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Pharmaceutical Production Problems Detected by Adverse Drug Reactions Reports: A Documentary Study from the German Democratic Republic, 1982 to 1990 | OMICS International
ISSN: 2161-0495
Journal of Clinical Toxicology

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Pharmaceutical Production Problems Detected by Adverse Drug Reactions Reports: A Documentary Study from the German Democratic Republic, 1982 to 1990

Lise Aagaard1,2,3*, Ulrich Meyer4*, Marion Schaefer5 and Ebba Holme Hansen1,2

1Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark

2Danish Pharmacovigilance Research project (DANPREP), Copenhagen, City Odense, Denmark

3Faculty of Health Sciences, University of Southern Denmark

4Department of Pharmacy, Ernst Moritz Arndt University, Greifswald, Germany

5Department of Clinical Pharmacology, Charite University Medicine, Berlin, Germany

*Corresponding Authors:
Prof. Lise Aagaard
Faculty of Health, University of Southern Denmark
JB Winsløws Vej 19, 5000 Odense C
Tel: +45 6550 3740
E-mail: [email protected]
 
Ulrich Meyer
Department of Pharmacy, Ernst Moritz Arndt University
Greifswald, Germany
E-mail: [email protected]

Received date: February 16, 2012; Accepted date: February 24, 2012; Published date: February 28, 2012

Citation: Aagaard L, Meyer U, Schaefer M, Hansen EH (2012) Pharmaceutical Production Problems Detected by Adverse Drug Reactions Reports: A Documentary Study from the German Democratic Republic, 1982 to 1990. J Clinic Toxicol 2:120. doi: 10.4172/2161-0495.1000120

Copyright: © 2012 Aagaard L, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Visit for more related articles at Journal of Clinical Toxicology

Abstract

Objectives: To characterise spontaneous adverse drug reactions (ADRs) reported in the former German Democratic Republic (GDR) and to identify ADRs related to quality problems with pharmaceuticals.

Material and methods: In 1964 a spontaneous ADR reporting system was established in the GDR with the purpose to collect information about possible toxic and damaging ADRs from medicine use. The spontaneous reporting system was also seen as an important tool for securing the quality of the pharmaceutical production. Data on ADRs occurring in the GDR were located in the national German archive, Bundesarchive in Berlin. Only ADR reports submitted from 1982 to 1990 were identified. The reports were analysed with respect to type of ADR (System Organ Class [SOC]) and substance.

Results: From 1982 to 1990 a total of 3990 ADR reports covering information about 6706 ADRs were submitted to the GDR health authorities. The largest share, 26% of all ADRs referred to the SOC “ skin and subcutaneous disorders ”, followed by the SOCs “ general disorders and administration site conditions ” (23% of total ADRs) and “ gastrointestinal disorders ” (11% of total ADRs). Two-thirds of all ADRs were related to the therapeutic groups: “ anti- infectives for socs use” (ATC group J) and “ blood and blood forming organs” (ATC group B). Approximately 85% of ADRs from ATC group B was reported for dextran 40, the majority of these ADRs of the general type, followed by skin ADRs and ADRs concerning respiratory disorders. Additionally a high number of circulatory collapse/shock were reported for dextran 40. The increased level of ADR reporting was related to an abnormal distribution of low and high molecules of dextran 40 occurring due to production problems. Fifteen percent of ADRs were reported for radiographic contrast media; the majority for the substance amidotrizoate, and more than one half of these were of the type skin and respiratory disorders.

Conclusion: In the GDR during the 1980s, the spontaneous ADR reporting system managed to detect serious pharmaceutical quality problems in dextran products. The products of lower quality could not be replaced easily due to lack of safer national alternatives as well as lack of foreign currency necessary to import of purer products from Western countries.

Keywords

Pharmacovigilance; Spontaneous Reporting Systems; German Democratic Republic; Pharmaceutical Quality; Dextran; Contrast Media

Introduction

The German Democratic Republic (GDR) (1949 to 1990) was known for its well developed pharmaceutical industry organized in state-owned companies that produced several pharmaceuticals, both original as well as generic products [1]. The generics were copies of pharmaceuticals already marketed 3 to 5 years previously in western countries and had to follow the international patent law [2]. Efficacy and safety assessments of generics were based on existing international data [1,2]. From 1951 to 1989 a total of 48 original products were developed by the GDR pharmaceutical industry, e.g. the anabolic steroid chlordehydromethyltestosteron (Oral-Turinabol®) and the beta-blocker talinolol (Cordanum ®) [1]. Despite the difficult financial situation after World War II innovative product development increased in the 1960s and 1970s resulting in an expansion of the GDR pharmaceutical industry [3]. However over the time, the temporary lack of chemicals, packing material, limited capacities for pharmacological and toxicological testing and production equipment restricted the further expansion [4]. Good Manufacturing Practice (GMP) and Good Laboraty Practice (GLP) based on the World Health Organization (WHO) standards were implemented in the GDR [5]. In the 1960s systems for the reporting of adverse drug reactions (ADRs) were established at national level, and internationally by the WHO, to collect information about ADRs following medicine use, particularly with regard to rare and serious reactions [6]. To comply with the WHO recommendations in the GDR a similar ADR reporting system was introduced in 1964 like in other countries, with the purpose to collect information about possible toxic and harmful ADRs from medicine use [5]. In addition in the GDR the spontaneous reporting system was also viewed as an important tool for securing the quality of the pharmaceutical production [7]. Internationally, only limited information about ADRs reported in the GDR as well as and other Eastern European countries has been available [8]. The fall of the Berlin wall has allowed access to reports on ADRs, that previous was treated as state secrets and with access to only a few people. The objective of this study was to characterise spontaneous ADRs reported in the GDR with respect to type of reported ADRs and suspected substances, and to identify ADRs related to quality problems with pharmaceuticals.

Setting

The pharmaceutical industry and medical supply system in the GDR

The GDR pharmaceutical industry was organized through a cooperation of all major pharmaceutical companies named GERMED with its main center at the Arzneimittelwerk (AWD) Dresden [3]. GERMED constituted 12 pharmaceutical factories and within GERMED specialization concerning therapeutic areas was supported. Berlin Chemie maintained the insuline production and Jenapharm the production of hormones and antibiotics [3]. Another form of specialization referred to the way of administration or dosage form of the medication, i.e. the production of eye drops and inhalation sprays were maintained by Ankerwerk Rudolstadt, suppositories and ovules by Pharmamed Naumburg and liquids by the company Ysat Wernigerode [3]. In the GDR prescription medicines were dispensed to patients free of charge and over-the- counter medicines were sold at low prices through state-owned pharmacies [9]. Approximately 75 % of licensed medications were prescription only [9]. In 1949 approximately 5000 medications was produced in the GDR, but this number was reduced much heavily to around 1700 in 1951, as only medications which were considered rational with respect to efficacy and safety were allowed to remain on the market [9]. The licensed medications were listed in the national medication compendium, the “Arznemittelverzeichnis”, which was issued annually [9]. Table 1 displays the distribution of the number of licensed pharmaceutical products in the GDR distributed by different manufacturers and listed in the “Arzneimittelverzeichnis” [9]. For a small country like the GDR, which did not have the economic power to have a pharmaceutical industry large enough to cover the need for all needed medical supplies within the GDR a considerable number of pharmaceuticals was also imported from other Eastern European countries as well as nonsocialist countries [4]. Over the years, approximately 1750 medications (range 1440 to 2043) were licensed for use in the GDR. Of these medications around 1000 (range 1343 to 1900) were produced by the GDR pharmaceutical industry and some of these even produced by local pharmacies called “Standardrezepturen” [4]. Another 250 pharmaceutical products (range 108 to 244) were imported from other socialist countries and about 200 (range 17 to 399) from non-socialist countries [4].

Year GDR productions Pharmaceuticals imported from Eastern Europe Pharmaceuticals imported from Western countries Total
1951 1900 NR NR 1900
1954 1511 NR NR 1511
1957 1685 NR NR 1685
1959 1680 NR NR 1680
1961 1440 NR NR 1440
1962 NA NA NA NA
1969 NA NA NA NA
1970 NA NA NA NA
1971 1397 108 17 1522
1972 1397 108 17 1522
1973 NA NA NA NA
1974 NA NA NA NA
1975 NA NA NA NA
1976 1348 148 29 1525
1977 NA NA NA NA
1979 NA NA NA NA
1980 1343 141 26 1510
1981 1367 204 249 1820
1982 NA NA NA NA
1983 NA NA NA NA
1984 NA NA NA NA
1988 1392 244 234 1870
1990 1412 232 399 2043

Table 1: Licensed pharmaceutical products (number) in the German Democratic Republic distributed by type of producer, listed in the national medicines compendium.

GDR national ADR reporting system

In 1964 a national ADR surveillance program was established by law by the GDR’s Ministry of Health and in 1969 an official ADR reporting form was launched together with information about the importance of reporting ADRs [7, 9-11]. Initially physicians and pharmacists were requested to report ADRs however reporting was voluntary. In 1981, in order to increase the number of submitted ADR reports, mandatory reporting was introduced for physicians [8]. To submit an ADR report the following information was required: age and gender of the patient; severity and characteristics of the ADR(s), suspected medicine and also concomitant medicines, indication for use, dosage, treatment period, date of onset of the ADR, causality assessment and other relevant information such as laboratory data if available [8]. All reports were made on paper as at that time no electronic reporting system or reporting by the telephone was established. The spontaneous reporting system was managed by the “Institut für Arzneimittelwesen der DDR” (IFAR) [8]. All suspected cases, including unknown ADRs, serious ADRs, ADRs due to interactions with other drugs, and ADRs resulting in endangering of life or resulting in death were to be reported and centrally documented [11]. Formal assessments of ADR reports were initiated in 1977. Scientific staff working at IFAR evaluated the reports and if the reported ADRs were suspected to be caused by defects in quality of the medicines, further investigations were initiated. All other cases were examined by the “Problem commission of Clinical Pharmacology” located in Dresden [11]. Hence the majority of ADR reports were only tracked in special cases, and no general practice for analysing these cases existed. Results of the internal analysis were usually not published and written feed-back was only provided to the reporter and pharmaceutical companies in cases where the ADRs were caused by a quality defect of the administered drug [11]. This system was in place until the German Reunification in October 1990. The GDR joined the international WHO collaboration on drug safety in 1983 and from the summer of 1985 until 1990 selected ADR cases were forwarded to the WHO database. The intention of the selection process was that only new ADRs should be reported to avoid “unnecessary”overreporting. The characteristics of these ADR cases have been reported elsewhere [8]. Table 2 lists selected cases of serious ADR cases leading to withdrawal of the products from the market in the GDR. Decisions of withdrawal were made on the basis of both own and international observations on serious ADRs.

Year of marketing Year of withdrawal Medication (s) Substance (s) Adverse drug reaction (s) GDR cases (N)
1966 1984 Enteroseptol Entero-Vioform Mexaform plus Clioquinol Dichlorquinol SMON* syndrome 0
1969 1984 Aminophenazone Oramon Pulmophyllin Aminophenazone Carcinogenic 0
< 1960 1984 Perclusone Wofapyrin henylbutazone combinations Bone marrow supression 11
1969 1984 Ketazon Kebuzon Bone marrow suppression 0
1981 1985 Sotropin H Somatrotopin Creutzfeld-Jacob Syndrome 0
1984 1985 Auroplex Lindane CNS reaction 5
1979 1985 Phenoro Canthaxanthin Retina sediments 3
< 1960 1986 Benedorm Pyrithyldion Dependence 1
< 1960 1986 Bromisoval (Alluval) Bromisovalerianyl Dependence 0
< 1960 1988 Phenylbutazone Phenylbutazone Bonemarrow suppression 84 (3 fatal)

Table 2: Medications marketed in the German Democratic Republic (GDR) but withdrawn due to negative risk-benefit evaluations by health authorities, selected cases 1982 to 1990.

Materials and Methods

Data on ADRs reported in the GDR were provided from several sources and types of material. Material was searched in the national German archives, Bundesarchive, in Berlin as well as databases and websites. All relevant identified material was retrieved. The analysed material covered the period from 1964 to 1990 and derived from two main sources: a) ADR data reported in the German Democratic Republic from 1982 to 1990 and b) reports and correspondences between GDR health authorities and pharmaceutical companies and other relevant stakeholders. Information about ADRs occurring in the GDR and reported to IFAR from 1982 to 1990 was retrieved. Documents from 1969 to 1981 could not be located in the archive although former employees of the IFAR had confirmed that all files were stored in the Bundesarchive after the reunification (personal communication). Furthermore, we were not able to get copies of the original ADR reports, but were allowed access to extracts of information which had been manually entered into protocols by IFAR employees at the time of reporting. In these protocols information about suspected medications, batch number, reported ADRs, deaths and whether the reports had been forwarded to the Prague Pharmacovigilance centre and/or the WHO ADR database VigiBase was present. For some of the ADR reports information about evaluation patterns as well as established quality problems for the reported batches was found, however, this information was not systematically documented, and therefore could not be included in this study.

Analysis

Data were extracted from the ADR register and protocols into Excel files using the following categories: ATC (anatomical therapeutic chemical) [12] code of medications, trademark and active substance of the medicines, ADRs coded according to MedDRA terminology at System Organ Class (SOC) level [13]. The process was very time consuming due to the large amount of data which were written in German language and had to be translated into English. In order to present the large amount of data in a comprehensive way, the medicines for which the ADRs are reported are presented at ATC level 1. Information about seriousness of reported ADRs as well as age and sex of patients was not available in the ADR protocols of IFAR.

Results

From 1982 to 1990 a total of 3990 ADR reports (range 233 to 537 per year) covering information about 6706 ADRs (range 373 to 926) were submitted to the GDR health authorities. Approximately 60% of ADR reports concerned inpatients and 40 % outpatients. On average, 10 fatal ADR cases were reported per year (range 7 to 20). Table 3 displays the number of ADRs reported in the GDR from 1982 to 1990 classified according to the affected system organ class (SOC) and the therapeutic groups. The largest share, 26% of all ADRs referred to “skin and subcutaneous disorders”, followed by the SOC “general disorders and administration site conditions” (23% of total ADRs) and “gastrointestinal disorders” (11% of total ADRs).

ATC/System Organ Class Blood Card. Cong. Ear Eye Gen. Gastr. Hepa Imm. Inf. Inj. Inv. Met. Mus. Nerv. Preg. Psyc. Renal Resp. Repr. Skin Social Surg. Vasc. Total
Alimentary tract & metabolism (A)                                                  
A01/A02/A03/A04 0 9 0 0 3 11 11 1 1 0 0 2 0 2 16 1 4 0 2 1 11 0 0 0 75
A06/A07/A08/A09 4 3 0 0 0 5 14 4 1 1 0 0 0 0 5 0 0 0 15 0 15 0 0 3 70
A10/A11 1 3 0 0 0 26 5 0 7 1 1 3 3 0 6 0 1 1 0 3 34 0 0 3 98
A12/A14/A16 1 2 0 0 0 2 8 1 0 1 0 0 0 1 2 0 0 0 2 0 3 0 0 2 25
Total A 6 17 0 0 3 44 38 6 9 3 1 5 3 3 29 1 5 1 19 4 63 0 0 8 268
Blood & blood forming organs (B)                                                  
B01 8 3 0 0 0 44 12 3 3 1 0 6 0 4 7 0 0 0 4 1 25 0 6 9 136
B02 1 4 0 0 0 8 2 0 5 0 0 1 0 0 0 0 0 0 9 0 1 0 0 4 35
B03 1 3 0 0 0 54 28 0 3 4 0 5 0 0 5 0 2 2 9 0 6 0 0 9 131
B05/06 1 108 0 1 9 554 122 0 104 11 2 96 0 14 41 4 9 7 187 0 227 0 2 103 1602
Total B 18 118 0 1 9 660 164 3 115 16 2 108 0 18 53 4 11 9 209 1 259 0 8 125 1904
Cardiovascular system (C)                                                  
(C01 1 8 0 0 2 10 15 0 3 0 1 1 0 0 8 0 0 0 5 2 15 0 0 5 76
C02 4 1 0 0 3 8 13 42 3 1 0 1 0 0 8 0 2 3 3 0 11 0 0 0 103
C03/C04/C05 1 8 0 0 2 8 31 0 9 0 0 5 0 3 13 0 0 1 1 0 36 0 0 2 120
C07/C08/C09/C10 0 4 0 1 4 11 13 4 3 1 0 0 0 3 11 0 3 0 3 2 33 0 0 1 97
Total C 6 21 0 1 11 37 72 46 18 2 1 7 0 6 40 0 5 4 12 4 95 0 0 8 396
Dermatologicals (D)                                                  
D01/D02/D03 1 0 0 0 2 2 5 0 0 1 0 0 0 1 3 0 1 0 0 0 16 0 0 0 32
D04/D05 0 1 0 0 3 3 20 0 0 0 0 1 0 0 3 0 0 0 0 0 7 0 0 0 38
D06/D07 0 0 0 0 0 5 1 0 0 1 0 0 0 3 1 0 0 0 1 0 7 0 0 1 20
D08/D11 0 0 0 0 0 2 0 0 2 0 0 0 0 0 1 0 0 0 0 0 61 0 0 0 66
Total D 1 1 0 0 5 12 26 0 2 2 0 1 0 4 8 0 1 0 1 0 91 0 0 1 156
Sex hormons (G)                                                  
G01/G02 0 0 0 0 0 3 2 0 0 0 0 0 0 0 2 0 1 0 1 0 4 0 0 4 17
G03/G04 0 2 0 0 1 29 10 10 1 0 0 1 0 2 4 0 0 0 0 0 20 0 0 7 87
Total G 0 2 0 0 1 32 12 10 1 0 0 1 0 2 6 0 1 0 1 0 24 0 0 11 104
Systemic hormonal prep. (H)                                                  
H01/H02 0 9 0 0 0 31 9 0 2 1 0 4 0 1 5 0 1 0 16 0 29 0 0 9 117
H03/H04 1 2 0 0 0 3 2 2 0 0 0 0 0 0 1 0 0 0 0 0 9 0 0 1 21
Total H 1 11 0 0 0 34 11 2 2 1 0 4 0 1 6 0 1 0 16 0 38 0 0 10 138
Anti-infectives for systemic use (J)                                                  
J01 11 24 1 3 11 158 77 25 53 12 0 10 0 7 38 0 4 1 40 1 334 0 1 26 837
J02/J04/J05/J06 4 1 0 0 0 53 3 1 3 6 0 0 0 5 5 0 0 3 1 0 31 0 0 4 120
J07 15 25 1 3 11 211 80 26 56 18 0 10 0 12 43 0 4 4 41 1 365 0 1 30 957
Total J 30 50 2 6 22 422 160 52 112 36 0 20 0 24 86 0 8 8 82 2 730 0 2 60 1914
Antineoplastic & immuno. (L)                                                  
L01/L02/L04 3 4 0 0 0 18 4 3 4 4 0 1 0 0 4 0 0 0 5 0 17 0 0 2 69
Total L 3 4 0 0 0 18 4 3 4 4 0 1 0 0 4 0 0 0 5 0 17 0 0 2 69
Musculoskeletal system (M)                                                  
M01 12 10 0 0 0 40 56 25 4 12 0 5 0 4 15 0 4 2 10 0 64 0 0 16 279
M02/M03/M04 2 8 0 0 1 19 42 0 5 0 6 1 0 3 11 0 3 0 2 0 37 0 0 1 161
Total M 14 18 0 0 1 59 118 25 9 12 6 6 0 7 26 0 7 2 12 0 101 0 0 17 440
Nervous system (N)                                                  
N01 2 10 0 0 1 45 12 5 13 2 0 10 0 0 35 0 3 0 14 0 37 1 0 19 209
N02 9 16 1 2 1 48 17 4 18 1 1 4 0 2 18 0 3 2 14 0 72 0 0 15 248
N03 2 2 0 1 3 17 20 6 3 0 0 1 0 0 16 0 5 1 1 0 31 0 0 0 109
N04/N05/N06/N07 17 11 0 0 3 34 23 7 2 1 1 4 0 0 25 0 13 1 5 0 13 0 1 12 173
Total 30 39 1 3 8 144 72 22 36 4 2 19 0 2 94 0 24 4 34 0 153 1 1 46 739
Antiparastic (P)                                                  
P01 5 2 0 0 0 3 3 0 0 0 0 0 0 0 2 0 2 1 2 0 3 0 0 1 24
P02 1 0 0 0 0 1 8 0 0 0 0 0 0 1 1 0 0 0 0 0 1 0 0 1 14
P03 1 0 0 0 4 1 3 0 0 0 0 0 0 2 5 0 2 0 1 0 4 0 0 2 25
Total P 7 2 0 0 4 5 14 0 0 0 0 0 0 3 8 0 4 1 3 0 8 0 0 4 63
Respiratory system                                                  
R01/R02/R03 0 10 0 0 0 34 16 0 2 1 0 4 0 3 9 0 7 0 87 0 38 0 0 19 230
R05/R06 0 4 0 0 11 4 8 0 0 0 0 0 0 0 3 0 5 0 3 0 12 0 0 0 50
Total 0 14 0 0 11 38 24 0 2 1 0 4 0 3 12 0 12 0 90 0 50 0 0 19 280
Sensory organs (S)                                                  
S01 0 1 0 0 28 2 0 0 1 0 0 1 0 0 0 0 0 0 1 0 17 0 1 2 54
Total S 0 1 0 0 28 2 0 0 1 0 0 1 0 0 0 0 0 0 1 0 17 0 1 2 54
Various (V)                                                  
V01/V03/V04 0 10 0 0 3 100 33 1 8 0 1 15 0 0 11 0 0 2 19 0 37 0 0 23 263
V06 0 7 0 0 0 55 5 0 1 5 0 5 0 0 3 0 0 1 11 0 13 0 0 2 108
V08/V09/V10 6 27 0 0 9 77 132 3 43 1 2 29 0 3 39 0 8 2 71 0 165 0 0 61 678
Total V 6 44 0 0 12 232 170 4 52 6 3 49 0 3 53 0 8 5 101 0 215 0 0 86 1049
Others 5 2 0 0 5 18 5 2 12 4 0 2 1 2 2 0 3 1 4 0 109 0 0 4 181
Total 121 300 3 11 108 1525 720 171 323 85 12 179 4 75 374 5 82 30 489 11 1755 1 12 317 6706

Table 3: Adverse drug reactions (N) reported in the German Democratic Republic distributed by therapeutic group (Anatomical Therapeutical Chemical Code [ATC]) and type (system organ class) 1982 to 1990.

ADRs by therapeutic group

Two-thirds of all ADRs were seen in the therapeutic groups: “antiinfectives for systemic use” (ATC group J), predominantly antibacterials (ATC group J01) and vaccines (ATC group J07) and “blood and blood forming organs” (ATC group B). Approximately 15% of ADRs were reported for medications from ATC group V (various), particularly for contrast media agents (ATC group V08). Within ATC group B the majority of ADRs was reported for plasma volume expanders, particularly dextrans (N = 773). Table 4 displays the characteristics of ADRs reported for dextran containing products marketed in the GDR reported from 1982 to 1990. The majority of reports, 83% of total ADRs was reported for dextran 40, followed by 11% of ADRs reported for dextran 40/mannitol, and 6% of reports were reported for dextran 75. For dextran 40, the majority of reported ADRs were of the type “general disorders and administration site conditions” (N = 181), i.e. chills and temperature changes; followed by ADRs concerning skin reactions (N = 108) and ADRs concerning respiratory disorders (N= 101). A large number of circulatory collapse/shock (N = 39) and anaphylactic reactions (N= 25) was also reported for dextran 40. Table 5 displays the characteristics of ADRs for the contrast media agent amidotrizoate natrium in the GDR from 1982 to 1990. The majority of ADRs (23% of total ADRs) were of the type skin disorders, i.e. urticaria followed by gastrointestinal ADRs (vomiting and nausea) (21% of total) and respiratory ADRs (11% of total), i.e. difficulty breathing.

System Organ Class Dextran 40 Dextran 40, 100 mannitol Dextran 75
Cardiac disorder Bradycardia (6) Decreased heart Rhythm (1) Atrial fibrillation (1)
  Cardiac disorder (13) Tachycardia (6) Tachycardia (1)
  Palpitation (1) Heart race (1) Cardiac disorder (2)
  Tachycardia (28)    
Total 48 8 4
Eye disorders Conjuctivitis (2) NR NR
  Eye burning (2)    
  Pupil dilatation (1)    
Total 5 0 0
General disorders Chills (88) Chills (10) Injection site reaction (1)
  Dead (1) Temperature increased (6) Chills (2)
  Dizziness (1) Pain (1) Temperature increased (3)
  Temperature changes (79) Injection site reaction (1)  
  Head pressure (1) Fever (1)  
  Pain (5)    
  Hypotonie (3)    
  Incompability (1)    
  Lack of consciousness (2)    
Total 181 19 6
Gastrointestinal disorders Vomiting (42) Stomach pain (1) Nausea (2)
  Stomach pain (2) Nausea (3) Vomiting (1)
  Nausea (29) Vomiting (2)  
  Mouth blister (2)    
  Hyperstomie (1)    
  Diarrhea (4)    
Total 80 6 3
Infections and infestations Flu symptoms (1) NR Pyrogen reaction (1)
  Pyrogen reaction (2)    
Total 3 0 1
Investigations Blood pressure increased (10) Increased pulse (1) Decreased blood pressure (1)
  Pulse changes (3) Blood pressure changes (6) Hypertension (1)
Total 13 7 2
Immune system disorders Anaphylactic reaction/shock (25) Anaphylactic reaction/shock (4) Anaphylactic reaction/shock (11)
Total 25 4 11
Musculoskeletal disorders Muscle pain (24) Back pain (1) NR
Total 24 1 0
Nervous system disorders Parasthesies (2) Headache (3) Convulsions (1)
  Headache (4) Restlessness (1)  
  Vertigo (1) Uterus contraction (1)  
  Restlessness (2)    
  Tingling (2)    
  Trembling (1)    
Total 12 5 1
Psychiatric disorders Psychiatric disorder (2) Anxiety (1) Anxiety (1)
Total 2 1 1
Renal and urinary disorders Kidney pain (3) Kidney pain (2) NR
Total 3 2 0
Respiratory disorders Bronchospasm (74) Lung oedema (2) Difficulty breathing (11)
  Cough (3) Difficulty breathing (8)  
  Cyanosis (17) Cyanosis (2)  
  Lung oedema (7)    
Total 101 12 1
Skin and subcutaneous disorders Urticaria (22) Skin redness (3) Erythema (1)
  Rash (2) Urticaria (1) Hot flashes (1)
  Pruritus (26) Exanthem (5) Lip oedema (1)
  Swelling (3) Hot flashes (1) Rash (3)
  Erythem (5) Oedema (3)  
  Oedema (10)    
  Blister (8)    
  Hot flashes (1)    
  Exanthem (26)    
  Itching (5)    
Total 108 13 6
Vascular disorders Circulatory collaps/schock (39) Circulatory collaps/schock (4) NR
Total 39 4 0
Total ADRs (N) 645 82 46

Table 4: Characteristics of adverse drug reactions (N) reported for dextrans containing products reported from 1982 to 1990 in the German Democratic Republic (numbers in brackets).

System Organ Class Adverse drug reaction (s) N
Blood and lymphatic system disorders Hemiparesis 6
  Thromboembophlebitis 2
Total   8
Cardiac disorder Bradycardia 1
  Hypotoni 4
  Palpitation 1
  Tachycardia 10
  Cardiac condition 12
Total   28
Eye disorders Conjunctivitis 1
  Eye pressure 6
  Ptosis eye lids 1
  Pupil dilatation 1
Total   9
Gastrointestinal disorder Diarrhea 6
  Mouth swelling 10
  Nausea 50
  Vomiting 54
  Aphonia 1
  Lack of efficacy 1
  Stomach pain 4
Total   126
General disorders and administration site conditions Dizziness 3
  Back pain 1
  Chills 12
  Dead 1
  Feeling uncomfortable 1
  Injection site reaction 14
  Aplasia 2
  Loss of consciouness 6
  Temperature changes 16
Total   56
Hepatobiliary disorders Icterus 1
  Increase in transaminases 1
  Liver damage 1
    3
Immune system disorders Anaphylactic schock/reaction 44
Total   44
Infection and infestations Pyrogen reaction 1
Total   1
Injury, poisoning and procedural complications Drug intolerance 2
Total   2
Investigations Hypotoni 1
  Disturbance of heart rhytm 1
  Changes in blood pressure 17
  Pulse disturbances 6
Total   25
Musculoskeletal and connective tissue disorders Muscle tremor 3
Total   3
Nervous system disorders Convulsions 8
  Headache 2
  Hemiparesis 1
  Parasthesia 8
  Partial half-page syndrom 1
  Restlessness 2
  Somnolence 4
  Tremble 1
  Vertigo 6
Total   33
Psychiatric disorder Apati 1
  Amnesia 1
  Anxiety 4
Total   6
Renal and urinary disorders Kidney pain 1
  Oliguria 1
Total   2
Respiratory, thoracic and mediastinal disorders Cyanosis 8
  Difficulty breathing 51
  Lung oedema 7
Total   66
Skin and subcutaneous disorders Blister 23
  Erythema 5
  Exanthem 15
  Itching 2
  Oedema 33
  Skin redness 17
  Urticaria 44
Total   139
Vascular disorders Circulatory collaps/schock 42
  Cerebral ischamie 1
Total   43
Total ADRs reported for amiotrizoat natrium   594

Table 5: Characteristics of adverse drug reactions reported for amiotrizoat natrium used as contrast media (ATC group V08AA01) in the German Democratic Republic, 1982 to 1990.

Discussion

This is the first study which retrospectively has evaluated spontaneous ADR reports submitted to the national health authorities in the GDR from 1982 to 1990. The GDR spontaneous reporting system was well functioning and able to detect production problems in the pharmaceutical industry. Analysis showed that the majority of ADR reports were found related to dextran 40 products as well as contrast media agents. As only limited information in the archives about age and gender of the patients affected by the reported cases as well as seriousness of reported ADRs was available we focus on the following aspects of ADR reporting:

Number of reported ADRs

The reported ADRs corresponds to an annual reporting rate of 27 reports/million inhabitants/year which is low compared to the number of licensed medicines in the GDR and the size of the population. In the same period the reporting rate in West Germany was 89 reports/ million inhabitants/year [11]. Within the Comecon countries reporting rates varied widely, from 7 reports/million inhabitants/ year in the Soviet Union to 243 reports/million inhabitants/year in Czechoslovakia [11]. Spontaneous reporting systems are known to be biased by underreporting [14]. In the GDR information about medications, both efficacy and safety topics were published in the medical journal “Medicamentum” which was issued monthly by the GDR pharmaceutical industry. This practice may have contributed to underreporting, because the GDR physicians might have assumed that everything of importance was already known. Despite the low number of ADR reports, the reported ADRs were in line with ADRs reported in other countries with respect to type and suspected medications.

ADRs reported for dextrans

This study showed that spontaneous ADR reports had detected quality problems in relation to the production of dextran 40 at Serumwerk Bernburg. In the 1960s it was known that an abnormal distribution of low and high dextran molecules could lead to an increased risk of serious ADRs such as shock and vascular disturbances when infused in children and pregnant women [15-18], and guidelines for handling serious ADRs were published [19]. In the 1970s the number of reports on ADRs such as anaphylactic shocks, bronchospasm, and circulatory collapses/shocks reported for dextran 40 increased in the GDR. Internationally only few studies analysing spontaneous ADRs from use of dextrans has been reported [19-21]. In the US 366 reports, 25% of these being serious, was reported for dextran 40 and dextran 70 from 1969 to 2004 [20]. The majority of serious ADRs were anaphylaxis/anaphylactic events [20]. From 1970 to 1979 the incidence of severe ADRs per unit administered dextran 40 in Sweden was 0.013% [21]. We only have few informations about the GDR ADR rates, however in 1982 the rate of serious ADRs was estimated as being 0.011% increasing to 0.02% in 1984 [22]. The numerous ADRs lead to considerations whether the figures from GDR represented a real increase in reports in the GDR, given that reporting rates had increased temporarily due to previous under-reporting, or if there were specific problems with GDR products of dextrans [22]. An inspection carried out by IFAR at Serumwerk Bernburg in 1978 showed that only 50 % of dextran 40 and dextran 75 molecules were within the optimal range of molecule size, and high share of high number dextran molecules was suspected to have caused the reported ADRs [22]. In order to curb the increasing number of serious ADRs a new production method, partial fractionation, was introduced for dextran 75 in 1980, and the number of ADR reports declined [22]. In 1984 it was decided to introduce a new production technique for dextran 40, continuous fermentation, which was also used internationally, however due to lacking of financial resources and production orders at Serumwerk Bernburg the technique, could not be implemented until 1990 [23]. In 1985 import of dextran 1 (Promit) from Knoll AG in West Germany for restricted use in gynaecology was initiated as it was assumed that the injection of dextran 1 before dextran 40 could reduce the level of serious ADRs [24]. Due to limited production capacities of dextran 40 at Serumwerk Bernburg an additional import of dextran 40 from Sweden was necessary, however this dextran was reserved for use outside the health care sector, and due to the restricted availability of foreign currency the import could not be increased [25]. During the whole process IFAR never considered suspending the market authorization for dextran 40 as it was not possible for pharmacological reasons; gelatine was not a suitable substitute and hydroxyethyl starch was not available on the GDR market. Dextrans were used in severely ill patients to increase plasma volume and IFAR had to weigh between not delivering dextrans to the patients who need it resulting in many fatal cases, ore delivering dextrans with pharmaceutical quality problems possibly resulting in other cases of ADRs. Other examples of quality problems with production of pharmaceuticals in the GDR have also been identified [28]. In 1978 sterility problems in the production of Mydrum® (tropicamid) eye drops produced at the Ankerwerk in Rudolstadt were detected, and the contamination with pyrogens was due to problems with the bottle-washing machine. In order to solve the contamination problem it was suggested that the content of benzalconiumchlorid was increased of factor 20, rather than implementing a new machine that was in accordance with GMP standards [28]. Ampicillin for injection produced at Pharmachim was also contaminated with pyrogens, resulting in many ADR reports of skin reactions and increased temperature, however no information was found in the archive about which measures were implemented to tackle these problems [29].

ADRs reported for contrast media agents

For the contrast media agents’ amidotrizoat amidotrizoat and adipiodon a large number of allergic ADRs were reported, reactions that were already well known at that time and which were communicated to the GDR physicians through Medicamentum [26,27]. The large number of ADRs was not found to be related to pharmaceutical quality problems, and as the number of reports was comparable to international data, no further investigations were made.

Strength and weaknesses of this study

The strength of this study is that it is the first which systematically has collected information about ADRs reported in the GDR. The included material comprised ADR reports collected over many years which varies in quality and length. The present work was based on documentary textual sources located in archives and elsewhere in Berlin and represents the authors’ interpretations of the analyzed documents. The analysed material does not allow us to conclude if the GDR pharmaceutical industry in general was suffering from major problems with maintaining the pharmaceutical quality or if the pharmaceuticals were of lower quality than those produced in Western countries. In the dextran case correspondences between IFAR and Serumwerk Bernburg indicated that a high number of ADRs was reported in the GDR due to quality problems, but due to continuous lack of financial resources and equipment it was often not possible to improve the pharmaceutical quality sufficiently [30].

Conclusion

This study showed that the GDR spontaneous reporting systems were able to detect, in addition to its original purpose, pharmaceutical quality problems. This was further investigated for the production of dextrans. However, due to the lack of safer alternatives and foreign currency necessary to import purer products from Western countries, the products of lower quality could not be replaced easily.

Acknowledgement

Professor Dr. habil. Joachim Richter and Dr. Helmuth Koch, former Institut für Arzneimittelwesen, German Democratic Republic for their valuable information and advice during the research process and Ms Andrea Seitz, Wala Heilmittel GmbH for assistance with literature searches.

Funding

This work was supported by the authors’ place of work. No additional funding was received.

Contributors

L Aagaard, U Meyer, M Schaefer and EH Hansen designed the study, analysed data and wrote the first version of the manuscript. L Aagaard did the sampling. All authors saw and approved the final version of the manuscript.

Conflict of Interest Statement

We have no conflicts of interest to declare.

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