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.

ALERT- Analysis of adverse drug reactions and medication errors in adults

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

Consortium partners: Central institute for statutory health care [Zentralinstitut für die kassenärztliche Versorgung (Zi)]: Maike Below; University Hospital Bonn- Institute for Medical Biometry, Informatics and Epidemiology (IMBIE): Prof. Dr. Matthias Schmid; Department of Clinical Pharmacology and Pharmacoepidemiology at Heidelberg University Hospital (UKHD): Prof. Dr. Julia Stingl; University Hospital Bonn – Staff unit for medical-scientific technology development and coordination (MWTek): PD Dr. Sven Zenker

Background

An adverse drug reaction (ADR) is defined as a noxious and unintended reaction to a medicinal product. 20-80% of these are estimated to be avoidable. To be able to avoid ADRs, databased knowledge about the occurrence and type of ADRs as well as the associated factors, that might increase the risk, is of importance. According to the EU definition, a medication error (ME) is an unintended failure in the drug treatment process that leads to, or has the potential to lead to, harm (e.g. ADR) to the patient. MEs can occur at any step in the medication process and are considered to be preventable.

Aim

The aim of the project is the characterization of risk constellations for ADRs and MEs in adults in Germany. Within the project, a special focus shall be set on polymedicated patients, older patients and severe ADR. Subsequently recommendations for action shall be established to reduce the risk of ADR and ME.

The project can be divided into three sub-goals:

1. Generation of quantifying data regarding frequency, severity and risk factors of ADR and ME in the real world setting within Germany.
2. In-depth analysis of polymedicated patients, older patients and severe ADR to enable a conclusion on the causes of ADR and ME.
3. Creation of key facts as foundation for recommended actions.

Methodology

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

In this study, five divergent real world datasets are used:

1. ADRED-cohort: Systematically collected ADRs and MEs in a multicentered, prospective cohort study to drug associated symptoms, which led to a presentation in emergency departments
2. Spontaneous reports from the EudraVigilance (EV) database: Spontaneously submitted reports of ADRs and MEs with ADRs from healthcare professionals, patients and their relatives, with and without hospitalization.
3. Cases reported to BfArM’s ‘drug therapy safety’ (Arzneimitteltherapiesicherheit) database: Spontaneously submitted reports of MEs without or without reported ADR and potential MEs from healthcare professionals, patients and their relatives, with and without hospitalization.
4. Routine data from the Association of Statutory Health Insurance Physicians: The nationwide pharmaceutical prescription data pursuant to §300 Abs. 2 SGB V and the diagnostic data pursuant to §295 SGB X, in the outpatient sector, across all statutory health insurances.
5. Electronic health records from the University Hospital Bonn: Collection of diagnoses, drug therapies and clinical records from hospitalized patients.

In a superordinate, systematic descriptive analysis (part 1), quantifying evaluations of the reports from EV, the AMTS case collection and ADRED are performed separately in each data source. Then (Part 2), focused in-depth analyses on polypharmacy patients, elderly patients and severe ADRs are carried out in each data sources. Complementary analyses are performed in the data of the Zi and in the electronic health records of the Bonn University Hospital.

Funding

This project receives funding from the Innovation Committee of the Federal Joint Committee (G-BA; funding reference number: 01VSF24020).

EVAS – Evaluation and enhancement of analyses in spontaneous reporting databases

BfArM: Prof. Dr. Bernhardt Sachs (BfArM), Dr. Diana Dubrall (BfArM; Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), University hospital Bonn (UKB))

Cooperation: Prof. Dr. Matthias Schmid (IMBIE), Dr. Diana Dubrall (BfArM, IMBIE), Priv.-Doz. Dr. Sven Zenker (IMBIE, UKB; Department of Anesthesiology and Intensive Care Medicine, UKB; Staff Unit for Medical and Scientific Technology Development and Coordination, UKB)

Background

The continuous evaluation of the safety of drugs after marketing authorization is one important task in everyday pharmacovigilance practice. In our preceding projects „Establishment of analyses methods in the spontaneous adverse drug reaction database for the investigation of regulatory relevant pharmacovigilance issues (ADR database analyses)“ and „ANKA – Combined analyses of adverse drug reaction reports and clinical routine data using machine learning methods“ we already established methods for the analyses of spontaneous adverse drug reaction (ADR) reports in spontaneous ADR reporting databases and clinical routine data [1, 2, 3, 4, 5].
The quality and completeness of information provided in spontaneous ADR reports is crucial for the assessment of the causal relationship between drug intake and ADR occurrence. A semi-automated algorithm analysing the completeness of information of spontaneous ADR reports from the European ADR database EudraVigilance was developed in our previous project ANKA. This algorithm will be further tested and validated in EVAS.
Nowadays, around half of all spontaneous ADR reports from Germany are reported by patients and/or their relatives [6], which is why the assessment and evaluation of these reports is of significant importance and an additional task in EVAS.
In ANKA we already analysed clinical routine cases of the UKB. The potential of clinical routine data for the detection and analysis of ADRs will be further investigated in EVAS.

Aims

The overarching aim of EVAS is the evaluation and enhancement of analyses in spontaneous ADR databases. Therefore, three different research questions will be addressed:The study aims to identify and better understand both genetic and non-genetic risk factors for angioedema caused by ACE inhibitors and sartans. In this respect, it seeks to uncover how genetic mechanisms interact with individual lifestyle and environmental factors.
In the long term, a deeper understanding of these underlying biological pathways may serve as a foundation for developing new therapeutic approaches and treatment options.

1. The evaluation and enhancement of analyses in spontaneous ADR reporting databases by using automated and artificial intelligence (AI) supported applications.
2. A more deeply investigation of spontaneous ADR reports submitted by patients and their relatives to develop suggestions to further increase their value.
3. The assessment of the potential of analyses of clinical routine data for the detection and analysis of ADRs.

The project started on 01.05.2024.

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.
5. Dubrall D, Wicherski J, Below M, et al. Analyses of Adverse Drug Reactions to Fluoroquinolones in Spontaneous Reports Before and After the Referral and in Clinical Routine Cases. Drugs R D. 2025 Jan 25; https://doi.org/10.1007/s40268-024-00499-x.
6. Christ P, Dubrall D, Schmid M, Sachs B. Comparative Analysis of Information Provided in German Adverse Drug Reaction Reports Sent by Physicians, Pharmacists and Consumers. Drug Saf. 2023; 46(12): 1363-1379.

Funding

EVAS is funded by own resources of the Federal Institute for Drugs and Medical Devices and the Institute for Medical Biometry, Informatics and Epidemiology.

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.

vARIANCE – Study to investigate the risk of angioedema with angiotensin converting enzyme inhibitors

Project lead BfArM: Prof. Dr. med. Bernhardt Sachs
Contributors: Julian Hameister, Dr. Diana Dubrall, Dr. Michael Steffens

Project lead Institute of Human Genetics: Prof. Dr. med. Markus Nöthen, Prof. Dr. med. Andreas Forstner, Dr. rer. nat. Per Hoffmann
Contributors: Julian Hameister, Dr. Carina Mathey

Background

Angioedema caused by ACE inhibitors or angiotensin I receptor blockers (ARBs, commonly known as "sartans") is an acute swelling that occurs in the deeper layers of the skin or mucous membranes. It typically affects the head and neck region but can also involve other areas. While these swellings are generally not life-threatening, they can become dangerous—potentially even fatal—when they involve the tongue, throat, or larynx due to the risk of airway obstruction.
According to studies, around 0.1-0.7% of patients taking an ACE inhibitor develop angioedema during drug therapy. Despite this rather low risk for the individual patient, it is estimated that around 20,000-35,000 cases of ACE inhibitor-induced angioedema occur each year in Germany due to the widespread use of ACE inhibitors.
The precise reasons why some individuals develop angioedema while taking ACE inhibitors or sartans are not yet fully understood. However, current scientific evidence suggests that a combination of genetic predisposition and environmental or lifestyle factors is involved. Known non-genetic risk factors include for example older age (over 65), smoking, and the biological sex.

In terms of genetic risk factors, some candidate genes have been identified in association with angioedema triggered by ACE inhibitor treatments. These include, for example, the gene that codes for the bradykinin receptor (BDKRB2). In a recent meta-analysis, our research group identified a previously unknown genetic risk locus associated with ACE inhibitor-induced angioedema (Mathey et al. 2024).

Aim

The vARIANCE study is a joint research project of the Federal Institute for Drugs and Medical Devices (BfArM) and the Institute of Human Genetics at the University Hospital Bonn.

The study aims to identify and better understand both genetic and non-genetic risk factors for angioedema caused by ACE inhibitors and sartans. In this respect, it seeks to uncover how genetic mechanisms interact with individual lifestyle and environmental factors.
In the long term, a deeper understanding of these underlying biological pathways may serve as a foundation for developing new therapeutic approaches and treatment options.

Methodology

As part of the study, the genetic material (DNA) of affected patients will be examined using the latest molecular genetic analysis methods, for example whole genome sequencing. In this way, we hope to identify further genes that are causally involved in the occurrence of this angioedema.

Possible non-genetic (external) risk factors will also be investigated with the help of a questionnaire specially designed for the study. The questionnaire collects information about the type of angioedema that has occurred, the medication taken and the patients’ medical history and lifestyle habits.

References

1. Bulletin zur Arzneimittelsicherheit. Ausgabe 2. Juni 2017. „Arzneimittelinduzierte Angioödeme“ (Seite 13-23) und „Forschungsprojekt zu Arzneimittel-assoziierten Bradykinin-vermittelten Angioödemen“ (Seite 32-35).
2. Drug-induced angioedema: Focus on bradykinin. Sachs B, Meier T, Nöthen MM, Stieber C, Stingl J. Hautarzt. 2018 Apr;69(4):298-305.
3. Molecular Genetic Screening in Patients With ACE Inhibitor/Angiotensin Receptor Blocker-Induced Angioedema to Explore the Role of Hereditary Angioedema Genes. Mathey C, Maj C, Scheer AB, (…), Sachs B, Nöthen MM, Forstner AJ. Front Genet 2022 Jul 18;13:914376. doi:10.3389/fgene.2022.914376. eCollection 2022.
4. eta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus. Mathey CM, Maj C, (…), Sachs B, Nöthen MM, Forstner AJ. J Allergy Clin Immunol. 2024 Apr;153(4):1073-1082. doi:10.1016/j.jaci.2023.11.921. Epub 2024 Jan 31. PMID: 38300190.

Study website

https://variance-studie.info/

Funding

The study is funded by internal resources from the Federal Institute for Drugs and Medical Devices and the Institute of Human Genetics at University Hospital Bonn. Funding period: 2017–2028.