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Establishment of analysis methods in the spontaneous adverse drug reactions (ADR) report database for the investigation of regulatory relevant pharmacovigilance issues (ADR database analyses)

Project Lead: Prof. Dr. Bernhardt Sachs, Prof. Dr. J. Stingl, Dr. Norbert Paeschke, (BfArM); Contributers: Diana Dubrall

Cooperating institute: Prof. Dr. Matthias Schmid, Institute for Medical Biometry, Informatics, and Epidemiology (IMBIE), University Hospital of Bonn

Background:
One central task of the German Federal Institute for Drugs and Medical Devices (BfArM) is to monitor the safety of medicinal products. An essential methodological element of this regulatory monitoring of medicinal product safety is the spontaneous adverse drug reaction (ADR) reporting system.
Spontaneous ADR reports are unsolicited reports by physicians, pharmacists, patients or other sources, of suspected cases of adverse drug reactions (ADRs) occurring with the widespread, everyday use of a medicinal product.
Spontaneous ADR reports play an important role, as clinical trials prior to medicinal product approval can include only a limited number of selected patients. The limitations of these studies mean that rare ADRs, as well as those that only occur in certain vulnerable patients or after prolonged use, cannot be reliably detected. Additionally, new ADRs may occur during the medicinal product lifecycle, such as in the event of other indications for use or novel co-medications.
In Germany, health professionals (physicians, pharmacists etc.) are obliged by their professional conduct code, as also pharmaceutical companies according to the Medicinal Products Act §63 to pass on suspected cases of ADRs to the competent authorities. The spontaneous ADR reports are stored in an ADR database (since 22.11.2017: the European ADR database EudraVigilance) and can be analysed by means of computers.

Aims:
The aim of this project is to establish analytical methods that enable the targeted and scientifically sound investigation of potentially relevant pharmacovigilance issues beyond routine possibilities. The overall regulatory objective is the transfer of research results to the regulatory departments of the BfArM.
As an initial step a high level overview, general descriptive analysis of all spontaneous ADR reports in BfArM’s ADR database is carried out. Among others, this analysis is intended to determine how many reports are available which active substances and ADRs are most frequently reported, and from whom the ADRs originate (e.g. physicians, pharmacists, patients).

Methods:
Search algorithms will be generated for computer-based database queries and the results will be analyzed both from a biostatistical and a medical point of view. The methodology will then be established using three predefined questions as examples, i.e. drug-induced angioedema, photosensitive reactions and ADRs possibly in context with genetic polymorphisms.
From the medical point of view the causal relationship and the correctness of the diagnosis of the ADR reports will be evaluated on the basis of accepted international/national criteria. Depending on the number of cases, a representative sample will be analyzed, in order to extrapolate the estimates to the entire number of cases.
The biostatistical analyses foresee among others disproportionality measures (PRR, ROR), chi-square tests, Bayesian methods, and propensity scores. For the investigation of potential risk factors (e.g. comedications, underlying diseases), groups for comparison will be generated in the ADR database itself using random sampling and/or matching methods. If robust data for the exposure with the drugs of interest are available, these exposure data may be linked to the number of ADR reports for the respective medicinal product.

First results:
Descriptive analysis of spontaneous reports in the ADR database [1].

The number of spontaneous ADR reports received by BfArM has continuously increased during the analysis period 1978 (start of recording) until 2016. At the highest, summarizing hierarchy level, BfArM’s ADR database most frequently contained suspected ADR reports referring to "drugs for the treatment of nervous system disorders". At the level of the therapeutic subgroups, the most frequently reported suspected drugs with their most frequently reported ADRs are:

  • anti-thrombotics - thrombocytopenia
  • systemic antibiotics - diarrhoea
  • psycholeptics - drug dependence

Analysis according to the reporting sources revealed that patients more commonly reported subjectively perceived ADRs, while physicians more commonly reported findings or diagnoses that require medical expertise.

Reference:
[1] Dubrall D, Schmid M, Alešik E, Paeschke N, Stingl J, Sachs B. Frequent adverse drug reactions, and medication groups under suspicion - a descriptive analysis based on spontaneous reports to the German Federal Institute for Drugs and Medical Devices from 1978–2016. Dtsch Arztebl Int 2018;115(23):393-400.

Funding:
This project received funding from BfArM’s own resources and the Institute for Medical Biometry, Informatics, and Epidemiology (IMBIE), University Hospital of Bonn. Period of funding: 2016-2019.

Pharmgen_Angioedema – Characterization of molecular and external factors of potential impact in
bradykinin-mediated angioedema by the example of ACE-inhibitor or angiotensin receptor blocker induced angioedema

Project lead BfArM: Prof. Dr. Bernhardt Sachs; Contributors: Carina Mathey, Michael Steffens and others; BfArM

Project lead Institute of Human Genetics: Prof. Dr. med. Markus Nöthen, coordination: Dr. Christiane Stieber, Institute of Human Genetics, University Hospital of Bonn

Background:
The occurrence of angioedema upon treatment with drugs that affect the degradation of bradykinin, such as ACE-inhibitors or angiotensin receptor blockers (ARBs), is a known risk. The incidence of angioedema in patients treated with ACE-inhibitors is reported to be 0.1 - 0.7 % in Europeans. In Germany the absolute number of ACE-inhibitor induced angioedema is estimated to range between 20,000 and 35,000 cases per year owing to the huge use of ACE inhibitors. The occurrence of these angioedemas is not predictable and depends on the individual characteristics of the patient. Hence this joint research project with the Institute of Human Genetics at the University of Bonn does not focus on the drug, but on the individual risk factors of the patients.

Purpose:
The objective of this study is to characterize pharmacogenetic factors of potential impact in bradykinin-mediated angioedema by the example of ACE-inhibitor or ARB-induced angioedema. The secondary objectives of the study encompass the analysis of the patient’s history, including basic diseases, concomitant medication and lifestyle factors, such as smoking. The study’s high-level aim is to examine whether patient populations with a clearly higher risk can be identified enabling the introduction of appropriate risk-minimizing measures. In addition, the collected data will be used to build up a register for ACE and ARB-induced angioedema (without reference to personal data, initially limited for 20 years).

Methods:
On the genomic level both exploratory and focused analyses will be carried out. The explorative analyses will initially focus on array-based characterizations of frequent DNA sequence variations and their evaluation in genome-wide association studies (GWAS) of angioedema induced by ACE-inhibitors or ARBs. In later investigations, the rarer DNA sequence variations will be analysed in more detail based on exome (entire coding sequence) - or genome-sequencing. The focussed analysis will employ high-resolution investigations of pharmacogenetic candidate genes.
In order to characterize epigenetic factors, initial analysis of the DNA methylation status and further investigations of other epigenetic DNA modifications are planned.
The secondary targets are evaluated descriptively in the cases. For this purpose the following aspects, among others, will be addressed in a questionnaire: family burden with regard to angioedema, co-medication, basic and accompanying diseases, basic epidemiological parameters, smoking, potentially associated factors (operations, stress) and information on the incriminated drug.

References:
Bulletin zur Arzneimittelsicherheit. Ausgabe 2. Juni 2017. „Arzneimittelinduzierte Angioödeme“ (Seite 13-23) undForschungsprojekt zu Arzneimittel-assoziierten Bradykinin-vermittelten Angioödemen“ (Seite 32-35)

Funding:
This project received funding from BfArM’s own resources and the Institute of Human Genetics of the University Hospital Bonn. Period of funding: 2017-2021.

KiDSafe - Improving the supply of children and adolescents with medicinal products by increasing the
safety of medicinal product therapy

BfArM (consortium partner): Sarah Leitzen, Prof. Dr. Bernhardt Sachs, Prof. Dr. Julia Stingl

Consortium Lead:
Kinder- und Jugendklinik Erlangen, PD Dr. rer. nat. Dr. med habil. Antje Neubert

Cooperating consortium partners:
Universitätsklinikum Erlangen, Dr. Margarete Fischer-Bosch-Institut (IKP Stuttgart), Bundesinstitut für Arzneimittel und Medizinprodukte, Universitätsklinikum Würzburg, Universitätsmedizin Mainz, Universitätsklinikum Leipzig, Universitätsklinikum Aachen, Universität Leipzig, BIPS Bremen, Techniker Krankenkasse, Deutsche Gesellschaft für Kinder- und Jugendmedizin (DGKJ), Bundesvereinigung Deutscher Apothekerverbände (ABDA)

Background:
The efficacy and safety of medicinal products is often investigated in adults only. As a result, many medicinal products are used off-label in children, i.e. outside their approved indication or other approval conditions. According to international studies about 42-90% of children and adolescents are treated off-label in hospitals and 46-64% are treated off-label in the out-patient sector. This off-label use can be associated with an increased risk of ADRs since the organism of children and adolescents is still developing and thus may react differently to the medicinal product as it is the case in adults.

Purpose:
The aim of KiDSafe is to improve medicinal product safety in children and adolescents and to reduce the risk of ADRs. The aim of the research project at BfArM is to create a parallel, descriptive analysis of the ADRs reported within the framework of KiDSafe and the ADRs available in BfArM’s ADR database, in particular taking into account off-label use, medication errors and any quality defects reported. This will be realised within the framework of a PhD project.

Description of project and methods:
The project is a structured quality assurance measure that provides evidence-based information and specific recommendations for the use of medicinal products in children and adolescents to physicians who treat children and adolescents, as well as to pharmacists.
KiDSafe comprises three modules:
Module 1: Use of a web-based drug information system with a dose database (PaedAMIS)
Module 2: Participation in pharmacological quality circles (PaedZirk)
Module 3: Systematic recording of ADRs and medication errors in children and adolescents (PaedReport). This module has two objectives:

  1. generating relevant signals from KiDSafe with regard to medicinal products safety, especially concerning the off-label use in paediatrics
  2. laying a foundation for an optimized pediatric spontaneous reporting system for ADRs and medication errors based on the experience gained with KiDSafe, since a continuously intensified reporting in off-label use could increase the safety of medicinal product use in children

BfArM participates in module 1 by compiling regulatory information on approved medicinal products. Furthermore, BfArM works primarily in module 3 according to the following research aspects:

  1. a descriptive analysis of ADRs reported within KiDSafe, in particular regarding off-label use, medication errors and reported quality defects
  2. a parallel comprehensive descriptive analysis of ADR reports concerning children and adolescents in BfArM’s ADR database. ADR reports will be analysed with regard to concerned age groups, suspected drugs and reported ADRs. The focus is on ADR reports in which an off-label use, a medication error and indications for quality defects were reported.
    In addition, a systematic analysis of data reported in the medical literature referring to ADR reports in children with a focus on off-label use as well as on further ADRs that may come into focus within the project.

These research aspects of the KiDSafe project are related to a BfArM research project* that investigates pharmaceutical quality, efficacy and safety of heat-sterilized glucose solutions which are also used in children and adolescents, with regard to resulting glucose degradation products after steam sterilization. For both projects, a descriptive analysis of reports informing about quality defects in glucose solutions will be carried out in BfArM’s and the European ADR database.

*Title: „Impact of the addition of selected drugs to heat-sterilized glucose solutions for parenteral administration with respect to quality, efficacy and safety“

Funding:
This project is funded by the Innovation Committee for the funding announcement “New forms of care” by the Federal Joint Committee. Funding reference number: 01NVF16021.