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TABLE OF CONTENTS FOR DIF'S "Diabetics World"

Annual Adverse Drug Experience Report:
1995

http://www.fda.gov/medwatch/safety/ar95.pdf

Deanne E Knapp, Janet I Robinson, and Annie L Britt

Surveillance and Data Processing Branch
Division of Pharmacovigilance and Epidemiology
Office of Epidemiology and Biostatistics
Center for Drug Evaluation and Research
Food and Drug Administration

ACKNOWLEDGEMENT

The authors wish to thank Ms. Traci R. Tate for preparing the manuscript, graphs, and tables.

Annual Postmarket Adverse Drug Experience Report: 1995

Lilly Humulin 8th worst for Adverse Events

TABLE OF CONTENTS

ANNUAL ADVERSE DRUG EXPERIENCE REPORT: 1995.... .    1

ACKNOWLEDGEMENT...................................................... .    1

TABLE OF CONTENTS........................................................     1

INTRODUCTION..................................................................  .. 2

TYPES OF           ............................................................. .... 3

GEOGRAPHIC LOCATION OF INITIAL REPORTER............. ..... 5

SEX AND AGE OF PATIENTS................................................. 6

SERIOUS OUTCOMES........................................................... 7

LATENCY BETWEEN SUSPECT DRUG AND ADE ONSET....... 8

SUSPECT DRUGS BY ENTRY NAME AND NEW MOLECULAR
ENTITY STATUS....................................................... ............. 10

DRUG CLASSES STRATIFIED BY HEALTH PROFESSIONALS
OR CONSUMERS, TYPE OF REPORT, & YEAR ..................... 10

ROUTES OF SUSPECTDRUGS.............................................. 11

ABATEMENT OF ADVERSE EVENT....................................... 11

REOCCURRENCE OF ADVERSE EVENT.................. . ........... 12

BODY SYSTEMS................................................................... 12

ADVERSE EVENTS............................................................... 13

DRUG CLASSES ASSOCIATED WITH BODY SYSTEM
ADVERSE EVENTS............................................................... 14

INTRODUCTION

This report presents a descriptive overview of the 130,950 evaluable¹, postmarket adverse
drug experience (ADE) cases received by the US Food and Drug Administration (FDA) during
calendar year 1995². A case consists of the original report of an ADE on a patient plus
any followup² information.

FDA has long conducted a program to monitor ADEs for marketed drugs. As part of this
program, a computerized ADE database was begun in 1969 and has accumulated about 1.2
million cases. The primary purpose for maintaining the database is to serve as an early warning
or signaling system for ADEs not detected during premarket testing. The ADE system depends
upon detection of an adverse clinical event by a health professional or consumer, attribution of the
clinical event to prior administration of a particular drug ("suspect" drug), and reporting of the
ADE to the manufacturer of the suspected drug or directly to FDA. Data from these ADE cases
are coded and entered into the computerized ADE database. Copies of the ADE cases
are stored on microfilm or an imaging system. Up to five drugs per case may be entered into the
computerized ADE database; the five can be a combination of "suspect" and "concomitant"
drugs. Up to four adverse events per case and their associated body systems can be coded into
the database, using FDA's "Coding Symbols for Thesaurus of Adverse Reaction Terms"
(COSTART).

1.    Excludes “React Uneval” cases.

2.    The 1995 postmarket ADE computerized data file used for this report was created June
1996.

Reporting of postmarket ADEs by health professionals and consumers is voluntary. They may
send their reports directly to FDA ("Direct" reports), to the drug manufacturer ("Manufacturer"
reports), or both. Drug manufacturers are required by law and regulation to submit to FDA any
postmarket ADE reports received by any means from health professionals or consumers.

It is important to remember certain caveats when using data from FDA's postmarket ADE
database:

1.                For any given ADE case, there is no certainty that the suspected drug
caused the ADE. This is because physicians and consumers are encouraged to report
all suspected ADEs, not just those that are already known to be caused by the drug. The
adverse event may have been related to an underlying disease for which the drug was
given, to other concomitant drugs, or may have occurred by chance at the same time the
suspect drug was administered.

2.                Accumulated ADE cases may not be used to calculate incidences or estimates
of drug risk. Numbers from these data should be carefully interpreted as reporting
rates and not occurrence or incidence rates.

Over the next pages, various kinds of data and information are presented on the postmarket
ADE cases computerized into the FDA ADE database during calendar year 1995. Due to
rounding, the percentages in tables and graphs may not total to 100%. Figures 1 and 2 present
copies of the postmarket ADE forms used by manufacturers and health professionals or
consumers, respectively [and the Figure: 3500A MedWatch Mandatory Form and Figure 3500:
MedWatch Voluntary Form are both excluded from the FDA Report
located at http://www.fda.gov/medwatch/safety/ar95.pdf].

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TYPES OF REPORTS

There are three types of reports in the FDA computerized postmarket ADE database:

1.                      Manufacturer-reported cases concerning ADEs not in present official FDA
labeling with serious outcomes (i.e., death, life-threatening, hospitalization, permanent
disability, congenital anomaly, cancer, or overdose). These cases are known in regulatory
language as "15-day Alert Reports" because the manufacturer has 15 working days to
submit this type of report to FDA.

2.                      All other manufacturer-reported cases. These cases are known in regulatory
language as "Periodic Reports" because the manufacturer is required to submit them to FDA
on a cyclical basis.

3.                      Cases sent directly to FDA by health professionals or consumers ("Direct
Reports").

As shown in Figure 3, reports submitted to FDA via manufacturers accounted for 88%
(115,663) of the 130,950 postmarket ADE cases. Only 12% (15,287) were submitted directly to
FDA. 15-day reports were 16% (20,434) of the total.

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REPORTING BY HEALTH PROFESSIONALS
AND CONSUMERS

As shown in Figure 4, in 1995, for a little over one-third of the 130,950 postmarked ADE
cases, consumers were the original reporters. Figure 4 also shows that, over a 3-year trend
(1993-1995), reports from consumers have increased both in absolute numbers and
proportionally whereas those from health professionals have done the opposite.

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GEOGRAPHIC LOCATION OF INITIAL
REPORTER

As shown in Table 1, the initial reporter for 83% (108,735) of the 130,950 postmarket
ADE cases was located within the US or its territories. Nine percent (11,843) of the cases were
missing location source. For the 108,735 US cases, the top-two ranked regions, Middle and
South Atlantic, accounted for two-fifths of the cases.

There were eight percent (10,372) of the postmarket ADE cases where the initial report
source was foreign. There were four countries which each accounted for <=10% of the foreign
cases: France (22%, 2,288), Japan (14%, 1,490), Germany (13%, 1,310), and United Kingdom
(12%, 1,289).

^a US Census Regions are percentaged to 108,735

^b Foreign Countries are percentaged to 10,372 

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SEX AND AGE OF PATIENTS

As shown in Table 2, the ratio of female-to-male postmarket ADE cases was 1.6:1. For
females, the 20-39 year age group accounted for the greatest number of known sex-age cases,
whereas for males, it was the $60 year age group.

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SERIOUS OUTCOMES

As shown in Figure 5, hospitalization was the most recorded serious outcome; congenital
anomaly, the least.

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LATENCY BETWEEN SUSPECT DRUG
AND ADE ONSET

As shown in Figure 6, of the 130,950 postmarket ADE cases, 47% (61,412) had both a drug start date and an
adverse experience onset date for the first-listed suspect drug and the first-listed adverse experience, respectively,
and where the drug date was computerized as occurring before the adverse experience date. About half of these
cases noticed the adverse event occurred within one week of drug initiation.

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CLASSES OF SUSPECT DRUGS

Annual Postmarket Table 3 presents the top-10 ranked drug classes associated with the 153,842 suspect drugs
computerized from the 130,950 postmarket ADE cases. The top-ranked drug class, central nervous system agents,
accounted for approximately one-quarter of the drug class mentions³. Together with the 3 second and third
ranked drug classes, hormones and synthetic substitutes and cardiovascular drugs, these top three ranked drug
classes comprised about half of the total drug class mentions.

3.               The drug classification used was the American Hospital Formulary Service Pharmacologic - Therapeutic Classification (American
Society of Health-System Pharmacists, Bethesda, Maryland, 1996).

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SUSPECT DRUGS BY ENTRY NAME AND
NEW MOLECULAR ENTITY STATUS

Table 4 shows the top-10 ranked suspect drugs as entered on the 130,950 postmarket ADE reporting forms.
Three are nonprescription drugs, Aleve™, Today™, and Humulin™ insulin. Three are used by females (Norplant™,
Depo-Provera™, and Today™) and one primarily by males (Rogaine™). New Molecular Entities (NMEs) are defined
as new drugs approved within the past three years. For this 1995 report, NMEs are new drugs approved during
1992-5. Of the 153,842 suspect drugs computerized from the 130,950 postmarket ADE cases, 15% (23,275) involved
NMEs.

[† Excludes Novo Human insulins, Lilly Humalog,, NovoRapid, Lantus and all other synthetic insulins and all natural insulins.]

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DRUG CLASSES STRATIFIED BY HEALTH PROFESSIONALS OR CONSUMERS,
TYPE OF REPORT, AND YEAR

Table 5 shows the top-five ranked drug classes associated with suspect drugs, stratified by whether the initial
reporter was a health professional or consumer, the type of report, and year the case was computerized into the
FDA postmarket ADE database.

1995 Data. In 1995, there were 141,578 drug class mentions where type of initial reporter and type of report
were known. For consumers, only two of the top-five ranked drug classes were common to all report types: central
nervous system agents and hormones and synthetic substitutes. For health professionals, there were four drug
classes of the top-five ranked drug classes common to all report types: central nervous system agents, antineoplastic
agents, anti-infective agents, and cardiovascular drugs. The only drug class in the top-five ranked drug classes
common to both consumers and health professionals across report types was central nervous system agents.

Trend data from 1993 to 1995 show that only one drug class in the top five-ranked drug classes was
common to both consumers and health professionals as well as all report types for all years: central nervous system
agents.

Captioned 3 page Table 5 is missing from the http://www.fda.gov/medwatch/safety/ar95.pdf pages.

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ROUTES OF SUSPECT DRUGS

Table 6 presents the top-10 ranked routes of administration associated with the suspect drugs. There were
125,726 routes mentioned in conjunction with the 130,950 postmarket ADE cases. About three-fifths of the route
mentions noted the oral route of administration.

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ABATEMENT OF ADVERSE EVENT

For the 153,842 suspect drug mentions, 74% (113,921) had an answer to the question of whether the adverse
event abated after the suspect drug was stopped or the dose was reduced. Figure 7 shows the distribution of
responses. Thirty percent (34,433) of these 113,921 abate mentions indicated a positive dechallenge ("Yes"
response).

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 REOCCURRENCE OF ADVERSE EVENT

For the 153,842 suspect drug mentions, 70% (107,439) had an answer to the question of whether the adverse
event reappeared after reintroduction of the suspect drug. Figure 8 shows the distribution of responses. Four
percent (4,635) of these 107,439 reoccur mentions indicated a positive rechallenge ("Yes" response).

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BODY SYSTEMS

There were 140,182 body system mentions associated with the adverse events of the 130,950 postmarket
ADE cases. The distribution of these mentions across the 12 body systems is presented in Figure 9. Four body
systems each had ³10% of the 140,182 body system mentions: body as a whole (systemic adverse events) -
32%, nervous and skin and appendages systems - each with 12%, and digestive system - 10%.

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ADVERSE EVENTS

Table 7 shows the top-10 ranked adverse events reported with the 130,950 postmarket ADE cases. The top
ranked ADE was "no drug effect"; 10% of the ADE cases reported this event. Metrorrhagia (2% of ADE cases), of
course, would be female associated.

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DRUG CLASSES ASSOCIATED WITH
BODY SYSTEM ADVERSE EVENTS

Table 8 presents the four body systems comprising the most adverse events, each of which has been cross-
tabulated by its top-five ranked suspect associated drug classes³. Central nervous system agents and hormones
and synthetic substitutes held the top-two ranks, respectively, for all four body systems. Two other drug classes were
in the top-five ranks for all four body systems, cardiovascular drugs, and anti-infective agents.

3 See Previous

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