Networking of Eye Hospitals on a National Level for Promoting and Advancing Conduct of Clinical Trials

The complexity of clinical studies is increasing for all partners involved. This applies to any area of medicine, public-funded investigator-initiated trials as well as industry-driven trials, sponsors as well as study centers and impacts all stages of a study, from planning, preparation, implementation, and actual conduct. To overcome these various challenges at ophthalmological study centers, the exchange of experiences and cooperation between the centers appears particularly prudent and useful. In multicenter trials, synergies could be used during study preparations, patient recruitment, and trial conduct, thereby gaining time and efficiency. This is possible, for example, through centrally managed negotiations of the contract and study budget.

All study centers are under pressure between the legitimate requirement to cover costs by law [1] and on the part of their administrations and, on the other hand, sponsors or Clinical Research Organizations (CROs), which offer remuneration that may either be based on clinical routine or a “fair market value.” Nevertheless, it is not uncommon that a study procedure according to the trial protocol and manuals requires 10 times the time than same procedure in clinical routine.

Today, a professional study team in ophthalmology that each center must set up for a specific study often includes more than 20 medical and nonmedical members. Financial as well as academic interest of clinical trial sites must be prioritized. Therefore, for example, naming all contributors on clinical trial publications would seem important and objectively justified both for the motivation of the individuals and for their academic careers [2, 3].

In this paper, we describe measures and approaches that were developed in the DOG Working Group Clinical Study Centers in order to avoid inefficiency in the study preparation of ophthalmological multicenter studies, to promote joint action by the German study centers involved, to represent the academic and economic interests of the centers, to negotiate fair remuneration for study achievements, to increase the quality of study implementation of ophthalmological trials, to qualify study teams, and to intensify the dialogue with industry. We describe these activities for ophthalmology here, but they may definitely serve as a role model for other medical professional associations and – beyond national borders – be applicable to other countries for the benefit of study quality and the sake of interests of study sites.

The activities of the working group (WG) are shown in detail in Table 1 from its founding up to and including 2023.

Since its founding in 2011, the number of members and the effectiveness of the WG have grown steadily (see Table 1). Regular group meetings take place twice a year, at the AAD and DOG annual conferences, while the exchange in between these meetings is also lively. Solutions can be found quickly via the mailing list, especially for current study questions and problems. This means that even small study centers can always benefit from support from the WG in all respects. The primary aim of the group was to provide a platform for exchange between the study centers – namely, the entire team of medical as well as nonmedical members of the study groups – on all study-relevant topics. From the beginning, it was important that study coordinators were heard and involved in all meetings equally. To provide a forum for informal exchange on practical study questions, a study coordinator meeting usually follows the WG meetings. The agendas of the WG meetings always include “hot topics” in clinical studies such as institutional overhead, recruitment problems, consultation studies, and – of high importance – academic interests of young physicians involved in clinical trials.

To improve recruitment at all sites, a patient video “Participating in a clinical study: is this something for me?” (DOG Video Award 2022; [4]) was created with study patients. This video is available to the public, namely, other site participation in clinical trials, even beyond ophthalmology [4]. The continuous exchange regarding general topics of clinical trials with industry and regulatory bodies has always been a focus of the WG and resulted in their participation in symposia organized by the WG (see Table 1).

A specific initiative to promote the attractiveness of Germany as study location has been started together with industrial partners committed to ophthalmology. In joint actions, we plan to promote the image of clinical trials and improve recruitment strategies.

Since 2017, courses on clinical study topics have been offered at the annual large meetings. These initially focused on mandatory training courses on Good Clinical Practice, in which emphasis was placed on as many practical exercises and interactivity as possible.

After a regulatory update to the requirements for medical investigators, these Good Clinical Practice courses were only required if investigators were not continuously working in clinical trials or when national or EU laws changed, these courses were suspended. Great demand for better qualifications for calculating study budgets led to a new course of the WG on these aspects. Here too, practical exercises including role plays, for example, negotiations, are important elements.

Shortly after the founding of the WG, the first DOG recommendation was prepared and published (2014, updated 2018): recommendations for the planning and implementation of research projects on behalf of third parties [5]. It recommends central (coordinating investigator) negotiations and describes the legal framework, and important and often neglected cost areas such as study preparations, overhead, longer time requirements for study procedures compared to clinical routine, effort for audits and inspections, premature termination of studies, serious adverse events, and consultation studies. These are studies from other disciplines in which ophthalmological examinations have to be carried out, usually to determine the safety of drug therapy.

The next DOG recommendation prepared by the WG concerned publication regulations in multicenter studies [3]. In the past, and in some cases still today, the scientific interests of the physicians working on studies have been sometimes disregarded. Based on the ethical principles of the International Committee of Medical Journal Editors (ICMJE), the obligation to publish study results is emphasized and clear rules for authorship are described, which must be observed, especially in large multicenter studies. In this process, too, the coordinating investigator has a central role and responsibility to ensure that the rights of the study doctors involved are protected [3].

A further approach of the WG was a nationwide survey of ophthalmological study centers that recorded time spent on different tasks of clinical trials over a longer period and resulted in the finding that most of the time is spent on documentation and administration and this is true for any member of the study team. Interestingly, even senior physicians who were very experienced in studies significantly underestimated the time required for examinations, procedures, or processing of biospecimens themselves. The study results underlined that the time required for study-related activities is in no way comparable to clinical routine and can therefore only be calculated based on the time needed [6].

In the future, further recording will shed light on collaboration with medical contract institutes (CROs). In the last 2 decades, sponsors have increasingly delegated regulatory and organizational study tasks to such companies. As a rule, CROs represent the main interface for collaboration with the participating study centers. The main purpose of their involvement is to support the study centers in achieving maximum study quality. The study centers merged in the WG experience a varying quality of collaboration with CROs. In the future, these experiences will be systematically recorded by the participating centers and evaluated by the WG or the coordinating investigator. A special questionnaire was developed and published by the WG [7].

The DOG Working Group Clinical Study Centers will continue to be committed to all study-related topics in ophthalmology as described above. All topics addressed in this article do also apply to publicly funded clinical trials: quality of trial performance by qualified study teams, budget calculations, efficacy of patient recruitment, fair publication regulations for all involved physicians, etc. All phases of clinical trials deserve increased public funding because industry-sponsored trials will never cover all scientific questions around optimal treatments. For example, head-to-head studies may definitely be of public health interest and in need of public funding. In addition, many preclinical developments are derived from university research institutions, and many clinical questions derive from hospital physicians’ clinical experience. Therefore, it seems more than logical to perform clinical trials embedded in the academic setting. Most study centers of the WG participate in publicly funded clinical trials as well as industry-driven clinical trials which are mandatory to make a novel treatment enter the market and available to.

Based on considerable joint interests and goals, a continuous dialogue with the industry has been established with the aim to promote Germany as a study location in ophthalmology. So far, some of the opportunities that arise in ophthalmology through the existence of the WG as a possible coordination point and, for example, through the favoring of central negotiations ([5]), have not been used much by the industrial partners hitherto. This surprises because central negotiations of contracts and budgets are also a recommendation of the most recent VFA study ([8]). An early contact by the industry with the WG in the preparation phase of ophthalmological studies could lead to time savings and more efficiency of study processes.

The German university institutions (MFT and VUD), together with the pharmaceutical industry (VFA), have developed and published important joint statements on study budgets and general aspects of clinical studies [9]. In recent years, important milestones have been achieved jointly by VFA and German University Medicine; for example, mutually agreed model contractual clauses are now available in German and English [10‒12]. Their use (which the WG is strongly supporting) will lead to drastic time savings in the preparation of clinical studies in Germany and thus reduce a significant location problem.

Significantly increasing challenges in clinical studies over the past decades and the need to position themselves together in this situation led to the German clinical study centers in the DOG founding a WG in 2011. In this, exchange and joint action have become possible, from study preparations including negotiations on contracts [5] and study budgets to opportunities for improvement in the recruitment of suitable patients [4], optimal patient care and overcoming study-specific stumbling blocks to protecting academic interests of young physicians in study groups when publishing study results [13].

The DOG is the oldest medical professional association in the world and, according to current research, also the only specialist society in Germany which provides a WG for clinical study centers. Table 2 shows an overview emphasizing that there are practically no WGs or sections within other medical societies in Germany focusing on clinical trials to the same extent. This is surprising and offers the unique possibility to use the WG as a template for other societies. The WG pursues the goal of increasing the quality of studies in Germany both in IITs and in studies sponsored by either public funding or the industry (training courses). The WG aims at qualifying study centers for excellence in trials (training courses) and of promoting the interests of German study centers in all directions (course offerings; regular exchange with industrial sponsors and regulatory bodies).

At the European level, the EVICR network [14] has been indispensable in the field of ophthalmology for 2 decades and has an important role and function as a contact point for sponsors in the search for study centers for industrial studies, but above all as a coordination point for European IITs, research-initiated multicenter trials. Most sites associated in the German WG are also certified members of the EVICR network. In addition, and completion, it is essential that there is a joint WG on the national level in which study centers organize, support, and represent common interests.

As identical challenges related to clinical trials definitely apply for other disciplines in medicine and not only in our country, the WG may serve as a model to be useful and helpful for other areas of medicine and in other nations. On each national level, there is a high need for joint action and exchange between participating study sites.

In summary, we present our WG, its development, strategies, and activities here to motivate and encourage other medical societies in Germany and furthermore, medical societies of other countries, to use this as template for their own clinical trial work and interests. All strategies described here can be followed independent from potential differences regarding regulatory frameworks or research infrastructures.

Adeline Adorf, Universitätsklinikum Münster (UKM); Sabine Aisenbrey, Vivantes Klinikum Neukölln; Katharina Allgeier, Universitätsklinikum Freiburg; Isabella Baur, Universitätsklinikum Augsburg; Anna Beck, Augenklinik, Universitätsmedizin Mainz; Eckart Bertelmann, Charité Universitätsmedizin Berlin; Daniel Böhringer, Univ.-Augenklinik Freiburg; Christian Karl Brinkmann, Dietrich-Bonhoeffer-Klinikum, Neubrandenburg; Lars Choritz, Univ.-Augenklinik Magdeburg; Christoph Deuter, Universitätsklinikum Tübingen; Christoph Ehlken, Klinik für Augenheilkunde, Kiel; Verena Anna Englmaier, Universitätsklinikum Münster; Nicole Eter, Univ.-Augenklinik Münster; Silvia Falkenau, Univ.-Augenklinik Münster; Nicolas Feltgen, Universitätsspital Basel, CH; M. Dominik Fischer, Universitäts-Augenklinik Tübingen; Monika Fleckenstein, University of Utah, USA; Luise Fornoff, Augenklinik des Klinikums der Stadt Ludwigshafen; Sigrid Freissinger, Vivantes Klinikum Berlin; Thomas Armin Fuchsluger, Universitätsklinikum Rostock; Olga Furashova, Klinikum Chemnitz; Maria-Andreea Gamulescu, Universitätsklinikum Regensburg; Maximilian Gerhardt, Klinikum der Universität München; Daniela Goos, Universitätsklinikum Freiburg; Melanie Haar, Medizinische Hochschule Hannover; Carsten Heinz, Augenzentrum am St. Franziskus-Hospital Münster; Frank G. Holz, Univ.-Augenklinik Bonn; Herbert Jägle, Universitätsklinikum Regensburg; Stephanie Joachim, Universitäts-Augenklinik; Vinodh Kakkassery, Klinikum Chemnitz; Katarzyna Kallus, Universitätsmedizin Göttingen; Andrea Kapfelsberger, Universitätsklinikum Tübingen; Hakan Kaymak, MVZ Breyer, Kaymak, Klabe, Oberkassel; Ulrich Kellner, MVZ Augenärztliches Diagnostik-und Therapiecentrum Siegburg GmbH; Ramin Khoramnia, Univ.-Augenklinik Heidelberg; Vanessa Klabunde, Universitätsmedizin Göttingen; Christina Korb, Univ.-Augenklinik und Poliklinik, Mainz; Andrea Koschinski, Augenzentrum am St. Franziskus-Hospital; Christine Kremer, Universitätsklinikum Freiburg; Caroline Kümmet, Studienambulanz der Universitäts-Augenklinik Würzburg; Larissa Lahme, Augenklinik UKM, Münster; Monica Lang, Augenklinik Darmstadt; Stefanie Leidigkeit, Universitätsklinikum Freiburg; Sandra Liakopoulos, Department of Ophthalmology, Köln; Raffael Liegl, Universitätsaugenklinik Bonn; Katrin Lorenz, Augenklinik der Universitätsmedizin Mainz; Angela Maischein, Augenklinik des Klinikums der Stadt Ludwigshafen; Anna Mangold, Universitätsmedizin Göttingen; Anja Mayer, Universitäts-Augenklinik Bonn; Leonie Menghesha, Augenklinik Uniklinik Köln; Anke Messerschmidt-Roth, Philipps-Universität Marburg; Elisabeth M. Messmer, Univ.-Augenklinik München; Anna Milverstaedt, Augenklinik des Klinikums der Stadt Ludwigshafen; Fanni Eszter Molnar, Univ.-Augenklinik; F. Mühmel, Klinikum Chemnitz; Stefanie Otto, Augenklinik Marburg; Tobias Peters, STZ eyetrial am Department für Augenheilkunde, Tübingen; Kristina Pfau, Universitäts-Augenklinik Basel, CH; Amelie Pielen, Universitätsklinik für Augenheilkunde, Hannover; Matus Rehak, Universitätsklinik für Augenheilkunde und Optometrie, Med. Universität Innsbruck, AU; Andrea Rindtorff, STZ eyetrial am Department für Augenheilkunde, Tübingen; Denise Ruch, Augenzentrum am St. Franziskus-Hospital Münster; Marc Schargus, Asklepios Klinik Nord – Heidberg; Stefanie Schmickler, Augenzentrum Nord-West, Ahaus; Frank Schüttauf, Klinik und Poliklinik für Augenheilkunde, UKE Hamburg; Anne Schwietering, Universitätsklinikum Freiburg; Dorina Seger, Universitätsklinikum Freiburg; Georg Spital, Augenarztpraxis, Münster; Dmitrij Subbotin, Johannes Gutenberg Universität Mainz; Svenja Tamm, Klinik und Poliklinik für Augenheilkunde; Regensburg; Daniela Vollhardt, KKS Marburg-Gießen; Bettina von Livonius, Univ.-Augenklinik München; Christian K. Vorwerk, Augen-MVZ Prof. Vorwerk, Magdeburg; Anja Wienigk, Klinikum Chemnitz; Barbara Wilhelm, STZ eyetrial am Department für Augenheilkunde, Tübingen; Stephanie Winterhalder, Universitätsklinikum Freiburg; Melanie Ziegler, STZ eyetrial am Department für Augenheilkunde, Tübingen; Sonja Zobel, Studienambulanz der Universitäts-Augenklinik Würzburg; Caroline Zurmühlen, Klinik für Augenheilkunde, Münster.

B.J.W: financial: STC eyetrial at the Centre for Ophthalmology, University Hospitals Tübingen, Tübingen, Germany, and Egon Schumacher-Stiftung; nonfinancial: speaker of the DOG (German Society of Ophthalmology) Clinical Study Centers Working Group. F.G.H: financial: Acucela, Allergan, Apellis, Bayer, Biogen, Bioeq/Formycon, Roche/Genentech, Geuder, Heidelberg Engineering, Iveric Bio, Pixium Vision/Science, Novartis, Zeiss, Alexion, Alzheon, Annexon, Astellas, Boehringer Ingelheim, Grayburg Vision, Janssen, Lin BioScience, Stealth BioTherapeutics, Aerie, Oxurion, Oculis, and 4DMT; nonfinancial: founding member of the DOG (German Society of Ophthalmology) Clinical Study Centers Working Group. K.L: financial: Department of Ophthalmology of the University Medical Center Mainz, Ethikkommission der Landesärztekammer Rheinland-Pfalz, Bayer, Novartis, and Roche; nonfinancial: speaker of the DOG (German Society of Ophthalmology) Clinical Study Centers Working Group.

No funding source was used for the current manuscript, nor the Working Group described in the manuscript.

B.J.W., F.G.H., and K.L. have accepted responsibility for the entire content of this manuscript, consented to its submission to the journal, and reviewed and approved the final version of the manuscript.

The content of this paper was presented as a poster at the annual meeting of the German Society of Ophthalmology (DOG) Conference 2023.