Adverse Drug Reactions Reported in the German Democratic Republic: A Retrospective Analysis of Reports to the WHO-ADR Database

doi:10.4236/ojsst.2011.12006

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Open Journal of Safety Science and Technology, 2011, 1, 60 -74

doi:10.4236/ojsst.2011.12006 Published Online September 2011 (http://www.SciRP.org/journal/ojsst)

Adverse Drug Reactions Reported in the German

Democratic Republic: A Retrospective Analysis of

Reports to the WHO-ADR Database

Lise Aagaard1,2,3, Marion Schaefer4, Ulrich Meyer5, Ebba Holme Hansen1,2,3

1Department of Pharmacology and Pharmacotherapy, Section for Social Pharmacy,

Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Den mark

2FKL-Research Centre for Quality in Medicine Use, Copenhagen, Denmar k

3Danish Phar macovigila nce Research pro j ect (DANPREP), Copenhagen, Denm ark

4Institut für Klinische Pharmakologie, Charitè University Medicine, Berlin, Germany

5Institut für Pharmazie, Ernst Moritz Arndt University, Greifswald, Germany

E-mail: [email protected]

Received June 11, 2011; revised July 22, 2011; accepted August 2, 2011

Abstract

The German Democratic Republic (GDR) joined the WHO collaboration on drug safety in 1983 in order to

strengthen their national pharmacovigilance system. We aim to characterize adverse drug reaction (ADR)

reports which were forwarded to the WHO-ADR database by the GDR health authorities, as these data is

unknown to the public. ADR reports were analysed with respect to time, type of reporter, age and sex of the

patient, category of ADR (System Organ Class [SOC]), seriousness and suspected medicines. The unit of

analysis was one ADR. A total of 180 individual ADR reports covering 329 ADRs were forwarded from

1985 to 1990. The largest share of ADRs was reported for psychotropic medicines (23% of total ADRs) fol-

lowed by anti-infectives for systemic use (19% of ADRs), and medicines for the cardiovascular system (16%

of ADRs). The largest share of reported ADRs was from the SOC “hepatobiliary disorders” (16% of total

ADRs), followed by the SOCs “skin and subcutaneous disorders” (14% of total ADRs) and “blood and lym-

phatic disorders” (11% of total ADRs). Approximately 10% of ADRs were serious and included fatal cases.

In conclusion, only a limited number of ADR cases occurring in the former GDR, the majority being non-

serious, were located in the WHO database. However from government files we know that a large number of

serious and fatal ADRs were reported, but information about these were never communicated to the public.

Keywords: Pharmacovigilance, Spontaneous Reporting Systems, VigiBase, German Democratic Republic

1. Introduction

During the 1960s, in the wake of the thalidomide catas-

trophe in the late 1950s [1], pharmacovigilance systems

were established in many western European countries,

Canada and Australia [2]. The World Health Organiza-

tion (WHO) established an international reporting system

in 1968 and over the years an ever-increasing number of

countries have joined this collaboration [3]. In the second

half of the 20th century, a separate pharmaceutical policy

system was established in the previous Council for Mu-

tual Economic Assistan ce (Comecon) countries, but little

is known to the public about the principles of this system.

The German Democratic Republic (GDR) was well-

known for its large production of pharmaceuticals, often

copies of medications developed by pharmaceutical

companies in capitalistic countries, produced in large

state-owned companies which supplied the other Come-

con members [4]. New medicines were introduced years

later in the GDR than in western European countries, and

due to safety reasons thalidomide was never marketed in

the GDR. Medicines safety was of great importance to

the East German politicians and to increase medicines

safety in the GDR, a national ADR reporting system was

established in 1964 [4-5]. Limited information about data

reported to this system was communicated to the pre-

scribers and patients, as such type of information was

considered as being a state secret and only available to

L. AAGAARD ET AL.

people working with drug regulation. Available product

information and/or patient leaflets were of very limited

quality or non-existing and difficult to get access to, as

these documents were only produced in a limited number

of copies [4].

Internal documents from the GDR health authorities

revealed that from 1981 to 1983 spontaneous reports

covering information about more than 120 deaths from

use of anti-rheumatic medications containing indome-

tacin (Metindol/Amuno), diclofenac (Rewodina), phenyl-

butazone (Butaz olidin ), aminophenazone + phenylbuta-

zone (Wofapyrin) and the antidiarrheal Mexaform plus

(phanquinon + dichlorhydroxychinolin) and dichlorhy-

droxychinolin (Endiaron) existed, but no restrictions for

the use of these products were made [4]. For the X-ray

contrast agent iomeglamic acid (Falignost) several seri-

ous cases of allergies and anaphylactic shocks were re-

ported which led to changes in the production, as radio-

graphic examination were frequently used as a diagnostic

method in the GDR [4].

Of political reasons the GDR were not able to join the

international WHO collaboration on medicines safety

until 1983, despite that other Comecon countries such as

Bulgaria, the Czech Republic, Poland and Romania had

already joined this collaboration in the 1970s. From 1985

until the German reunification in 1990, ADR reports

were forwarded to the WHO ADR database, VigiBase by

the GDR health authorities [4,6-7].

We aim to characterize these ADRs reports, as these

data has never been published before, and therefore

would be of interest to the public.

2. Methods

2.1. Design

We retrospectively analysed all ADR reports occurring

in the GDR which were reported to VigiBase from July

1985 to May 1990. ADR data were placed at the disposal

of this study in anonymous form with encrypted identi-

fication of the medicine user. ADR reports were pro-

vided by the Uppsala Monitoring Centre (UMC) as

CIOMS reports, and data from these reports were manu-

ally entered into Microsoft Excel. The unit of analysis

was one ADR.

We analysed the reports with regard to type of reporter,

age and gender of the patient, type (system organ class

[SOC]) and seriousness of reported ADRs with respect to

medications involved.

2.2. Seriousness and Causality Criteria

The severity of ADRs was rated as certain, probable or

possible according to the CIOMS scale [1]. Causality

was rated as established, probable, possible, improbable

and not to be ascertained. Reports were later classified as

being serious or non-serious according to international

criteria.

2.3. Classification of reported ADRs

Any ADRs reported were classified according to the in-

ternational classification system Medicinal Dictionary

for Regulatory Activities (MedDRA) by preferred term

(PT) and (SOC) [8].

2.4. Setting

A national ADR reporting system was established in

1964 by law by the GDR’s Ministry of Health [5]. The

system was managed by the “Institut für Arzneimittel-

wesen der DDR” (IfAr), and physicians and pharmacists

were required to report ADRs [4-5].

An official reporting form (“Meldung von Schädlichen

Arzneimittelwirkungen”) had to be completed, and the

following information was required: age and gender of

the patient; severity and characteristics of the ADR(s),

suspected and concomitant medicines, indication for use,

dosage, treatment period, date of onset of ADR, causality

assessment and other relevant information such as labo-

ratory data if available (internal documents).

2.5. Medicine Use in the GDR

Medicines licensed for use in the GDR were listed in the

“Arzneimittel Verzeichnis”, published periodically by

the IfAr and containing information about the active

ingredients of available medicines, dosage, warnings,

ADRs and contra-indications [6]. From 1945 to 1990

approximately 1770 different types of medicines (pres-

cription medicine, over-the-counter medicine, comple-

mentary medicine, herbals, homeopathic medicine, aller-

gen extracts, blood products and radioactive medications)

were licensed for use in the GDR [7]. The number and

assortment varied over time. In the same period, up to

57,000 different pharmaceutical products were licensed

for use in West Germany [7]. In the beginning of the

1960s, the number of medicines imported into the GDR

constituted 5% of all licensed medicines in the GDR, but

this share increased up to approximately 30% of all

licensed medicine in 1989/1990 [6]. The imported me-

dicines were produced by pharmaceutical companies

located in COMECON member states (estimated 20%)

or in Western European countries (estimated 10%), and

imported in the GDR by the special office/pharmacy:

“Beratungsbüro für Arzneimittel”, which worked for the

L. AAGAARD ET AL.

GDR Ministry of Health. Medicines imported from

Western countries had to be paid with Western curren-

cies, therefore the import was limited, and the aim was in

most cases to substitute in the future with GDR or

COMECON production [6]. Prescription medicines were

free in the GDR, and over-the-counter medicines were

inexpensive. Medicine prices were fixed by the state, and

rarely changed from 1945 to 1990 [6].

3. Results

In total 180 individual ADR reports covering 329 ADRs

were reported from 1985 to 1990. The ADR reports were

of high quality and very detailed with information about

causality assessment and reaction outcome. Approxi-

mately 10% of reported ADRs were serious and 13 fatal

cases were located (Table 1), however these ADRs were

all known ADRs. Two-thirds of the total ADRs were

reported by hospital physicians, 23% of ADRs by gen-

eral practitioners and 12% of ADRs were reported by

specialist physicians. Serious ADRs were only reported

by hospital physicians. No ADRs were reported by

pharmacists.

3.1. ADRs by Age and Sex

The majority of reported ADRs (88% of total) occurred

in adults, followed by 6% of ADRs reported in children

from ages 3 to 10. Less than six percent of ADRs was

reported in children up to two years of age and in ado-

lescents (ages 11 - 17). Forty percent of ADRs was re-

ported for males and sixty percent of ADRs for females.

3.2. ADRs by Type and Seriousness

The largest share of reported ADRs was from the SOC

“hepatobiliary disorders” (16% of total ADRs), followed

by the SOCs “skin and subcutaneous disorders” (14% of

total ADRs) and “blood and lymphatic disorders” (11%

of total ADRs).

3.3. ADRs by Medication

Less than 10% of ADRs were reported for medications

imported from non-socialistic countries. The largest

share of ADRs was reported for psychotropic medicines

(23% of total ADRs) followed by anti-infectives for sys-

temic use (19% of ADRs), and medicines for the cardio-

vascular system (16% of ADRs).

4. Discussion

This is the first study to retrospectively analyse sponta-

neous ADR reports from the former German Democratic

Republic submitted to the WHO-ADR database. From

1985 to 1990 only a selected number of ADR reports

Table 1. Characteristics of serious adverse drug reactions le ading to death reported to Vigibase, Ger man Democratic Repub-

lic, 1985-1990.

Case no. Year ATC group Medicine Active substanceAdverse drug reaction (ADR)Indication GenderAge (year)

1 1985 M01AB05 Rewodina Diclofenac Pancytopenia Spondolysis Female64

2 1988 P01BD01 Tindurin Pyrimethamine Agranulocytosis Perinatal condition Male 1

3 1988 N02BB02 Analgin Metamizole/lidocainAgranulocytosis Nasopharyngitis Male 49

4 1988 J01ED07 Mebacid Sulfamerazine Epidermal necrolysis Chronic bronchitis Female61

5 1988 J01BA01 Berlicetin Chloramphenicol Marrow depression Chronic bronchitis Female49

7 1989 J01CA01 Ampicillin Ampicillin Anaphylactic shock Chronic bronchitis Female52

8 1989 M01AA06 Ketazone Kebuzone Purpura

Thrombocytopenia Effusion of joint Female74

9 1988

N02BB04

M01AA06

Eufibron

Ketazone

Propyphenazone

Kebuzone

Disseminated intravascular

coagulation

Marrow depression

Cardiomyopathy

NA Male 17

10 1989 P01AB01 Clont Metronidazole Anaphylactic shock NA Female51

11 1990 V08AA01 Visotrast Amidotrizoic acidAnaphylactic shock Hydronephrosis Male 68

12 1990 M03CA01 Pavulon Pancuronium Bradycardia

Cardiac arrest NA Male 5 mo.

13 1990 N05AH02 Alemoxan Clozapine Agranulocytosis NA Male 50

NA: not *vailable; mo: months.

L. AAGAARD ET AL.

were forwarded to VigiBase despite that around 400 to

500 ADR reports were reported annually to the GDR

health authorities [4]. The low number of reports sub-

mitted to VigiBase was due to the fact that when the

GDR joined the WHO collaboration the IfAr decided

that only unknown and severe ADRs should be reported

to VigiBase. The ADR reports located in VigiBase were

in line with observations from other western European

countries with respect to type and suspected medication

[9-10]. Few serious cases were reported, however cau-

sality was only established in three cases. Only a small

number of serious ADRs was reported in the GDR,

however, several cases of hepatitis and anaphylactic

shock were classified as non-serious although causality

was rated as being certain or possible. In the cases of

anaphylactic shock the reported medicines were often

administered intravenously (IV) or subcutaneously (SC).

Only one case of pancytopenia reported for diclofenac

was located despite that many other serious ADR cases

were reported in the 1970s and 1980s [4].

As we only have ADR data from the last six years of

the existence of the GDR, it was not possible to conduct

a time trend analysis. The UMC could not guarantee that

the actual number of ADR reports from the GDR au-

thorities had been higher, but reports included in this

study only represent those reported to VigiBase. In gen-

eral, the ADR reports were of high quality and thorough,

but due to their low number, they only represent a lim-

ited number of the ADRs which eventually occurred in

the former GDR. To explore whether a greater number of

ADRs was reported elsewhere in East Germany, one

would need access to the archives from the former East

Germany.

5. Conclusions

Only selected information about ADRs occurring in the

former GDR was located in the WHO database. However

from government files we know that a large number of

serious and fatal ADR cases were reported to national

authorities, but information was never communicated to

the patients or prescribers.

6. References

[1] E. B. Andrews and R. D. Mann, “Pharmacovigilance,”

2nd Edition, John Wiley & Sons, Chichester, 2007.

[2] W. H. Wardell, G. P. Velo and N. M, Jarocha, “Drug

Development, Regulatory Assessment and Post Market-

ing Surveillance,” Plenum, New York, 1981.

[3] S. Olsson, “The Role of the WHO Programme on Interna-

tional Drug Monitoring in Coordination Worldwide Drug

Safety Efforts,” Drug Safety, Vol. 19, No. 1, 1998, pp.

1-10. doi:10.2165/00002018-199819010-00001

[4] Ministerium für Gesundheitswesen. Arbeitsgruppe für

Organisation und Inspektion beim Ministerrat, Kontrolab-

teilung. Bericht über Stand und erforderliche Massnah-

men zur weiteren Erhöhung der Arzneimittelsicherheit in

der DDR. Pharmazie und Technik. Berlin, 1984.

[5] J. Richter and M. Wolski, “40 Jahre Regelung und

Überwa Chung des Arzneitmittelverkehrs in der Deuts-

chen Demokratischen Republik,” Pharmazie, Vol. 44, No.

10, 1989, pp. 666-671.

[6] M. Bőhm, K. Gerccke, L. Kny, H. Probst and J. Richter,

45 Jahre Pharmazie in Deutschland Ost. 7bDirekt Apo-

thekenservice AG, Fürstenfeldbruck, Berlin, 2007.

[7] J. Richter, H. J. Seidelin, M. Böhm, H. G. Keune and E.

Gueinzius, “Arzneimittel-und Apothekenrecht der

Republic,” Akademie-Verlag, Berlin, 1985.

[8] The Medical Dictionary for Regulatory Activities

(MedDRA). http://www.meddramsso.com

[9] L. Aagaard, L. H. Nielsen and E. H. Hansen, “Consumer

Reporting of Adverse Drug Reactions: A Retrospective

Analysis of the Danish Adverse Drug Reaction Database

from 2004 to 2006,” Drug Safety, Vol. 32, No. 11, 2009,

pp. 1067-1074. doi:10.2165/11316680-000000000-00000

[10] J. de Langen, F. van Hunsel, A. Passier, L. de Jong-van

den Berg, K. van Grootheest, “Adverse Drug Reaction

Reporting by Patients in the Netherlands: Three Years of

Experience,” Drug Safety, Vol. 31, No. 6, 2008, 515-524.

doi:10.2165/00002018-200831060-00006

L. AAGAARD ET AL.

Supporting Information

Additional supporting information may be found in the online version of this article in Table S1.

Table S1. Characteristics of adverse drug reaction reports from the German Democratic Republic (GDR) to Vigibase, 1985 to

1990.

Case

no. Year ATC Medicine Manufacturer Active

substance

Adverse

drug reaction SeriousIndication GenderOutcome Causality Dose Admin.ReporterAge

(years)

1 1985 H02AB06 Prednisolut GDR Prednisolon Bradycardia No Bronchitiss MaleRecovered Certain 25 mg IV Hospital59

1985 H02AB06 Prednisolut GDR Prednisolon Apnoea No Bronchitis MaleRecovered Certain 25 mg IV Hospital59

1985 H02AB06 Prednisolut GDR Prednisolon Anaphylactic

shock No Bronchitis MaleRecovered Certain 25 mg IV Hospital59

2 1986 N05CM02 Distraneurin AstraZeneca Clomethiazole Hypotonia No Psychoses MaleRecovered Certain 3 DF OralHospital46

1986 N05CM02 Distraneurin AstraZeneca Clomethiazole Bradycardia No Psychoses MaleRecovered Certain 3 DF OralHospital46

s 1986 N05CM02 Distraneurin AstraZeneca Clomethiazole Circulatory

failure No Psychoses MaleRecovered Certain 3 DF OralHospital46

1986 N05CM02 Distraneurin AstraZeneca Clomethiazole Anaphylactic

shock No Psychoses MaleRecovered Certain 3 DF OralHospital46

3 1986 C05BX01 Calcium

dobesilate GDR Calcium

dobesilate Fever No

Retinal

disorders Female NA Probable 750 mg OralSP 71

4 1986 N05AD01 Haloperidol Hungary Haloperidol Palpitation No Psychoses FemaleRecovered Certain 3 mg OralGP 10

1986 N05AD01 Haloperidol Hungary Haloperidol Somnolence No Psychoses FemaleRecovered Certain 3 mg OralGP 10

1986 N05AD01 Haloperidol Hungary Haloperidol Dyskinesia

tardive No Psychoses FemaleRecovered Certain 3 mg OralGP 10

1986 N05AD01 Haloperidol Hungary Haloperidol Anxiety No Psychoses FemaleRecovered Certain 3 mg OralGP 10

5 1986 N03AB02 Phenytoin GDR Phenytoin Nausea No Epilepsy FemaleRecovered Possible 300 mg OralGP 45

1986 C02AB01 Dopegyt Hungary Methyldopa Ataxia No Hypertension FemaleRecovered Possible 300 mg OralGP 45

1986 C02AB01 Dopegyt Hungary Methyldopa Diplopia No Hypertension FemaleRecovered Possible 300 mg OralGP 45

6 1986 N03AF01 Finlepsin GDR Carbamazepine Rash maculo-papularNo Trigeminal

nerve disorder FemaleRecovered Certain 400 mg OralSP 61

7 1987 J01XE01 Nitrofurantin GDR Nitrofurantoin Alveolitis

allergic No Urinary tract

infection FemaleRecovered Certain NA OralGP 70

1987 J01XE01 Nitrofurantin GDR Nitrofurantoin Fever No Urinary tract

infection FemaleRecovered Certain NA OralGP 70

8 1987 C02AB01 Dopegyt Hungary Methyldopa Fever No Hypertension MaleRecovered Certain 500 mg OralHospital59

9 1988 M01AB05 Rewodina GDR Diclofenac Anaphylactic shockNo Cervical

spondylosis FemaleRecovered Possible 2 DF OralHospital 55

1988 M01AB05 Rewodina GDR Diclofenac Bronchospasm No Cervical

spondylosis FemaleRecovered Possible 2 DF OralHospital 55

10 1989 H02AB06 Prednisolut GDR Prednisolon Anaphylactic shockNo Myeloid

leukaemia Female Recovered w.

sequaelae Certain 100 mg IV SP 54

1989 H02AB06 Prednisolut GDR Prednisolon Cardiac arrest No Myeloid

leukaemia Female Recovered w.

sequaelae Certain 100 mg IV SP 54

1989 H02AB06 Prednisolut GDR Prednisolon Apnoea No Myeloid

leukaemia Female Recovered w.

sequaelae Certain 100 mg IV SP 54

11 1989 A07EC01 Sulfasalazine Yugoslavia Sulfasalazine Hepatic necrosis No Ulcerative

colitis Male Recovered w.

sequaelae Certain 8 DF OralHospital48

1989 A07EC01 Sulfasalazine Yugoslavia Sulfasalazine Hepatitis No Ulcerative

colitis Male Recovered w.

sequaelae Certain 8 DF OralHospital48

12 1989 A02BA01 Altramet GDR Cimetidine Alopecia No Duodenal ulcer MaleRecovered Probable 800 mg OralHospital30

13 1989 J01XE01 Nifurantin GDR Nitrofurantoin Bronchospasm No Pyelonephritis MaleRecovered Certain 200 mg OralHospital35

L. AAGAARD ET AL.

1989 J01XE01 Nifurantin GDR Nitrofurantoin Cyanosis No Pyelonephritis MaleRecovered Certain 200 mg OralHospital35

1989 J01XE01 Nifurantin GDR Nitrofurantoin Coughing No Pyelonephritis MaleRecovered Certain 200 mg OralHospital35

1989 J01XE01 Nifurantin GDR Nitrofurantoin Fever No Pyelonephritis MaleRecovered Certain 200 mg OralHospital35

14 1989 D10AX05 Avlosulfon Wyeth-Ayerst Dapsone Anaemia

haemolytic No Erythematous