91

life-threatening or

fatal)

815 Medical, medical ICU, and

coronary care unit at one

university teaching hospital in

Boston

Bowman and others, 1994

Any adverse experience

associated with the use of a drug,

including experiences rated

“possible” on the Naranjo scale

Inpatient 29.7

(18.7 moderate or

severe)

1,024 Internal medicine and ICU at

one county general hospital

in Indiana

aWe extracted from this definition the injuries that drugs caused.

bSeven percent of reported ADEs were present at admission.

The studies also differed in their approach and intensity of data collection.

The Brennan and Thomas studies were strictly retrospective reviews of

medical records. The four other studies in table II.1 all collected data

prospectively (while patients were undergoing treatment), although

Classen first screened cases by applying computer algorithms to patients’

records in order to identify the cases most likely to experience an ADE.

Page 28 GAO/HEHS-00-21 Adverse Drug Events
Appendix II 

Estimating the Overall Incidence of Adverse

Drug Events

Prospective data collection meant that information from a medical record

could be supplemented with interviews with the staff who cared for a

particular patient.

Differences in the studies’ definitions affected the ADE rates they found.

The two studies with the apparently least restrictive definitions, Steel and

Bowman, reported the highest rates. Similarly, the differences in the

studies narrow substantially when the rates from the Brennan and Thomas

studies are compared with those for the more severe cases in the other

studies.

In contrast, there is no apparent relationship between type of hospital

(university or teaching versus community) and rates of observed ADEs. The

three studies of individual university hospitals varied from one another by

a wide margin. Meanwhile, the single available study of a community

hospital (Bowman) had the highest reported rate, while the Brennan and

Thomas studies, which combined both teaching and nonteaching hospitals

(but did not break them out separately for ADEs), had the lowest rates.

These variations may largely reflect differences on other dimensions (for

example, the definition of ADE) as well as potentially large variations

across individual institutions. Whether teaching or community hospitals

are likely to have higher ADE rates remains an open question.

Studies of Nursing

Homes Suggest That

ADEs Are Common

Among Residents

Nursing home residents, like hospital patients, are typically sick or frail

and receive many medications, circumstances that would tend to increase

their vulnerability to ADEs. Indeed, the three small-scale studies we

identified that sought to measure the incidence of ADEs in nursing homes

were all quite consistent in finding a high prevalence of ADEs. (See table

II.2.)

Page 29 GAO/HEHS-00-21 Adverse Drug Events
Appendix II 

Estimating the Overall Incidence of Adverse

Drug Events

Table II.2: Three Studies of ADEs in Long-Term-Care Facilities

ADE definition

ADEs per

patient-month Study size Site studied

Gerety and others, 1993

Known reaction to drug, appropriate temporal

sequence, no alternative explanation (Naranjo

algorithm)

0.44

(115 per 100

admissions)

175 One university-affiliated Department of

Veterans’ Affairs nursing home

Cooper, 1996

Any noxious and unintended effect of a drug

that occurs at doses used in humans for

prophylaxis, diagnosis, or therapy judged at

least “probable” on the Naranjo scale

134 per 100

admissionsa

332 Two rural nursing homes

Cooper, 1986

Drug-related problem, any unwanted

consequence from using or not using drug

therapy

0.71 

(1,200 per 100

admissions)

102 One long-term-care facility attached to

a small community hospital

aADEs not reported per month.

As in the studies of inpatient ADEs, the definition of ADE varied widely. It

could include not only the kinds of events considered to be an ADE—for

example, Cooper (1986) counted an inability to pay for prescribed

medications—but also the degree of certainty required that a drug had

caused the event in question. The two other studies, with narrower

definitions, reported markedly lower rates, but even they found that a

majority of nursing home residents experienced ADEs.27

The Data on

Emergency

Department Visits and

Hospital Admissions

Are Insufficient for

Estimating Overall

ADE Frequency

Unlike ADE rates for inpatient and long-term care, which apply to events in

the specific institutions where the data are collected, ADE rates reported

for emergency department visits and hospital admissions relate to care

that previous health care providers have already given to patients. The

rates reported for inpatient ADEs have quite a different meaning from those

presented in either studies of emergency department visits or hospital

admissions. The former report on the probability that an individual patient

will experience an ADE, while the latter focus on the proportion of

emergency department and hospital patient volume brought about by ADEs.

Studies of emergency department visits and hospital admissions differ

primarily in level of severity. The first examine ADEs serious enough to

27The substantial variation in both the ADE rates reported and the definitions employed, combined

with the small number of institutions and patients studied, leaves considerable uncertainty about the

specific rate of ADEs among nursing home residents. A more precise estimate would require one or

more larger-scale studies that assessed the frequency of ADEs across multiple facilities. One such

assessment is under way in 18 nursing homes in central and eastern Massachusetts.

Page 30 GAO/HEHS-00-21 Adverse Drug Events
Appendix II 

Estimating the Overall Incidence of Adverse

Drug Events

motivate an emergency department visit, while the second are about

patients whose ADEs required inpatient care.

To use data from studies of emergency department visits and hospital

admissions to estimate an overall rate of ADEs for a given population, two

requirements must be satisfied. First, the data must be from all the

hospitals serving the targeted population or at least from a representative

sample. Second, additional data have to be collected on ADEs that took

place during a hospital episode and were treated in the hospital where

they occurred. Patients transferred to another hospital to treat an ADE

would normally appear in the admissions data for the receiving hospital,

but those treated for ADEs in the hospital where they occurred would not

be associated with any admission.28

Each study that we found on emergency department visits and hospital

admissions for ADEs was limited to a single institution. (See tables II.3 and

II.4.) The rates these studies reported, therefore, depend on the particular

mix of patients each hospital attracted relative to the alternative providers

available in its geographic area. Without information about ADE admissions

to other hospitals in these areas, there is no way of knowing how similar

the rates the studies reported are to those prevailing among other

providers.

28The results of the Harvard Medical Practice Study suggest that a large proportion of serious ADEs

occur and are treated during the same hospitalization. Although separate figures for drug-related

adverse events were not reported, for adverse events overall, 49 percent were in this category. Most of

the remaining adverse events would appear as hospital admissions, including 31 percent that occurred

during a previous hospitalization and 15 percent that occurred in an outpatient setting (Brennan and

others, 1991, p. 373).

Page 31 GAO/HEHS-00-21 Adverse Drug Events
Appendix II 

Estimating the Overall Incidence of Adverse

Drug Events

Table II.3: Four Studies of Emergency Department Visits for ADEs

ADE definition

ADEs per 100

visits Study size Site studied

Schneitman-McIntire and others, 1996

•Unfavorable effect of drug use plus poor

compliance, inappropriate self-medication,

inappropriate prescribing, and drug interactions

•ADR: undesired adverse effects + allergy +

drug interactions

•Hospital admission for ADE

1.73

1.23

0.244

62,216 The emergency department of a

health maintenance organization

medical center in Walnut Creek, Calif.

Prince and others, 1992

•Drug-related illness 

•ADR: undesirable event reasonably and

temporally associated with the use of a drug at

normal doses + drug interactions

•Hospital admission for drug-related illness

2.88

0.815

0.697

10,184 One tertiary care hospital in

Pittsburgh, Penna.

Dennehy and others, 1996

•Drug-related illness

•ADR: noxious and unintended effect or the

result of drug therapy

•Hospital admission for drug-related illness

3.97

1.27

0.635

1,260 One university teaching hospital in

San Francisco, Calif.

Smith and others. 1997

•Drug-related problem

•ADR: any undesirable or unexpected

drug-related event + drug interactions

•Hospital admission for drug-related problem

4.24

0.469

0.625

5,757 One university teaching hospital in

Lexington, Ky.

Page 32 GAO/HEHS-00-21 Adverse Drug Events
Appendix II 

Estimating the Overall Incidence of Adverse

Drug Events

Table II.4: Four Studies of Hospital Admissions for ADEs

ADE definition

ADE rate among

hospital

admissions Study size Site studied

Lakshmanan and others, 1986

Admission for adverse reactions to medical

therapy, surgery, or diagnostic proceduresa

4.2% 834 Medical, ICU, and oncology wards at one

public teaching hospital in Cleveland, Ohio

Nelson and Talbert, 1996

Known reaction to drug; appropriate temporal

sequence; no alternative explanation (Naranjo

and Hallas algorithms)

5.3 452 Medical, cardiac, and ICU wards at one

university-affiliated county hospital in Bexar

County, Tex.

Bigby and others, 1987

Hospital admission from emergency department

with ADE, ADE not defined

6.9 686 One teaching hospital in

Cambridge, Mass.

Colt and Shapiro, 1989

Undesired or unintended response to medication

at appropriate dosage for prophylaxis,

diagnosis, or therapy

9.4 244 Medical ward at one community teaching

hospital in Pittsburgh, Penna.

aWe extracted from this definition the injuries that drugs caused.

Whatever the differences in patient populations examined in these studies,

they reported relatively consistent ADE rates. This may stem in part from

the fairly uniform definition of ADE they applied. For emergency

department visits, the studies stated that around 2 to 4 percent involved a

rather broad category of drug-related illness or problems, while

approximately 1 percent related to ADRs more narrowly defined. The range

in studies of hospital admissions is somewhat wider and higher—roughly 4

to 9 percent. The fairly diverse hospitals, both geographically (California,

Pennsylvania, and Texas) and in institutional affiliation (public, private

community, university, and health maintenance organization), yielded

relatively consistent results.

Nevertheless, none of these studies provides information as complete on

the full range of ADEs as do the Brennan and Thomas studies. They alone

both build on a sample representative of a broad-based population (if still

short of nationwide) and have a data collection approach that

encompasses ADEs wherever they occur—during a hospital stay or before

admission, either in another hospital or in an outpatient setting. The only

ADEs missed in the Brennan and Thomas studies are those that were not

treated in a hospital. They would also be missed in all the other studies,

Page 33 GAO/HEHS-00-21 Adverse Drug Events
Appendix II 

Estimating the Overall Incidence of Adverse

Drug Events

except by studies of patients with ADEs who made emergency department

visits.

Page 34 GAO/HEHS-00-21 Adverse Drug Events
Appendix III 

Sixteen Studies Estimating ADE Costs in the

United States

Study Site Eligible patients Method Cost estimate

Bates and others,

1997

Brigham and Women’s

Hospital and

Massachusetts General

Hospital, Boston, Mass.

All 4,108 patients

admitted to a stratified

random sample of

medical and surgical

units and intensive care

and nonintensive care

units; excluded obstetric

units

Compare comparable

patients with ADEs to

those without

An increased hospital cost of

$2,595 per ADE and $4685 per

preventable ADE; $5.6 million per

year in additional costs with $2.8

million attributable to preventable

ADEs

Bootman, Harrison,

and Cox, 1997

Nursing facilities (no

specific sites studied)

No patients studied Expert panel estimated

ADE rates and

treatments needed

$7.6 billion in costs to third-party

payer from drug-related morbidity

and mortality in nursing homes

Classen and others,

1997

LDS Hospital, Salt Lake

City, Utah

All 91,574 hospital

admissions

Compare comparable

patients with ADEs to

those without

Hospital cost of $2,013 per ADE;

4-year cost of $4,482,951

(excludes liability costs and the

cost of injury to patients)

Col and others, 1990 Unspecified community

teaching hospital

315 consecutively

admitted elderly patients

Assess ADRs in patients

who experienced them;

no comparison group

Hospital cost of $2,147 per

patient admitted with ADE related

to noncompliance (total cost of

$77,289 for 3 months); cost of

$4,237 per patient admitted with

ADR (total cost of $224,542 for 3

months)

Cooper, 1987 Unspecified nursing

home

All residents; sample of 6

cases of ADEs to

generate cost estimate

Assess ADRs in patients

who experienced them;

no comparison group

$3,749 per episode that resulted

in hospitalization; up to $340,942

in costs could have been avoided

over a 2-year period.

Cullen and others,

1997

Brigham and Women’s

Hospital and

Massachusetts General

Hospital, Boston, Mass.

All 4,031 patients

admitted to sample of

intensive care and

general care units

Comparisons between

patients who had first

ADE in the ICU and the

remaining ICU patients

and between medical

and surgical patients

with an ADE

Costs after ADE of $9,192 per

ADE in surgical general care unit,

$17,437 in medical general care

unit, $17,577 in medical intensive

care unit, and $20,959 in surgical

intensive care unit; total cost

$1,366,840 over 6 months

Dennehy and

others, 1996

University of California,

San Francisco

1,260 emergency

department patients (68

percent of all emergency

department patients)

Assess ADEs in patients

who experienced them;

no comparison group

Hospital costs of $283 for patients

with ADE who were not

hospitalized, $2,815 for those who

were; $308 for patients with

preventable ADEs not

hospitalized, $2,752 for those who

were; total annual cost $602,597,

with $391,342 coming from

avoidable ADEs

Evans and others,

1993

LDS Hospital, Salt Lake

City, Utah

All hospitalized patients Compare patients with

ADEs to those without

Average cost of hospitalization for

patients with ADEs from allergic

or idiosyncratic reactions was

$30,617, from known toxicities

$23,256; average cost for patients

without ADEs was $6,320

(continued)

Page 35 GAO/HEHS-00-21 Adverse Drug Events
Appendix III 

Sixteen Studies Estimating ADE Costs in the

United States

Study Site Eligible patients Method Cost estimate

Evans and others,

1994b

LDS Hospital, Salt Lake

City, Utah

All 60,836 hospitalized

patients

Compare comparable

patients with ADEs to

those without

$1,939 higher cost for patients

with an ADE than for those

without; total annual cost of

$1,103,291

Johnson and others,

1995

Unspecified

ambulatory settings

No patients studied Expert panel estimated

ADE rates and

treatments needed

$76.6 billion in annual costs to

third-party payers associated with

management of drug-related

mortality and morbidity

Johnson and others,

1997

Unspecified

ambulatory settings

No patients studied Expert panel estimated

ADE rates and

treatments needed

$45.6 billion savings for

third-party payers if

pharmaceutical care was

instituted nationwide, a 59.6

percent reduction from $76.6

billion

Prince and others,

1992

Mercy Hospital,

Pittsburgh, Penna.

All 10,184 emergency

room visits

Assess ADEs in patients

who experienced them;

no comparison group

Average hospital charge per

admission for a patient with an

ADE was $8,888; total annual cost

of $631,048

Schneider and

others, 1995

Ohio State University

Medical Center,

Columbus, Ohio

109 patient charts

reviewed; selection

criteria not stated

Assess ADEs in patients

who experienced them;

no comparison group

Average institutional cost of $783

per ADE; total annual cost of

$1,497,148

Stoukides,

D’Agostino, and

Kaufman, 1993

Roger Williams Medical

Center, Brown

University, Providence,

R.I.

All 13,703 emergency

room visits

Assess ADEs in patients

who experienced them;

no comparison group

Average cost of $333.81 per

emergency department visit; total

cost of $39,389.58 for 6 months

Sullivan, Kreling,

and Hazlet, 1990

Unspecified hospitals

(based on other

studies)

2,942 hospital

admissions from seven

studies reviewed

Metaanalysis $8.5 billion spent on

hospitalizations in 1986 because

of noncompliance

Thomas and others,

1999

28 hospitals in

Colorado and Utah

14,732 randomly

selected hospital

discharges

Physicians and

malpractice claims

adjusters estimated the

extent of disability and

future health care use

from data from medical

records of patients with

ADEs

$5.2 billion hospital costs to treat

ADEs nationwide; $12.2 billion,

including outpatient care, lost

wages, and lost household

production

Page 36 GAO/HEHS-00-21 Adverse Drug Events
Appendix IV 

Experts We Consulted

David Bates, M.D., Chief, Division of General Medicine, Brigham &

Women’s Hospital, Boston, Mass.29

J. Lyle Bootman, Ph.D., Executive Director, Center for Health Outcomes

and PharmacoEconomic Research, College of Pharmacy, University of

Arizona, Tucson, Ariz.

Michael R. Cohen, M.S., President, Institute for Safe Medication Practices,

Huntingdon Valley, Penna.

Nancy A. Dreyer, Ph.D., Chief Executive Officer, Epidemiology Resources

Inc., Newton Lower Falls, Mass.

David I. Goldsmith, M.D., Senior Medical Director, Safety Surveillance,

Sanofi Pharmaceuticals, New York, N.Y.29

Hershel Jick, M.D., Director, Boston Collaborative Drug Surveillance

Program, Lexington, Mass.

Judith K. Jones, M.D., Ph.D., President and Chief Executive Officer, The

Degge Group, Arlington, Va.29

Lucian Leape, Ph.D., Professor, Harvard School of Public Health, Boston,

Mass.

Murray M. Lumpkin, M.D., Deputy Center Director, Center for Drug

Evaluation and Research, U.S. Food and Drug Administration, Rockville,

Md.29

Henri R. Manasse, Jr., Ph.D., Sc.D., Executive Vice President and Chief

Executive Officer, American Society of Health-System Pharmacists,

Bethesda, Md.29

Thomas J. Moore, Fellow, Center for Health Policy Research, School of

Public Health and Health Services, George Washington University,

Washington, D.C.29

Robert C. Nelson, Ph.D., RCN Associates, Annapolis, Md., and Chair,

Committee on Quality Data for Risk Assessment of Drugs, International

Society for Pharmacoepidemiology, Washington, D.C.29

29Invited participant at the joint General Accounting Office and Drug Information Association session,

“Postmarketing Surveillance: Considerations for Policymakers,” conference on Adverse Event

Reporting: From Theory to Practice, Washington, D.C., Feb. 24, 1999.

Page 37 GAO/HEHS-00-21 Adverse Drug Events
Appendix IV 

Experts We Consulted

Richard Platt, M.D., Director of Research, Harvard Pilgrim Healthcare,

Boston, Mass.

Larry D. Sasich, Pharm.D., M.P.H., Research Analyst, Public Citizen’s

Health Research Group, Washington, D.C.30

Judith M. Sills, Pharm.D., Senior Director, U.S. Regulatory Affairs and

Global Product Safety, Warner-Lambert Consumer Healthcare, Morris

Plains, N.J.30

Bert Spilker, M.D., Ph.D., Senior Vice President for Scientific and

Regulatory Affairs, Pharmaceutical Research and Manufacturers of

America, Washington, D.C.30

Brian Strom, M.D., M.P.H., Director, Center for Clinical Epidemiology and

Biostatistics, University of Pennsylvania, Philadelphia, Penna.30

Eleanor M. Vogt, R.Ph., Ph.D., Senior Fellow, National Patient Safety

Foundation, American Medical Association, Washington, D.C.30

Ray Woosley, M.D., Ph.D., Chairman, Department of Pharmacology,

Georgetown University Medical Center, Washington, D.C.30

30Invited participant at the joint General Accounting Office and Drug Information Association session,

“Postmarketing Surveillance: Considerations for Policymakers,” conference on Adverse Event

Reporting: From Theory to Practice, Washington, D.C., Feb. 24, 1999.

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