Drug allergies depend on the individual characteristics of the patient and, unlike most other adverse drug reactions (ADRs), are therefore typically unpredictable. Although they account for a smaller proportion of all ADRs, some of these reactions, such as anaphylaxis or angioedema (swelling of the face), can be severe and potentially life-threatening.

Due to their visibility, cutaneous ADRs are more easily recognized than ADRs in other organs. The clinical spectrum ranges from mild rashes to life-threatening diseases that lead to blistering and detachment of large areas of the skin. In addition, cutaneous ADRs can also indicate ADRs affecting other organs.

Dedicated pharmacovigilance questions refer for example to the occurrence of ADRs in particularly sensitive patient groups such as children or the elderly.

Head of the Research group

Unscheduled (außerplanmäßiger) Prof. Dr. med. Bernhardt Sachs

Telephone: +49-(0)228-99-307-3156
E-Mail: bernhardt.sachs@bfarm.de

Curriculum vitae

Publications

The Research group

Projects

MEKIH - Analyses of medication errors in children and adolescents and development of recommendations for action

BfArM (consortium partner): Prof. Dr. Bernhardt Sachs, Dr. Claudia Kayser, Dr. Diana Dubrall [University Hospital Bonn- Institute for Medical Biometry, Informatics and Epidemiology (IMBIE)], Severin Domgörgen

Universitätsklinikum Erlangen (consortium lead): Prof. Dr. Antje Neubert (Department of Paediatrics and Adolescent Medicine), Dr. Armin Ströbel (Center for Clinical Studies), Dr. Irmgard Toni (Department of Paediatrics and Adolescent Medicine)

Background

According to the EU definition a medication error (ME) describes an unintended failure in the drug treatment process that leads to, or has the potential to lead to, harm to the patient. Compared to adults, children and adolescents are more likely to be affected by potential adverse drug reactions related to ME. This higher risk, among others, is related to only limited data being available concerning the use of some drugs in children and adolescents, missing dosing information, as well as inappropriate dosage forms and complex dosage calculations.

Aim

The aim is to identify risk constellations for ME based on the analysis of reports on (potential) ME in order to develop recommendations for actions to prevent ME in the future.

Methodology

This is a retrospective, exploratory, non-interventional, pharmaco-epidemiological study.

In this project three different datasets of ME reports in children and adolescents will be analysed:

1. KiDSafe‐cohort: systematically collected reports of ME which led to hospitalisation in twelve German hospitals, further information: https://kinderformularium.de/sign_in/kidsafe (in German)
2. Spontaneous reports from the EudraVigilance database: spontaneously submitted reports of ME with and without hospitalisation reported by health care professionals, patients and their relatives
3. Cases reported to BfArM’s ‘drug therapy safety’ (Arzneimitteltherapiesicherheit): ME with and without hospitalisation as well as potential ME reported by health care professionals, patients and their relatives

The reports of the three datasets differ regarding the methodology of the data collection, the quantity of reports and the reporting source, thereby enabling a broader approach towards the analysis of ME in children and adolescents.

Funding

This project receives funding from the Innovation Committee of the Federal Joint Committee (G-BA; funding reference number: 01VSF22045).

KerXeM - Development and characterisation of human in-vitro keratinocyte cell culture models to address research topics in dermatopharmacology and drug allergy

Project lead: Federal Institute for Drugs and Medical Devices (BfArM): Prof. Dr. Bernhardt Sachs (BfArM), Philipp Deck (BfArM; University of Bonn)

Consortium partner: Rheinische Friedrich Wilhelms University University of Bonn, pharmaceutical institute: Prof. Dr. Günther Weindl, University Hospital RWTH Aachen (UKA), Department for Dermatology and Allergology: Prof. Dr. Amir Yazdi, University Hospital Bonn (UKB), Department for Urology: Prof. Dr. Guido Fechner

Background

Beside its main function providing a protection barrier against external factors the skin also possesses distinctive immunological and metabolic properties. In particular keratinocytes are capable to metabolize xenobiotics via various enzymes (biotransformation). In addition, as non-professional antigen-presenting cells (APC) they can present antigens to T cells and thereby induce immunological responses.

These properties are also of regulatory interest for the Federal Institute for Drugs and Medical Devices (BfArM) since allergic skin reactions are frequently reported adverse drug reactions and metabolization of drugs in the skin is relevant in terms of dermatopharmacology.

Aims of the project

The overall aim of the project is to develop and characterize human in-vitro keratinocyte cell culture models to address research topics in dermatopharmacology and drug allergy.

The project can be divided into the following sub-goals:

1. Establishment of in-vitro keratinocyte skin models in 2D/3D-structure with extracellular matrix components.
2. Analysis of selected xenobiotic-metabolizing enzymes at the level of gene and protein expression.
3. Analysis of the functional biotransformation of selected drugs with suitable analytical methods.
4. Analysis of the effects of generated metabolites on the keratinocytes in the culture models.

Funding

This project received funding from own resources of the Federal Institute for Drugs and Medical Devices and the Pharmaceutical Institute of the Rheinische Friedrich-Wilhelms-Universität Bonn. The funding period is 3 years.

WOLGA - Further development, optimization and application of an algorithm for the detection of serious adverse drug reactions on the basis of claims data

BfArM (Consortium partner): Prof. Dr. Bernhardt Sachs, Dr. Diana Dubrall, Patrick Christ

Consortium Lead: Prof. Dr. Ulrike Haug, Prof. Dr. Pigeot, Dr. Oliver Scholle, Leibniz Institute for Prevention Research and Epidemiology – BIPS, Contributers: Nikolaj Rischke

Background

Serious adverse drug reactions (ADRs) which lead to hospitalisation have far-reaching consequences for both patients and the health care system.

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 (ADR) occurring with the widespread, everyday use of a medicinal product. These spontaneous ADR reports are forwarded to the European Medicines Agency and stored in the European database EudraVigilance. Analyzing spontaneous ADR reports allows, among others, the detection of previously unknown as well as rare ADR that occur under certain conditions (e.g. certain comorbidities) or in particularly vulnerable populations (e.g. children, pregnant women, elderly people).

Besides spontaneous ADR reports, insurance data represent a valuable database for the recording and characterization of serious ADR. The pharmacoepidemiological research database GePaRD of the Leibniz Institute for Prevention Research and Epidemiology (BIPS) contains pseudonymised accounting data of four German statutory health insurances and includes claims data of more than 25 million persons.

With a view to detect ADR-related hospital admissions based on hospital routine data in Germany, algorithms have been developed which, however, are subject to certain limitations.

Aims

The aim of this project is the optimization of an algorithm for the detection of ADR related hospital admissions. This optimized algorithm should enable a continuous monitoring of insurance data, with regard to the occurrence of serious ADR and the identification of risks and vulnerable patient groups.

This in turn is a decisive basis for the development of concepts to avoid (serious) ADR, thereby improving patient safety and reducing costs for the health care system.

Methods

As a first step, a research strategy will be defined to investigate ADR related hospitalizations in both the EudraVigilance and the GePaRD database.

As a second step a qualitative and quantitative analysis of all ADR related hospitalizations identified in the insurance data as well as in EudraVigilance will be performed.

Based on this comparison, it is planned to assess the potential of the identification and characterization of ADR related hospitalizations by the use of insurance data and to optimize the algorithm.
In a feasibility study it is planned to develop new strategies to crosslink ADR related hospitalization reports of both sources on a case level.

Funding

This project received funding by the Federal Joint Committee, 01VSF19018

KIAM - AI-based expression analysis of marker genes for the in vitro detection of drug sensitization

BfArM (Consortium partner): Prof. Dr. Bernhardt Sachs, Dr. Andreas Glässner

Life & Brain GmbH Bonn (Head of consortium): Prof. Dr. Markus Nöthen, Dr. Per Hoffmann

University Hospital RWTH Aachen, Clinic for Dermatology and Allergology (Consortium partner): Univ.-Prof. Dr. Amir Yazdi, Dr. Gerda Wurpts

Background

Drug allergies are a particularly relevant form of allergy. The diagnosis of drug allergies is currently based on:

1. Medical history and classification of the clinical phenotype of the reaction.
2. In vivo tests: prick, intracutaneous and epicutaneous test. These skin tests can be time consuming, have limited sensitivity and are standardized for few active ingredients only.
3. In vitro (laboratory) tests: These consist of i) methods for the detection of specific antibodies (IgE) in immediate-type reactions which are available for a few drugs only and ii) cell-based test systems such as the lymphocyte transformation test (LTT).
4. Provocation tests: These tests bear the risk of an allergic reaction and are therefore often rejected by patients. They are contraindicated, if a severe allergic reaction had occurred in the medical history.

In summary, the currently available methods to diagnose a drug allergy are limited. In contrast, there is a great need for a reliable method, which can be used in routine diagnostics. This method should be safe, not stressful for the patients, and not too time consuming. In this respect, in vitro tests are particularly suitable as they only require a blood sample to be taken from the patient and provide the opportunity to test more than one suspected drug.

Preceding work - INA project

In the last decades, great progress has been made in the analysis of the genome-wide gene (=transcriptome) as well as protein (=proteome) expression with regard to costs, measurement accuracy and time of analysis. Hence, these methods have found their way into broad scientific application now. Therefore, the aim of a previous project of the applicants (INA, project code: EFRE-0801755) was to develop a test procedure which can be used for the in vitro detection of a drug allergy applying current methods for gene and protein expression. The project was funded by the European Fund for Regional Development (EFRE). As a starting point, the LTT was applied to stimulate peripheral blood mononuclear cells (PBMC) in vitro with the suspected drug (LTT platform). Subsequently, PBMC were analyzed for drug-specific activation with respect to the transcriptome and proteome. Here, differences in gene and protein expression should be identified that could serve as novel markers for the in vitro detection of a drug sensitization.

Aims of the project

The KIAM project is based on the preceding work of INA. The overall aim of KIAM is the development of a website prototype with a user-friendly interface, where, after entering expression data for marker genes, AI-based algorithms will predict the drug allergy status of the person. The expression of the marker genes in the PBMC will be determined by real-time PCR. Prior to this, the reliability of the marker genes identified in the INA project will be determined.

This method of a personalized in vitro diagnostic of drug allergies should be prospectively applicable in the broader routine diagnostics in health care.

Project description and methods

The project will analyze patients with a confirmed drug allergy and control subjects without allergy to the drug of interest. PBMCs will be isolated from blood samples and co-incubated with the culprit drug. After completion of the co-incubation, gene expression in the PBMC will be analyzed by real-time PCR with respect to the identified marker genes.

The main working steps of this project are (lead partners in brackets):

1. recruitment of patients with a confirmed drug allergy and control persons without drug allergy (Clinic for Dermatology and Allergology, University Hospital RWTH Aachen)
2. isolation of PBMC from patients and control persons and co-incubation of these PBMC with the culprit drug followed by isolation of their RNA (Federal Institute for Drugs and Medical Devices, BfArM)
3. analysis of gene expression by real-time PCR (Life & Brain GmbH).
4. bioinformatic analysis of the data (Federal Institute for Drugs and Medical Devices).
   

Funding

This project is funded by the state of North Rhine-Westphalia (ZukunftBio.NRW) and by own resources of the involved partners. Funding period: 9/2023 - 9/2025.

ANKA - Combined analyses of adverse drug reaction reports and clinical routine data using machine learning methods

Project Lead: Prof. Dr. Bernhardt Sachs (BfArM), Dr. Diana Dubrall (BfArM, IMBIE);

Cooperating partners: Prof. Dr. Matthias Schmid (IMBIE), Dr. Diana Dubrall (BfArM, IMBIE), Priv.-Doz. Dr. Sven Zenker (IMBIE; Staff Unit Medical-Scientific Technology Development and Coordination (MWTek), University Hospital of Bonn, Germany, Department for Anaesthesiology and Operative Intensive Care Medicine (KAI), University Hospital Bonn, Germany)

Background

One of the major tasks in drug safety is the continuous surveillance of adverse drug reactions (ADRs) after marketing approval. In the preceding project “Establishment of analysis methods in the spontaneous adverse drug reactions (ADR) report database for the investigation of regulatory relevant pharmacovigilance issues (ADR database analyses)”, methods for analyzing ADR reports in ADR databases were established [1, 2, 3, 4]. However, these analyses are subject to certain limitations such as the unknown amount of underreporting and the lack of drug prescription data. In order to increase the significance of ADR database analyses these should be considered in context with other complementary data such as demographical data of the respective population, the number of drug prescriptions, data with regard to specific diseases, or data derived from the analyses of ADR databases from other countries.

In addition to the analyses of aggregated data, the significance of ADR database analyses can be increased by performing individual assessments of each ADR report or a random sample thereof. Individual case assessments refer to the evaluation of the causal relationship (between the ADR and the intake of the reported suspected drug), and the quality and completeness of the information provided in each ADR report. Such individual case assessments are a very time consuming process. This prompted us to search for methods to preselect well-documented cases with an at least possible causal relationship.

Aim

The aim of the project is to increase the significance of ADR database analyses by putting the results in context with analyses in other complementary databases such as databases containing drug prescription data or ADR databases from other countries.

Among others, application of machine learning methods are envisaged. In addition, it is planned to establish conditions to preselect - based on machine learning methods - well documented ADR reports with an at least possible causal relationship.

The project started on 01.12.2020, more information will follow.

References

1. Dubrall D, Schmid M, Alešik E, Paeschke N, Stingl J, Sachs B. Frequent Adverse Drug Reactions, and Medication Groups under Suspicion. Dtsch Arztebl Int. 2018 Jun 8; 115(23): 393-400.
2. Sachs B, Dubrall D, Fischer-Barth W, Schmid M, Stingl J. Drug-induced anaphylactic reactions in children: A retrospective analysis of 159 validated spontaneous reports. Pharmacoepidemiol Drug Saf. 2019;28(3):377-388.
3. Dubrall D, Just KS., Schmid M, Stingl JC, Sachs B. Adverse drug reactions in older adults: a retrospective comparative analysis of spontaneous reports to the German Federal Institute for Drugs and Medical Devices. BMC Pharmacol Toxicol 21, 25 (2020).
4. Dubrall D, Schmid M, Stingl JC, Sachs B. Angioedemas associated with renin-angiotensin system blocking drugs: Comparative analysis of spontaneous adverse drug reaction reports. PLoS One. 2020 Mar 26;15(3):e0230632.

Running time

01.12.2020 - 31.12.2023

Funding

The Project is funded by the Federal Institute for Drugs and Medical Devices (BfArM) own resources and the Institute for Medical Biometry, Informatics, and Epidemiology (IMBIE), University Hospital of Bonn.

vARIANCE – 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) und „Forschungsprojekt 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.