Paul Ehrlich Institute Research Articles

Limited availability of methods for the detection of xenotransplantation-relevant viruses in veterinary laboratories.

The German Xenotransplantation Consortium is in the process to prepare a clinical trial application (CTA) on xenotransplantation of genetically modified pig hearts. In the CTA documents to the central and national regulatory authorities, that is, the European Medicines Agency (EMA) and the Paul Ehrlich Institute (PEI), respectively, it is required to list the potential zoonotic or xenozoonotic porcine microorganisms including porcine viruses as well as to describe methods of detection in order to prevent their transmission. The donor animals should be tested using highly sensitive detection systems. I would like to define a detection system as the complex including the actual detection methods, either PCR-based, cell-based, or immunological methods and their sensitivity, as well as sample generation, sample preparation, sample origin, time of sampling, and the necessary negative and positive controls. Lessons learned from the identification of porcine cytomegalovirus/porcine roseolovirus (PCMV/PRV) in the xenotransplanted heart in the recipient in the Baltimore study underline how important such systems are. The question is whether veterinary laboratories can supply such assays. A total of 35 veterinary laboratories in Germany were surveyed for their ability to test for selected xenotransplantation-relevant viruses, including PCMV/PRV, hepatitis E virus, and porcine endogenous retrovirus-C (PERV-C). As comparison, data from Swiss laboratories and a laboratory in the USA were analyzed. Furthermore, we assessed which viruses were screened for in clinical and preclinical trials performed until now and during screening of pig populations. Of the nine laboratories that provided viral diagnostics, none of these included all potential viruses of concern, indeed, the most important assays confirmed in recent human trials, antibody detection of PCMV/PRV and screening for PERV-C were not available at all. The situation was similar in Swiss and US laboratories. Different viruses have been tested for in first clinical and preclinical trials performed in various countries. Based on these results it is necessary to establish special virological laboratories able to test for all xenotransplantation-relevant viruses using validated assays, optimally in the xenotransplantation centers.

Long-Term Stability of Cord Blood Units After 29 Years of Cryopreservation: Follow-Up Data From the José Carreras Cord Blood Bank.

The José Carreras Cord Blood Bank (CBB) located in Düsseldorf as of today stores 21 215 active cryopreserved cord blood units (CBUs) applicable as a source for hematopoietic stem cell (HSC) transplantation. Since the success of transplantation outcomes is mainly dependent on the cord blood quality, typical parameters are evaluated by a Stability Monitoring Program specified by the FACT Standards. The longest expiration time determined to date is 29 years for unseparated units, 25 years for manual and 18 years for automated volume-reduced units licensed by the Paul-Ehrlich Institute. According to the CBB stability program TNC count, TNC recovery, TNC viability, CD34+7AAD- viability, CD45+7AAD- viability and CFC count were determined for all 3 processing methods applied over time. As a measure of stability, unseparated units (processed 1993-1998) revealed a mean TNC viability of 88.91 ± 5.01% after 29 years of cryopreservation versus manual volume-reduced CBUs (processed 1998-2005) with a mean of 84.22 ± 10.02% after 25 years of cryopreservation versus automated volume-reduced CBUs (processed since 2005) with a mean of 88.64.91 ± 3.91% after 18 years of cryopreservation. In addition, these relevant parameters were retrospectively analyzed for released transplants in correlation to the storage time. Moreover, the follow-up data of recipients from CBUs cryopreserved directly (unseparated) versus CBUs cryopreserved after manual versus automated volume-reduction are presented here demonstrating an earlier engraftment in both volume-reduced groups as compared to unseparated CBUs. By this retrospective analysis, key questions are discussed regarding cord blood parameters in relation to processing methods, engraftment, and patient age (children and adults).

Dual-Temperature Microbiological Control of Cellular Products: A Potential Impact for Bacterial Screening of Platelet Concentrates?

An experimental study by the Paul-Ehrlich Institute (PEI) demonstrated that temperatures between 35 and 37 °C are too high for the growth of some bacterial strains (e.g., Pseudomonas fluorescens), leading to false negative results. Thus, the question of whether it is necessary to adapt incubation temperatures for the microbiological control of blood products, especially platelet concentrates (PCs), to enhance safety and regulatory compliance has arisen. In order to further elucidate this issue, the growth capability of different bacterial strains of interest in PCs and the detection efficacy of cultivation of these at different incubation temperatures must be taken into account. Therefore, we inoculated PCs with 46 different strains (3-6 PCs from different donors per strain) from different origins (PC isolates, reference strains) and stored PCs at 20-22 °C under constant agitation. On day three of storage, the inoculated PCs were sampled; aerobic and anaerobic culture bottles (BacT/Alert AST/NST) were each inoculated with 5 mL of sample, and culture bottles were incubated at 25 and 35 °C using the automated BacT/Alert Dual-temperature system. Bacterial proliferation was enumerated using a colony-forming assay. All strains of Enterobacteriacae (n = 5), Staphy-lococcus spp. (n = 11), Streptococcus spp. (n = 5), and Bacillus spp. (n = 4) and most Pseudomonas aeruginosa strains (4 of 5) tested showed the capability to grow in most inoculated PCs, revealing a faster time to detection (TTD) at an incubation temperature of 35 °C. The tested Pseudomonas putida (n = 3) strains showed a noticeably reduced capability to grow in PCs. Nonetheless, those with a notable growth capability revealed a faster TTD at an incubation temperature of 35 °C. Only one of the four Pseudomonas fluorescens strains tested (strain ATCC 13525) was able to grow in PCs, showing a faster TTD at an incubation temperature of 25 °C but also detection at 35 °C. The commonly detected bacteria involved in the bacterial contamination of PCs showed a superior TTD at 35 °C incubation. Only one P. fluorescens strain showed superior growth at 25 °C; however, the microbiological control at 35 °C did not fail to identify this contamination. In conclusion, the use of PC screening using a dual-temperature setting for microbiological control is presently not justified according to the observed kinetics.

Abstract 13 Long-Term Stability of Dus Cord Blood Units After >29 Years of Cryopreservation: Follow-Up Data from the José Carreras Cord Blood Bank

Abstract Introduction The José Carreras Cord Blood Bank (CBB) located in Düsseldorf stores 21215 active cryopreserved cord blood units (CBUs) and has released 1476 CBUs for allogeneic transplantation. The success of transplantations, but also the generation of cells for regenerative medicine for e.g. iPSC reprogramming, significantly depends on the quality of the cryopreserved CBUs after thaw. Objectives Therefore, typical parameters like cell count, recovery and viability are analysed from thawed CBUs yearly by a stability monitoring program according to the FACT standards. The longest cryopreservation period in liquid nitrogen tested to date is 338 months (>29 years) for unseparated units and 300 months (25 years) for volume-reduced units that are licensed by the Paul-Ehrlich Institute. Methods A retrospective analysis of unseparated CBUs processed from 1993-1997, CBUs processed from 1998-2005 by manual volume-reduction and CBUs processed since 2005 by automated volume-reduction applying the Sepax100 system was performed. In consideration of the distinct processing methods, storage time and existing follow-up data of released transplants, this approach should demonstrate the high CBU quality and proof the long-term engrafting capability of CBUs cryopreserved in liquid nitrogen. Results According to the CBB stability program means of TNC count (16.32±2.61 x 108), TNC recovery after thaw (106.8±13.91%, above 100% due to earlier applied cell-count method), TNC viability (88.91±5.01%), CD34+7AAD- viability (90.73±3.69%), CD45+7AAD- viability (69.09±5.38%) and CFC count (7.10±2.45 x 106) were determined after >29 years of cryopreservation for unseparated CBUs. In volume-reduced CBUs the mean TNC count (9.37±2.14 x 108), TNC recovery (97.78±3.70%), TNC viability (84.22±10.02%), CD34+7AAD- viability (88.11±5.16%), CD45+7AAD- viability (73.67±8.31%) and CFC count (1.37±0.59 x 106) were determined after 25 years of cryopreservation. Discussion In addition, these relevant parameters were retrospectively analyzed for released transplants in correlation to the storage time. The follow-up data of recipients from CBUs demonstrate an earlier engraftment of volume-reduced CBUs as compared to unseparated CBUs in accordance to an increased TNC count over time. With regard to applied processing methods, engraftment time and patient age (children and adults) this retrospective analysis confirms the high quality of old CBUs stored in the liquid phase at -196°C.

Single-step rapid chromatographic purification and characterization of clinical stage oncolytic VSV-GP.

Purification of viruses, especially for therapeutic purposes, is a tedious and challenging task. The challenges arise due to the size and surface complexity of the virus particles. VSV-GP is a promising oncolytic virus, which has been approved for phase I clinical trials by the Food and Drug Administration (FDA) of United States and Paul Ehrlich Institute (PEI) of Germany. The virus particles of VSV-GP are larger in size than vectors commonly used for gene therapy (e.g., adenovirus, adeno-associated virus, etc.). The current established proprietary clinical-grade manufacturing process for the purification of VSV-GP encompasses several chromatographic and non-chromatographic steps. In this study, we describe a new single-step purification process for the purification of VSV-GP virus, using cation exchange convective flow column with relatively higher yields. The purified virus was characterized for its quality attributes using TCID50 assay (for viral infectivity), host cell protein contaminant ELISA, SDS-PAGE, size exclusion chromatography (SEC), and cryo-electron microscopy. Furthermore, the purified viral therapeutic material was tested in vivo for its efficacy and safety. All these characterization methods demonstrated a therapeutic virus preparation of high purity and yield, which can be readily used for various studies.

Laboratory confirmed vaccine-induced immune thrombotic thrombocytopenia: Retrospective analysis of reported cases after vaccination with ChAdOx-1 nCoV-19 in Germany.

SummaryBackgroundVaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe adverse event of SARS-CoV-2 vaccination. We describe the characteristics of patients reported in Germany based on the Brighton Collaboration (BC) case definition criteria for Thrombosis and Thrombocytopenia Syndrome (TTS) and focus on patients with complete anti-platelet factor 4 (PF4)-antibody laboratory work up.MethodsThe adverse drug reaction database of the Paul-Ehrlich Institute was queried for TTS cases following ChAdOx1 nCoV-19 vaccination from February 1, until May 21, 2021. Cases with reports from the Greifswald laboratory were analysed in detail.FindingsPF4 antibody tests were available for 69 suspected TTS cases reported to the Paul-Ehrlich Institute, of whom 52 patients fulfilled the BC case definition; 37 (71%) women, 15 (29%) men, median age 46·0 years (interquartile range 31·0-60·3 years). Cerebral venous sinus thrombosis was confirmed in 37 (71%), (additional) multiple thromboses in 19 (37%) patients. Twelve patients died. Non-survivors showed lower platelet counts compared to survivors (median nadir 15,000/µL vs 49,000/µL; p<0·0001). Combined anti-PF4/heparin IgG ELISA and PF4-dependent platelet activation testing yielded sensitivity of 96% (95% confidence interval 87-100%) and specificity of 77% (50-93%) for TTS. Four patients with thrombocytopenia but without thrombosis presented with severe headache or cerebral bleeding, explaining the lower specificity.InterpretationVITT has high mortality and can present with isolated thrombocytopenia, severe headache, and bleeding. Demonstration of platelet activating anti-PF4 IgG has high sensitivity for TTS and captures a wider spectrum of clinically relevant VITT than the current BC case definition.FundingDeutsche Forschungsgemeinschaft: 374031971-TRR240; Domagk-Programm Universitätsmedizin Greifswald

Assessment of SARS-CoV-2 rapid antigen tests

Abstract Objectives Point-of-care antigen tests (PoC-AgTs) for the rapid detection of SARS-CoV-2 infection enable screening of additional populations with less effort, independent of laboratories and at a low cost. PoC-AgTs have therefore been included in national testing strategies with additional quality requirements to address limitations in specificity and sensitivity. Information given in the package inserts of the test providers should enable the user to evaluate the performance of a PoC-AgT in advance. The quality of this information has been independently assessed since the Corona Test Ordinance came into force in Germany in October 2020. Methods The completeness of analytical and diagnostic performance specifications was assessed for all package inserts publicly available via the Paul Ehrlich Institute (PEI). It was ascertained whether the minimum criteria, recommendations, and extended criteria of the PEI were comprehensibly fulfilled. The number of tests removed from the list by March 2021 was determined. Results By the closing date of the survey (17.11.2020), the PEI had listed 165 PoC-AgTs that formally fulfilled the minimum criteria and were thus reimbursed. A total of 78 identical systems were identified. Almost all providers were found to have gaps in the information on the validation results of their tests, meaning that an evaluation of performance is only possible to a limited extent. Until March 2021, 25 non-identical PoC-AgTs have been removed from the list. Conclusions Many PoC-AgTs could not be comprehensively evaluated based on the information provided by the provider. Users are therefore dependent on provider-independent sources of information.

Practical handling of allergic reactions to COVID-19 vaccines: Aposition paper from German and Austrian Allergy Societies AeDA, DGAKI, GPA and ÖGAI.

BackgroundFor the preventive treatment of the 2019 coronavirus disease (COVID-19) an unprecedented global research effort studied the safety and efficacy of new vaccine platforms that have not been previously used in humans. Less than one year after the discovery of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral sequence, these vaccines were approved for use in the European Union (EU) as well as in numerous other countries and mass vaccination efforts began. The so far in the EU approved mRNA vaccines BNT162b2 and mRNA-1273 are based on similar lipid-based nanoparticle carrier technologies; however, the lipid components differ. Severe allergic reactions and anaphylaxis after COVID-19 vaccination are very rare adverse events but have drawn attention due to potentially lethal outcomes and have triggered a high degree of uncertainty.MethodsCurrent knowledge on anaphylactic reactions to vaccines and specifically the new mRNA COVID-19 vaccines was compiled using a literature search in Medline, PubMed, as well as the national and international study and guideline registries, the Cochrane Library, and the Internet, with special reference to official websites of the World Health Organization (WHO), US Centers for Disease Control and Prevention (CDC), Robert Koch Institute (RKI), and Paul Ehrlich Institute (PEI).ResultsBased on the international literature and previous experience, recommendations for prophylaxis, diagnosis and therapy of these allergic reactions are given by a panel of experts.ConclusionAllergy testing is not necessary for the vast majority of allergic patients prior to COVID-19 vaccination with currently licensed vaccines. In case of allergic/anaphylactic reactions after vaccination, allergy workup is recommended, as it is for a small potential risk population prior to the first vaccination. Evaluation and approval of diagnostic tests should be done for this purpose.

A different response to cytomegalovirus (CMV) and Epstein–Barr virus (EBV) infection in UK people with multiple sclerosis (PwMS) compared to controls

The nature of past cytomegalovirus (CMV) infection in multiple sclerosis (MS) populations is relatively unexplored. Relationships between CMV infection markers and Epstein-Barr virus (EBV) infection markers in a UK resident population of people with MS (PwMS) and controls have been investigated. CMV and EBV nuclear antigen-1(EBNA-1)/virus capsid antigen (VCA) IgG levels were determined for 78 MS patients and anonymised controls by enzyme immunoassays. CMV IgG levels were expressed as Paul Ehrlich Institute (PEI) units/ml (U/ml) and EBNA-1/VCA IgG levels as enzyme units/ml. CMV IgG seroprevalence was lower (p = 0.0003) in PwMS (35.9% [95%CI: 25.2-46.5]) compared to controls (62.9% [95%CI:54.4-71.4). CMV IgG geometric mean levels in PwMS (353 PEI U/ml [95%CI:272-457]) were lower (p = 0.03) compared to the controls (492 PEI U/ml [95%CI:405-599]). EBNA-1 IgG levels were higher (p<0.0001) in PwMS compared to the controls and were lower (p = 0.238) in CMV seropositive PwMS (49.4 units/ml [95%CI:32.2-75.6]) compared to CMV seronegative PwMS (65.4 units/ml [95%CI:53.4-80.1]). These effects were not apparent with EBV VCA IgG. Several aspects of CMV and EBV infection in PwMS appear to differ compared to controls. The potential immunomodulatory effect of CMV infection on MS disease and potential interactions with EBV require further investigation.

Educational material as part of risk minimisation

Educational material, for example in the form of information booklets, checklists, patient alert cards, therapeutic passports, emergency ID cards, or videos, is an important aid for the safe use of amedicinal product or drug and supplements the summary of product characteristics and package information. It is ordered, tested and approved by the competent national authorities, the Federal Institute for Drugs and Medical Devices (BfArM) and the Paul Ehrlich Institute (PEI), and made available by the respective marketing authorization holder and published on the websites of BfArM and PEI. Educational material is part of the marketing authorization of amedicinal product. Since 1 December 2016, officially approved educational material can be recognized by the blue-hand logo in Germany. There is currently specific educational material for 202 active substances with further recommendations on how to avoid or reduce risks for patients. Although educational material is one of the most common additional risk minimisation measures, little is known about its effectiveness, including related process and outcome indicators. Key elements as well as an overview of educational material are described.

PHP222 - Advanced Therapy Medicinal Products (Atmps) In Europe 8 Years On: What Is The Path To Market Access So Far?

To examine the current EU5 market access landscape for ATMPs. Assessed the regulatory path, HTA assessments and funding mechanisms for ATMPs with EMA approval as of May 2016. Eight ATMPs are EMA approved as of May 2016. Of these, one was suspended (matrix-induced autologous chondrocyte implantation) and another withdrawn (sipuleucel-T). Germany: All ATMPs need to be authorised by the Paul Ehrlich Institute (PEI). Furthermore, the GBA could classify an ATMP as a procedure rather than a drug thereby bypassing AMNOG (e.g. autologous human corneal epithelial cells). The two ATMPs assessed under AMNOG (alipogene tiparvovec and sipuleucel-T), were both assigned “non-quantifiable additional benefit”. Talimogene laherparepvec is currently undergoing assessment with a final decision expected in mid-Dec 2016. Currently, alipogene tiparvovec is a hospital use only drug with reimbursement negotiated by the hospital and sickness funds on a case by case basis. In France, HAS assessed only two ATMPs (autologous cultured chondrocytes and alipogene tiparvovec) with reimbursement not being granted for either. Autologous cultured chondrocytes is the only ATMP that hospitals in Italy can currently import while it is available for hospital use only in Spain. Preliminary UK recommendation for autologous cultured chondrocytes and matrix-induced autologous chondrocyte implantation was for use in research only. Draft guidance on talimogene laherparepvec issued by NICE in March 2016 did not recommend use in melanoma. No other ATMP is currently routinely commissioned. All EMA approved ATMPs to date have faced EU5 market access challenges, with Germany being particularly complex. HTA assessments have been unfavourable largely due to the uncertainty with available data and – possibly – costs. The ATMP landscape is beginning to form and evolve. It will need to solidify for AMTPs to be viable for the companies seeking to market them and the patients who will benefit.

Evidence vs. efficacy in allergen-specific immunotherapy: Considerations using the example of tradable products in Germany.

The recently published S2k-guideline on (allergen-) specific immunotherapy (AIT) provides an excellent overview of the evidence on allergen preparations available for AIT in Germany based on the published efficacy studies. Publications based on the guideline are currently being used by the German associations of statutory health insurance physicians and German health insurance funds to open a discussion on the reimbursement status of allergen preparations. In our view, calling the reimbursement status of perscribable and tradable AIT preparations into question on the basis of an assessment of the current body of evidence in the guideline is to be rigidly opposed. In Germany the Paul Ehrlich Institute (PEI) is the only authority empowered to decide on the marketability of AIT preparations, and decisions on the reimbursement status of AIT products need to be based on cost-benefit analyses and not solely on an evaluation of the evidence. The present article aims to examine the relationship between the evidence, efficacy, tradability, and reimbursability of AIT preparations.

Incident reporting to BfArM - regulatory framework, results and challenges.

Medical devices are manifold and one of the most innovative fields of technology. As technologies advance, former limits cease to exist and complex devices become reality. Medical devices represent a very dynamic field with high economic relevance. The manufacturer of a medical device is obliged to minimize product-related risks as well as to demonstrate compliance with the so-called "essential requirements" regarding safety and performance before placing the device on the market. Any critical incident in relation to the application of a medical device has to be reported to the competent authority for risk assessment, which in Germany is either the Federal Institute for Drugs and Medical Devices (BfArM) or the Paul Ehrlich Institute (PEI) depending on the type of device. In this article, the German regulatory framework for medical devices and the resulting tasks for BfArM are described as well as the topics of its recently installed research and development group on prospective risk identification and application safety for medical devices. Results of failure mode and root cause analyses of incident data are presented as well as further data on cases with the result "root-cause analysis not possible". Finally an outlook is given on future challenges regarding risk assessment for medical devices.

Interplay between marketing authorization and early benefit assessment of drugs

The early benefit assessment of newly approved drugs with new active substances or new applications that came into force on 1 January 2011 still presents a challenge to the parties involved. This article highlights the interplay between drug marketing approval and early benefit assessment. The constellation of a European, and even an international, largely harmonized, drug authorization process, with a mostly nationally regulated drug reimbursement situation causes inevitably friction, which could be reduced through joint advice discussions during the planning phase for pivotal studies. In 2013, the Federal Institute for Drugs and Medical Devices (BfArM) and the Paul Ehrlich Institute (PEI) provided 439 scientific advice procedures, compared with 98 advice meetings held at the Federal Joint Committee (G-BA), for 12 of which the BfArM or PEI provided written advice. The numbers of advice meetings held at the G-BA are increasing; however, the national competent authorities are involved in only a fraction of these. From the perspective of the national competent authorities, prompt and consistent involvement in the advice procedures regarding early benefit assessment would be useful and desirable.

Risk Assessment of Single-Donor (Apheresis) Platelet Concentrates and Pooled Whole-Blood-Derived Platelet Concentrates

According to the risk estimates of the Robert-Koch-Institute (RKI) and the Paul Ehrlich-Institute (PEI) an equivalence cannot be assumed to exist between the two different platelet preparations. Differences between single-donor (apheresis) platelet concentrates (ATK) and pooled whole-blood-derived platelet concentrates (PTK) result from donor populations, donation intervals, and preparation techniques. There are no prospective randomized studies with regard to the clinical efficacy, which would unambiguously demonstrate equivalence of the therapeutic efficacy of PTK (buffy coat method) in comparison to ATK. The German Association of Blood Transfusion Services (StKB) points out that, due to the non-equivalence of PTK and ATK, it is incumbent on the transfusion physician to select the platelet concentrate, make the appropriate disclosures, and assume treatment responsibility. Proper compensation for ATK and PTK must be ensured by the health insurance companies, whereby a special indication for the selection of either PTK or ATK is not given. Exceptions are patients with known HLA antibodies in which only selected platelet concentrates may be administered. Otherwise, no indication exists in the selection of the different platelet concentrates (Article is in German).

Xenotransplantation of porcine islet cells as a potential option for the treatment of type 1 diabetes in the future.

Solid organ and cell transplantation, including pancreatic islets constitute the treatment of choice for chronic terminal diseases. However, the clinical use of allogeneic transplantation is limited by the growing shortage of human organs. This has prompted us to initiate a unique multi-center and multi-team effort to promote translational research in xenotransplantation to bring xenotransplantation to the clinical setting. Supported by the German Research Foundation, an interdisciplinary group of surgeons, internal medicine doctors, diabetologists, material sciences experts, immunologists, cell biologists, virologists, veterinarians, and geneticists have established a collaborative research center (CRC) focusing on the biology of xenogeneic cell, tissue, and organ transplantation. A major strength of this consortium is the inclusion of members of the regulatory bodies, including the Paul-Ehrlich Institute (PEI), infection specialists from the Robert Koch Institute and PEI, veterinarians from the German Primate Center, and representatives of influential ethical and religious institutions. A major goal of this consortium is to promote islet xenotransplantation, based on the extensive expertise and experience of the existing clinical islet transplantation program. Besides comprehensive approaches to understand and prevent inflammation-mediated islet xenotransplant dysfunction [immediate blood-mediated inflammatory reaction (IBMIR)], we also take advantage of the availability of and experience with islet macroencapsulation, with the goal to improve graft survival and function. This consortium harbors a unique group of scientists with complementary expertise under a cohesive program aiming at developing new therapeutic approaches for islet replacement and solid organ xenotransplantation.

Experiences and recommendations of the German Federal Institute for Drugs and Medical Devices (BfArM) concerning clinical investigation of medical devices and the evaluation of serious adverse events (SAE)

An integral part of the conformity assessment process for medical devices is a clinical evaluation based on clinical data. Particularly in the case of implantable devices and products of risk class III clinical trials must be performed. Since March 2010 applications for the authorization of clinical trials as well as for the waiver of the authorization requirement must be submitted centrally in Germany to the appropriate federal authority, the Federal Institute for Drugs and Medical Devices (BfArM) or the Paul Ehrlich Institute (PEI). In addition to authorization, approval by the responsible ethics committee is also required under law in order to begin clinical testing of medical devices in Germany. In this paper, the legal framework for the clinical testing of medical devices as well as those involved and possible procedures including evaluation criteria for the initial application of a trial and subsequent amendments are presented in detail. In addition, the reporting requirements for serious adverse events (SAEs) are explained and possible consequences of the evaluation are presented. Finally, a summary of application and registration numbers for all areas of extensive experience of the BfArM as well as requests and guidance for applicants are presented.

Medical devices. Regulatory framework and contribution of the German Federal Institute for Drugs and Medical Devices (BfArM) to the safe application

Medical devices are of great importance for the prevention, diagnosis and treatment of many diseases. With their broad range and interdisciplinarity, they represent both a very dynamic field of innovation and a significant sector of the economy. The European and thus the German Medical Devices Act aim in this context to make new medical devices for patients and users rapidly available while ensuring safety and performance at the same time. The main responsibility for this lies with the manufacturer. In addition, others are involved in a complex collaboration in the conformity assessment and also later in the marketing phase for the early identification, assessment and minimization of potential risks. This paper presents the legal framework for medical devices and the related roles and responsibilities of various stakeholders, especially the two federal agencies the German Federal Institute for Drugs and Medical Devices (BfArM) and the Paul Ehrlich Institute (PEI). From the perspective of the BfArM the procedure and criteria for risk assessment of incident reports are explained and the experiences and wishes from regulatory practice are described. The active engagement of the BfArM to contribute knowledge from the incident report assessment within the relevant standards organisations and the medical profession is described using examples of medical devices from the field of out-of-hospital ventilation. The paper concludes with a look at future challenges, e.g. in combination products, IT networks and automatization, as well as on current developments to improve risk identification and assessment in a European context.

Testing of medicinal products produced from pooled plasma

Medicinal products produced from human plasma fall under the administrative batch release procedure of the competent authority. In Germany, this has been carried out since 1995 by the Paul Ehrlich Institute (PEI), the responsible state control agency for blood products. Medicinal products released for the European and national market are tested for quality, efficacy and safety. Experimental testing of the final product and the starting materials, the plasma pools, as well as control of the production documentation guarantee a constantly high product safety. In the 28,000 batches tested since the beginning of the state controlled batch release testing of these blood products at the PEI, there has been no transmission of infectious viruses (HIV, HBV and HCV) to any patient. The batch release has made a contribution to the improvement of product quality. This procedure is still an important tool to ensure safety of blood products. The PEI is integrated in the batch release network of the European Directorate for the Quality of Medicines & Health Care (EDQM) in Strasbourg. Regulations and guidelines for official control authority batch release (OCABR) ensure harmonized procedures for mutual recognition of batch release on the European level. The EU certificates and German national certificates are requested and accepted in over 70 countries worldwide. Experimental testing in the EU and the requisite certificates have developed into a seal of quality for the world market.

Batch release of immunoglobulin and monoclonal antibody products

The Paul-Ehrlich Institute (PEI) is an independent institution of the Federal Republic of Germany responsible for performing official experimental batch testing of sera. The institute decides about the release of each batch and performs experimental research in the field. The experimental quality control ensures the potency of the product and also the absence of harmful impurities. For release of an immunoglobulin batch the marketing authorization holder has to submit the documentation of the manufacture and the results of quality control measures together with samples of the batch to the PEI. Experimental testing is performed according to the approved specifications regarding the efficacy and safety. Since implementation of the 15th German drug law amendment, the source of antibody is not defined anymore. According to §32 German drug law, all batches of sera need to be released by an official control laboratory. Sera are medicinal products, which contain antibodies, antibody fragments or fusion proteins with a functional antibody portion. Therefore, all batches of monoclonal antibodies and derivatives must also be released by the PEI and the marketing authorization holder has to submit a batch release application. Under certain circumstances a waiver for certain products can be issued with regard to batch release. The conditions for such a waiver apply to the majority of monoclonal antibodies.