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.

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].

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.

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.

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.

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).

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.

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).

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.

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].

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.

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.

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

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.

We have no conflicts of interest to declare.