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[U.S. Food and Drug Administration]

Annual Adverse Drug Experience Report: 1996

October 30, 1997

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

TABLE OF CONTENTS

  1. Introduction
  2. Figure 1: 3500A MedWatch Mandatory Form
  3. Figure 2: 3500A MedWatch Form, back
  4. Type of Reports
  5. Reporting by Health Professionals and Consumers
  6. Geographic Location of Initial Reporter
  7. Sex and Age of Patients
  8. Serious Outcomes
  9. Latency Between Suspect Drug Administration and ADE Onset
  10. Classes of Suspect Drugs
  11. Suspect Drugs by Entry Name and New Molecular Entity Status
  12. Drug Classes Stratified By Health Professionals or Consumers
  13. Top-5 Ranked Drug Classes Per Type of Reporter and Report
  14. Routes of Suspect Drugs
  15. Abatement of Adverse Event
  16. Reoccurrence of Adverse Event
  17. Body Systems
  18. Adverse Events
  19. Drug Classes Associated with Body System Adverse Events
  20. Annual FOI Report

 

INTRODUCTION

This report presents a descriptive overview of the 159,504 evaluable1, postmarket adverse drug experience (ADE) cases received by the US Food and Drug Administration (FDA) during calendar year 19962. A case consists of the original report of an ADE on a patient plus any follow-up information.

At this time, October, 1997, the SRS has accumulated about 1.4 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 by coded into the database, using FDA’s "Coding Symbols for Thesaurus of Adverse Reaction Terms" (COSTART).

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 postmarket ADE reports received by any means from health professional 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 1996. 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.

____________________
1 Excludes "React Uneval" unevaluable reactions cases.
2 The 1996 postmarket ADE Computerized data file used for this report was created October 1997.

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Standard MedWatch Form, front page

Medwatch Form, Page 1

 

Standard MedWatch Form, back page

Medwatch Form, Page 2

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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 languages 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 91.0%(145,021) of the 159,504 postmarket ADE cases. Only 9.0%(14,483) were submitted directly to FDA. 15-day report were 15.6%(24,815) of the total.

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Figure 3. Postmarket ADE Reports by Type of Report: 1996

Postmarket ADE Reports by Type of Report

N = 159,504

 

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REPORTING BY HEALTH PROFESSIONALS AND CONSUMERS

As shown in Figure 4, in 1996, there were 157,067 reporters for the 159,504 postmarket ADE cases, 64,752 (41.2%) reporters were consumers, 90,394 (57.6%) reporters were health professionals, and 1,921 (1.2%) were unknown sources. Figure 4 also shows that, over a four-year trend (1993-96), reports from consumers have increased both in absolute numbers and proportionally, whereas those from health professionals have gone up in absolute numbers.

Year: 1993 1994 1995 1996

N (000s) N (000s) N (000s) N (000s)
C 32 C 35 C 48 C 64
H 86 H 84 H 81 H 90
U 1 U 1 U 2 U 2

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GEOGRAPHIC LOCATION OF INITIAL REPORTER

As shown in Table 1, the initial reporter for 81.2% (129,521) of the 159,504 postmarket ADE cases was located within the US census regions; 9.6% (15,260) of cases were missing location.

There were 9.2% (14,723) of the postmarket ADE cases where the initial report source was foreign. There were four countries which each accounted for >= 9% of the foreign cases: France (31.2%), Japan (14.2%), United Kingdom (12.8%), Germany (9.2%).

 

Table 1. Postmarket ADE Reports by Geographic Location of Initial Reporter: 1996

N %
All Locations 159,504 100
US Census Region: 129,521 81.2
a New England 25,149 19.4
East South Central 23,355 18.0
Pacific 22,289 17.2
Middle West 22,207 17.2
West South Central 16,804 13.0
Middle Atlantic 16,763 12.9
Others 2,954 2.3
Foreign: 14,723 9.2
b France 4,593 31.2
Japan 2,094 14.2
United Kingdom 1,888 12.8
Germany 1,355 9.2
Others 4,793 32.6
Unknown 15,260 9.6

____________________
a US Census Regions are percentaged to 129,521
b Foreign countries are percentaged to 14,723

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SEX AND AGE OF PATIENTS

As shown in Table 2, the ratio of female-to-male postmarket ADE cases was 1.7:1. For both females and males, the >= 60 year age group accounted for the greatest number of known sex-age cases.

Table 2. Postmarket ADE Reports by Reports by Sex & Age of Patient: 1996

N %
ALL SEXES & AGES 159,504 100
All Females: 91,200 57.2
<= 19 yrs 5,971 3.7
20 - 39 yrs 19,855 12.4
40 - 59 yrs 20,980 13.2
>= 60 yrs 24,111 15.1
Unknown age 20,283 12.7
All Males: 53,761 33.7
<= 19 yrs 5,069 3.2
20 - 39 yrs 8,510 5.3
40 - 59 yrs 13,082 8.2
>= 60 yrs 17,418 10.9
Unknown age 9,682 6.1
Unknown Sex: 14,543 9.1
<= 19 yrs 439 0.3
20 - 39 yrs 163 0.1
40 - 59 yrs 242 0.2
>= 60 yrs 312 0.2
Unknown age 13,387 8.4

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SERIOUS OUTCOMES

As shown in Figure 5, hospitalization was the most recorded serious outcome; congenital anomaly, the least. ( One case could have more than one outcome).

 

Figure 5. Postmarket ADE Reports by Type of Serious Report: 1996

Serious Outcome

N = 105,599

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LATENCY BETWEEN SUSPECT DRUG ADMINISTRATION AND ADE ONSET

As shown in Figure 6, of the 159,504 postmarket ADE cases, 53.6% (85,517) had both a drug start date and an adverse experience onset date for the first-listed suspect drug and first-listed adverse experience, respectively, and the drug date was computerized as occurring before the adverse experience date. About half of these cases noted that the adverse event occurred within one week of drug initiation.

Figure 6. Postmarket ADE Reports by Latency Period: 1996

Latency (days)

N = 85,517

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CLASSES OF SUSPECT DRUGS

Table 3 presents the top-10 ranked drug classes associated with the 174,905 suspect drugs computerized from the 159.504 postmarket ADE cases. The top-ranked drug class, central nervous system agents, accounted for approximately little less than one-quarter of the drug class mentions3. Together with the second and third ranked drug classes, anti-infectives, and hormones and synthetic substitutes, these top three ranked drug classes comprised about half of the total drug class mentions.

 

Table 3. Postmarket ADE Reports by Top-10 Ranked Classes of Suspect Drugs: 1996

  N %
     
All Suspect Drug Mentions 174,905 100
     
Central nervous system agents 39,541 22.6
Anti-infective agents 21,388 12.2
Hormones & synthetic substitutes 20,956 12.0
Cardiovascular drugs 18,076 10.3
Skin & mucous membrane agents 13,927 7.9
Antineoplastic agents 12,552 7.2
Gastrointestinal drugs 10,580 6.0
Unclassified therapeutic agents 10,397 5.9
Autonomic drugs 8,189 4.7
Blood formation and coagulation 3,707 2.1

____________________
3 The drug classification used was the American Hospital Formulary Service Pharmacologic - Therapeutic Classification (American Society of Health-System Pharmacists, Bethesda, Maryland, 1997)

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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 159,504 postmarket ADE reporting forms.

New Molecular Entities (NMEs) are defined as new drugs approved within the past three years. For this 1996 report, NMEs are new drugs approved during 1993-96. Of the 174,905 suspect drugs computerized from the 159,504 postmarket ADE cases, 30.2%(29,584) involved NMEs.

 

Table 4. Postmarket ADE Reports by Top-10 Ranked Suspect Drugs: 1996

  N %
     
All Suspect Drug Mentions 174,905 100
     
Fosamax 6,197 3.5
Norplant 5,957 3.4
Prozac 3,506 2.0
Pepcid AC 3,104 1.8
Estraderm 2,890 1.7
Femstat 2,648 1.5
Rogaine 2,435 1.4
Paragard T380A 2,172 1.2
Nix 2,077 1.2
Zoloft 2,070 1.2

_________________
™ - Trademark

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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 classes3 associated with suspect drugs, stratified by whether the initial reporter was a health professional or consumer, the type of report, and year the cases was computerized into the FDA postmarket ADE database.

1996 Data. In 1996, there were 155,529 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.

 

Table 5. Top-5 Ranked Drug Classes Per Type of Reporter & Report: 1996

Reporter Type Report Type Drug Class N %
         
ALL ALL ALL 155,529 100
         
Consumer All All 64,858 41.7
  Mfr 15-day All 2,820 1.8
    Central nervous system agents 689 0.4
    Hormones and synthetic substitutes 482 0.3
    Anti-infective agents 309 0.2
    Cardiovascular drugs 271 0.2
    Autonomic drugs 233 0.1
         
  Mfr Periodic All 61,225 39.4
    Hormones and synthetic substitutes 11,709 7.5
    Skin and mucous membrane agents 10,612 6.8
    Central nervous system agents 10,073 6.5
    Gastrointestinal drugs 7,080 4.6
    Cardiovascular drugs 5,504 3.5
         
  Direct All 813 0.5
    Central nervous system agents 222 0.1
    Skin and mucous membrane agents 132 0.1
    Autonomic drugs 88 0.1
    Anti-infective agents 87 0.1
    Cardiovascular drugs 43 0.0
         
Health Professional All All 90,671 58.3
  Mfr 15-day All 20,200 13.0
    Central nervous system agents 4,264 2.7
    Anti-infective agents 3,851 2.5
    Antineoplastic agents 3,165 2.0
    Cardiovascular drugs 2,582 1.7
    Hormones and synthetic substitutes 1,274 0.8
         
  Mfr Periodic All 56,998 36.6
    Central nervous system agents 15,324 9.9
    Anti-infective agents 8,061 5.2
    Cardiovascular drugs 5,953 3.8
    Hormones and synthetic substitutes 5,434 3.5
    Antineoplastic agents 3,962 2.5
         
  Direct All 13,473 8.7
    Central nervous system agents 3,713 2.4
    Anti-infective agents 2,477 1.6
    Cardiovascular drugs 1,736 1.1
    Antieoplastic agents 1,398 0.9
    Blood formation and coagulation 919 0.6

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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 156,759 routes mentioned in conjunction with the 159,504 postmarket ADE cases. About three-fifths of the route mentions noted the oral route of administration.

 

Table 6. Postmarket ADE Reports by Top-10 Ranked Routes of Administration of Suspect Drugs: 1996

N %
     
All Routes 156,759 100
     
Oral 99,421 63.4
Intravenous 14,873 9.5
Subcutaneous 8,204 5.2
Topical 8,181 5.2
Transdermal 7,460 4.8
Vaginal 3,798 2.4
Inhalation 2,739 1.7
Intrauterine 2,318 1.5
Ophthalmic 2,094 1.3
Intramuscular 2,029 1.3

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ABATEMENT OF ADVERSE EVENT

For the 174,905 suspect drug mentions, 78.7% (137,632) 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. About one-quarter of these 137,632 abate mentions indicated a positive dechallenge ("Yes" response).

 

Figure 7. Postmarket ADE Reports by Abate response: 1996

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REOCCURRENCE OF ADVERSE EVENT

For the 174,905 suspect drug mentions, 76.2% (132,296) 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 (5,309) of these 132,296 reoccur mentions indicated a positive rechallenge ("Yes" response).

 

Figure 8. Postmarket ADE Reports by Reintroduction Response: 1996

N = 132,296

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BODY SYSTEMS

There were 159,515 body system mentions associated with the adverse events of the 159,504 postmarket ADE cases. The distribution of these mentions across the 12 body system mentions is presented in Figure 9. Four body systems each had > 10% of the 159,515 body system mentions: body as a whole (systemic adverse events) - 30.5%, skin and appendages system - 13%, nervous system - 11.7%, and digestive system - 11.4%.

Figure 9. Postmarket ADE Reports by Body System: 1996

N = 159,515

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ADVERSE EVENTS

Table 7 shows the top-10 ranked adverse events reported with the 159,504 postmarket ADE cases. The top ranked ADE was " No drug effect: - 10% of the ADE cases reported this event.

 

Table 7. Top-10 Ranked Adverse Events: 1996

Adverse Event N %
     
All Postmarket ADE Reports 159,504 100
     
No drug effect 15,918 10.0
Headache 5,133 3.2
Rash 4,090 2.6
Application site reaction 3,583 2.2
Diarrhea 2,445 1.5
Urticaria 2,373 1.4
Alopecia 2,237 1.4
Aggravation of existing reaction 2,236 1.4
Dizziness 2,002 1.3
Abdominal pain 1,875 1.2

 

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 crosstabulated by its top-five ranked suspect associated drug classes3. Three drug classes were in the top-five ranks for all four body systems, central nervous system agents, cardiovascular drugs, and anti-infective agents.

Table 8. Top-4 Ranked Body Systems with Their Respective Top-5 Ranked Suspect Drug Classes: 1996

Body System Suspect Drug Class N %
Body as a whole All 53,050 100
  Central nervous system agents 12,131 22.9
  Hormones and synthetic substitutes 7,216 13.6
  Skin and mucous membrane agents 6,378 12.0
  Anti-infective agents 4,816 9.1
  Cardiovascular drugs 4,566 8.6
       
Skin and Appendages All 21,792 100
  Hormones and synthetic substitutes 3,948 18.1
  Skin and mucous membrane agents 3,689 16.9
  Anti-infective agents 3,178 14.6
  Central nervous system agents 2,941 13.5
  Cardiovascular drugs 1,931 8.9
       
Nervous System All 20,515 100
  Central nervous system agents 8,265 40.3
  Anti-infective agents 2,209 10.8
  Cardiovascular drugs 1,763 8.6
  Hormones and synthetic substitutes 1,463 7.1
  Autonomic drugs 1,425 7.0
       
Digestive System All 20,059 100
  Central nervous system agents 4,105 20.5
  Anti-infective agents 4,081 20.3
  Gastrointestinal drugs 2,355 11.7
  Unclassified therapeutic agents 2,256 11.2
  Cardiovascular drugs 1,900 9.5

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ANNUAL FOI REPORT

1996

In 1996, the Surveillance and Data Processing Branch (SDPB) received a total of 2,162 Freedom of Information (FOI) requests. These requests were for adverse reaction cases collected by the Food and Drug Administration’s Spontaneous Reporting System (SRS). All requests are logged in by the central FOI office and triaged to various responsive divisions throughout the Center for Drugs.

SDPB processed FOI requests utilizing several forms of data accession. Compressed ASCII files were provided to mostly third-party businesses. Microfiche line listings or paper copies were also available depending on the preference of the requester. Case reports from the SRS database were obtained by people wanting a formalized version of the Medwatch form.

Law firms comprised the most FOI requests, with third-party organizations ranking second. Third were the pharmaceutical companies and last were consumers. However, consumers made more inquiries in 1996 than in previous years. This could have been attributed to media reporting and those consumers wanting to establish a more significant role in their drug therapy.

Hal Stepper

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