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

Lise Aagaard, Marion Schaefer, Ulrich Meyer, Ebba Holme Hansen Department of Pharmacology and Pharmacotherapy, Section for Social Pharmacy, Faculty of Pharmaceutical Sciences, University of Copenhagen, Copenhagen, Denmark FKL-Research Centre for Quality in Medicine Use, Copenhagen, Denmark Danish Pharmacovigilance Research project (DANPREP), Copenhagen, Denmark Institut für Klinische Pharmakologie, Charitè University Medicine, Berlin, Germany Institut für Pharmazie, Ernst Moritz Arndt University, Greifswald, Germany E-mail: laa@farma.ku.dk Received June 11, 2011; revised July 22, 2011; accepted August 2, 2011


Introduction
During the 1960s, in the wake of the thalidomide catastrophe in the late 1950s [1], pharmacovigilance systems were established in many western European countries, Canada and Australia [2].The World Health Organization (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 20 th century, a separate pharmaceutical policy system was established in the previous Council for Mutual Economic Assistance (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 Comecon 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 prescribers and patients, as such type of information was considered as being a state secret and only available to 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 indometacin (Metindol/Amuno), diclofenac (Rewodina), phenylbutazone (Butazolidin), aminophenazone + phenylbutazone (Wofapyrin) and the antidiarrheal Mexaform plus (phanquinon + dichlorhydroxychinolin) and dichlorhydroxychinolin (Endiaron) existed, but no restrictions for the use of these products were made [4].For the X-ray contrast agent iomeglamic acid (Falignost) several serious cases of allergies and anaphylactic shocks were reported which led to changes in the production, as radiographic 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.

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 identification of the medicine user.ADR reports were provided by the Uppsala Monitoring Centre (UMC) as CIOMS reports, and data from these reports were manually 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.

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.

Classification of reported ADRs
Any ADRs reported were classified according to the international classification system Medicinal Dictionary for Regulatory Activities (MedDRA) by preferred term (PT) and (SOC) [8].

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 Arzneimittelwesen 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 laboratory data if available (internal documents).

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 (prescription medicine, over-the-counter medicine, complementary medicine, herbals, homeopathic medicine, allergen 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 medicines 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 GDR Ministry of Health.Medicines imported from Western countries had to be paid with Western currencies, 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].

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.Approximately 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 general practitioners and 12% of ADRs were reported by specialist physicians.Serious ADRs were only reported by hospital physicians.No ADRs were reported by pharmacists.

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 adolescents (ages 11 -17).Forty percent of ADRs was reported for males and sixty percent of ADRs for females.

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).

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 systemic use (19% of ADRs), and medicines for the cardiovascular system (16% of ADRs).

Discussion
This is the first study to retrospectively analyse spontaneous 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 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 submitted 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 causality 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 authorities had been higher, but reports included in this study only represent those reported to VigiBase.In general, the ADR reports were of high quality and thorough, but due to their low number, they only represent a limited 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.

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.

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

Table 1 . Characteristics of serious adverse drug reactions leading to death reported to Vigibase, German Democratic Repub- lic, 1985-1990. Case no. Year ATC group Medicine Active substance Adverse drug reaction (ADR) Indication Gender Age (year)
NA: not *vailable; mo: months.