Medical science and technology are making rapid progress. We need comprehensive clinical research and trials to make sure that we can use the latest innovations in a safe and efficient way. Public and private funding programmes provide research teams with the necessary financial support.

In Austria, however, there used to be a lack of programmes that enabled the staff of university hospitals to join long-term projects and teams to carry out clinical trials. The Clinical Research Groups funding programme of the Ludwig Boltzmann Gesellschaft makes up for this shortcoming. The first call for proposals was organised in 2022, and the first three clinical research groups to be funded by the programme were then presented in September 2023. These three projects – MOTION, ATTRACT and the Austrian Digital Heart Program – will receive up to 8 million euros for up to 8 years.

This document briefly introduces the topic of clinical research and trials and presents the status of clinical research in Austria as well as the Clinical Research Groups funding programme of the Ludwig Boltzmann Gesellschaft. At the end of the document, you’ll find interviews with Dr. Thomas Reiberger, head of one of the funded research groups, and Dr. Elizabeth Eisenhauer, an internationally renowned expert in clinical trials.

Basic research in the life and social sciences and new technologies such as machine learning are providing promising results for various new prevention, diagnosis and treatment options and new approaches based on personalised medicine. With lifestyle-related diseases and antibiotics resistance on the rise and in the face of newly emerging infectious diseases, we need to study all these factors using a solid and comprehensive scientific approach. This will allow us to foster innovative ideas to deal with these challenges.

The translation of basic research in the fields of human biology and medicine into concrete treatment and therapy options for patients is a central aspect of clinical research. But scientific findings are not only transferred from labs to clinics. Doctors and healthcare practitioners in general gather important experiences in the field of medicine as part of their everyday work, and these serve as a source of ideas for clinical research.

Clinical research is carried out by medical universities, non-university research institutions and pharmaceutical companies. The tasks of medical universities cover three central categories: research, teaching and patient care. University clinics treat patients and carry out basic research, translating the results into new applications. They also provide ongoing and further training for medical and non-medical staff and junior scientists.

Controlled, randomised and double-blind studies are the gold standard. Controlled, randomised studies involve two groups of patients: one group receives a drug, while the other receives a non-effective placebo. Individual patients are randomly assigned to these two groups. Double-blind means that neither the patients nor the doctors in charge know which group receives the drug and which group receives the placebo. This guarantees that study results will be as accurate as possible. There are also non-interventional studies in which patients receive no new drugs and are only subjected to routine examinations.

Clinical drug trials comprise four phases. In Phase I trials, new drugs are tested on 10 to 50 subjects, usually healthy individuals. The goal is to collect data on tolerability, effects and side effects, undistorted by any diseases. Phase II trials aim to prove a drug’s efficacy and determine the required dosage. They involve 50 to 200 patients affected by a specific disease. Phase III trials study hundreds to thousands of subjects at different hospitals over a period of up to several years to prove a drug’s therapeutic efficacy and identify any rare side effects. A positive outcome of the Phase III trial is a precondition for an application for drug approval. Phase IV trials study the effects of long-term use of approved drugs.

This double function means that all university hospitals and their staff are subject to both the pressure of economic competition and the academic pressure to publish scientific papers. Patient care takes up a lot of time and thus competes with teaching and clinical research for the working hours of the staff at university hospitals, so that in many cases medical experts can only dedicate time to the latter in the later stages of their career. Providing more funding options can help to address this problem.

In its 2016 Future Strategy for Life Sciences and the Pharmaceutical Sector, the Austrian Ministry of Education, Science and Research (BMBWF) placed a particular focus on clinical research, which underlines this sector’s significance for research in Austria and aims to make the country a leader in this field.

In the latest performance agreement period, the Austrian Ministry of Education, Science and Research (BMBWF) has cooperated with the medical universities to make clinical research a priority. Measures in this context include funding coordination centres for clinical trials, establishing physician scientist programmes, and streamlining administrative processes between medical universities and hospital operators, as well as updating the rules governing ethics review committees to make them comply with the provisions of the new Clinical Trials Regulation (CTR). The FWF and the BMBWF have also cooperated to define a strategy for KLIF, the FWF’s funding programme for clinical research, with the aim of defining the best possible framework and goals for the programme and establishing a solid basis for its successful implementation.

The Anniversary Fund of the Oesterreichische Nationalbank, Austria’s central bank, was also dedicated to funding clinical research before its strategy was redefined in 2020. In addition to national funding programmes, the EU also contributes significant funds within the framework of Horizon 2020 and the European Research Council (ERC).

In 2016, the Austrian Research Council criticised the lack of funding for the staff of clinics. More funding would enable them to use more time and resources for clinical research teams, as well as for long-term projects and translational studies, which then ultimately result in an improvement of patient care. There is clear evidence that hospitals where clinical research is carried out achieve better treatment results, including for patients who do not participate in any clinical trials. Funding programmes dedicated to research groups enable junior scientists, in particular, to carry out clinical research alongside their work as physicians and thus enhance their career opportunities. The Austrian Research Council has identified a funding gap, which is addressed by the FWF’s funding programmes, but only to a certain extent. To finally close this gap, the Ludwig Boltzmann Gesellschaft launched a funding programme for clinical research groups in 2022.

The Ludwig Boltzmann Gesellschaft (LBG) is an independent research institution focusing on interdisciplinary health research and the translation of research findings into medical practice. The LBG supports a multitude of institutes which are committed to research in many different medical areas, ranging from oncology to rehabilitation, and also study structural aspects such as digital health.

Its Open Innovation in Science Center is a research and competence centre for open and collaborative research. One of its programmes is the Cancer Mission Lab, a funding programme for innovative project ideas to improve cancer prevention and diagnosis as well as quality of life for cancer patients.

Clinical Research Groups Funding Programme

In 2016, the Austrian Research Council stated that there was a lack of targeted funding programmes for non-commercial clinical research which, firstly, enable an efficient translation of findings and, secondly, allow young medical professionals to advance their academic careers. To close this gap and catch up with international leaders such as Germany, the Netherlands, Sweden and the UK, the LBG’s funding programme now provides long-term funding for clinical research groups. The goal is to create research associations and consortia in which experts from different fields and institutions work together, thus establishing research expertise for the long term and strengthening Austria’s position as a research centre at the international level. The Clinical Research Groups programme was delegated to the Ludwig Boltzmann Gesellschaft by the BMBWF. The Ministry played a major part in the programme’s development to ensure that it would complement other funding programmes and thus promote clinical research efficiently and in a targeted way.

Applications can be submitted for projects involving clinical trials (phases I to III) or other non-commercial clinical studies in combination with clinical pilot or accompanying studies carried out at Austrian medical universities or faculties which operate university hospitals, in cooperation with other institutions. If a project is selected for funding, it receives 0.5 to 1 million euros per year for a period of four years. After four years, an intermediate evaluation is carried out. If the evaluation result is positive, the funding period can be extended by a further four years.

A clinical research group may consist of 5 to 15 people whose clinical and non-clinical experience is expected to underline the project’s interdisciplinarity. Special emphasis is placed on diversity, equal opportunities and inclusion, both among researchers and in their research projects. The programme requires that at least a third of a group’s heads, deputy heads and sub-project managers must be women.

To support the research careers of young medical professionals, the deputy heads move up to the head positions of the research group after the intermediate evaluation, while other researchers get the opportunity to become deputy heads. In this way, researchers first gain experience as deputies and can then assume leadership responsibilities.

Another special feature of this funding programme is that mentors are part of the research groups. Mentors are researchers who are well established or hold a leading position at a clinical research institution and thus provide the applicants and their teams with a direct contact to the respective institution’s structures, support them with strategic experience and give them access to their wider network. This kind of support helps to ensure that the researchers are given the necessary leeway and resources at their research institutions.

The funding programme’s first call in 2022 was endowed with 16 million euros from the Federal Ministry of Education, Science and Research (BMBWF) and with 8 million euros from the Future Fund of the Republic of Austria. Between September and November 2022, 44 short proposals were submitted and then evaluated by a commission of research experts. Eight applicants were selected and invited to submit full proposals. The full proposals were peer-reviewed, and the applicants were interviewed by the expert commission. Finally, Austria’s Federal Minister of Education, Science and Research selected three research groups which had been recommended by the commission. Each of the groups will receive up to 8 million euros for a period of eight years. The three research groups which were selected in the programme’s first call are MOTION, ATTRACT and the Austrian Digital Heart Program.

MOTION

The portal vein transports blood from the abdominal organs to the liver. Increased pressure in this vein can lead to serious complications in patients with liver diseases such as cirrhosis. As part of the MOTION research project, Dr. Thomas Reiberger and his team are testing new treatments for portal vein hypertension in three clinical studies at the Division of Gastroenterology and Hepatology in cooperation with the Divisions of Anaesthesia and Radiology of the Medical University of Vienna and the CeMM Research Center for Molecular Medicine. In these studies, they are exploring new applications for existing drugs to treat different symptoms. Dr. Michael Trauner supports the MOTION team as a mentor.

The first study involves patients suffering from portal vein hypertension who are in the early stages of liver cirrhosis, which means that their liver is still fully functional. For a period of 12 weeks, participants are given telmisartan, a hypotensive drug that is already used to treat other diseases. The goal is to study the drug’s effects on portal vein hypertension.

In the second study, the participants are patients whose liver function is reduced due to liver cirrhosis. They receive norfloxacin, an antibiotic which acts mainly on the intestinal flora. The researchers hope that this might help to reduce intestinal bacteria and inflammatory mediators migrating from the intestines into the blood transported by the portal vein and thus reduce the pressure inside it.

In the third study, patients suffering from liver vessel disorders are treated with edoxaban, an anticoagulant. This study is a cross-over study, which means that a group of patients is observed for one year and then receives the drug for one year. Another group of patients is treated first and then observed. Previous studies have already delivered promising results concerning the drug’s effectiveness.

The MOTION research group cooperate closely with the Division of Anaesthesia, where the medical professionals have extensive experience with patients suffering from liver cirrhosis, and with colleagues from the Division of Radiology, who are using machine learning to develop new non-invasive diagnostic and prognostic methods. They also cooperate with the CeMM, whose experts help them to better understand the underlying interactions between portal vein hypertension and blood vessel cells.

ATTRACT

Glioblastomas are the most frequent malign brain tumours in adults, coming with a very bad prognosis, high mortality rates and a high symptom burden. In spite of intensive efforts, research has not achieved any breakthroughs for new therapies so far. This is partly due to the limited availability of active agents in the brain and the tumours’ frequent resistance to chemotherapy, targeted drugs and immunotherapy. A genetic defect occurring in 60 to 70 percent of glioblastoma patients results in a particularly strong resistance to chemotherapy. Under the auspices of the ATTRACT project, Dr. Anna Sophie Berghoff and her team are exploring new individualised methods for treating glioblastomas. A number of partners are working together on this project: the biomedical research centre CBMed, the medical universities at Innsbruck, Graz and Vienna, Karl Landsteiner University of Health Sciences, the university hospital at St. Pölten, Johannes Kepler University Linz, Danube Private University and the Austrian Institute of Technology. Dr. Matthias Preusser is the project’s mentor.

The ex-vivo drug screening platform developed by the CBMed, which is one of only five such platforms worldwide which are accessible to academics, is the ATTRACT project’s centrepiece. A machine can test the effectiveness of various drugs based on tumour cells extracted from the patients. In the study, 28 different active agents are tested ex vivo, i.e., outside the patients’ bodies, before the patients undergo treatment, thus enabling individualised therapies.

Another goal of the study is to build a new data base to collect and systematically store information on tumours, digitalised tissue samples of these tumours, and active agents and their efficacy, as well as clinical information for further functional and translational research. The idea is to use machine learning to analyse the data base and identify new biomarkers on the platform. This will help researchers to gain new insights into the functioning of glioblastomas and thus develop new treatments.

Austrian Digital Heart Program

Approx. 60 million people worldwide are affected by atrial fibrillation, making it the most frequent cardiac arrhythmia. In many cases, atrial fibrillation remains undiagnosed, increasing the risk of stroke, heart failure and embolism, i.e., blockage of blood vessels. What makes diagnosing atrial fibrillation even more difficult is that it often occurs only sporadically and causes few or even no symptoms, particularly in elderly patients. As a consequence, in 30 percent of all cases the disorder remains undiagnosed until complications occur. Under the auspices of the Austrian Digital Heart Program, Dr. Sebastian Reinstadler and his team are using an innovative digital approach to diagnose and treat the disorder at an early stage.

Previous studies have revealed that Austria has a high need for wide-ranging early detection methods: the country has the fourth highest rate of atrial fibrillation among men and the highest rate among women in all of Europe. At the Department of Cardiology and Angiology at the hospital of the Medical University of Innsbruck, Reinstadler and his team are working with experts from the Medical University of Graz and the Austrian Institute of Technology to develop a smart phone application which enables the user to test for atrial fibrillation. The user has to hold a finger up to the smart phone’s camera, and the device measures the circulation in the finger based on its red colouration, and can also determine the user’s heart rate and any irregularities.

Similar applications are already available on the market, but it is a challenge to actively reach the most affected demographic groups. The goal is to target the app primarily at elderly people, for whom atrial fibrillation can frequently lead to complications. Another priority for the team of the Austrian Digital Heart Program is to integrate their study data into the public health system via the Austrian electronic health record ELGA, in compliance with data protection provisions.

Reinstadler hopes that this pioneering project, which is mentored by Dr. Axel Bauer, will succeed in creating a blueprint for future digital studies in Austria and beyond.

Which disorder does the MOTION project address?

The project deals with portal vein hypertension, a frequent and serious complication of chronic liver diseases, particularly of cirrhosis or liver scarring, but also of liver vessel disorders without scarring. Portal vein hypertension can lead to internal bleeding, which has a high mortality rate, because blood from the blocked vessels may leak into the digestive tract. Ascites is another serious complication, which may result in pain, infections in the abdominal cavity and sepsis.

A reduction of portal vein hypertension in patients suffering from liver diseases improves their prognosis. However, no new treatment has been approved for more than 40 years now. And the currently available drug therapy with non-selective beta-blockers only works for just over 50 percent of patients. This means that there is a high clinical need which has not yet been addressed. The goal of our project is to meet this need.

What clinical trials are you carrying out as part of the MOTION project?

We are conducting three double-blind, controlled and randomised studies. In the first study, patients at an early compensated stage of liver cirrhosis are treated with the purpose of pushing back the scarring process. We administer telmisartan, an angiotensin receptor blocker, for twelve weeks. We expect this treatment to bring about a reduction in portal vein pressure, which will not occur in the placebo group.

In the second study, we treat patients suffering from advanced, decompensated liver cirrhosis with norfloxacin, an antibiotic which is only absorbed to a limited extent and works mainly in the intestines and on the intestinal flora. Norfloxacin is also tested in a randomised 12-week study against a placebo group. We hope that the intestinal microbiome will improve and that fewer gut bacteria and fewer inflammation mediators will migrate into the blood in the portal vein, which would then reduce the stress on the liver and the systemic circulation. We expect that to result in a reduction of portal vein pressure.

In the third study, patients suffering from blood vessel disorders in the liver, but not cirrhosis, are treated with edoxaban, a novel and direct anticoagulant agent. Our goal is to reduce portal vein pressure, as patients with blood vessel disorders in the liver are often prone to the formation of blood clots, particularly thromboses, in the area of the portal vein. In this study, patient groups are randomised in a cross-over design. This means that patients in one group receive treatment for one year and are then observed for one year, while patients in the other group are first observed for one year and then receive treatment. We are using this approach to establish the safety of this therapy, as bleeding is a possible complication of portal vein hypertension. Initial experimental studies and clinical data suggest that treatment with anticoagulant agents, including edoxaban, has a good safety profile and is effective.

Our clinical studies are complemented by mechanistic, translational and basic research that we carry out at the Divisions of Gastroenterology and Hepatology, Anaesthesia and Radiology of the Medical University of Vienna together with our partners at the CeMM of the Austrian Academy of Sciences, in particular research group leader Dr. Laura de Rooij.

Why do we need funding programmes for clinical research groups like the one run by the Ludwig Boltzmann Gesellschaft?

Due to the extensive regulations and high fees imposed by the European Medicines Agency (EMA) for conducting clinical drug trials and the sensible but far-reaching ethical provisions, it is currently almost impossible for clinicians to conduct academic drug trials, by which I mean trials that are not supported by the pharmaceutical industry. The existing funding programmes of the FWF and other agencies mainly provide funding for basic research. Up to now, there was no adequate funding for clinical research using drugs. Why? Because it is generally assumed that the pharmaceutical industry will pay for drug testing. However, most of the active agents that we use in our studies are no longer protected by patents. This means that the industry is no longer interested in funding our drug trials. In some cases, our research is also “risky” as we use drugs for applications and indications for which they have not been approved.

Disadvantaged and stigmatised patient groups suffering from liver diseases such as hepatitis C are often accused of causing their diseases through alcohol or drug addiction, and are thus blamed for their own suffering. These groups will benefit especially from the funding provided by the Ludwig Boltzmann Gesellschaft for our MOTION research group. Thanks to this funding programme we have the unique opportunity in the field of hepatology to conduct clinical trials with promising drugs independently of the pharmaceutical industry to develop effective treatments for our patients suffering from portal vein hypertension.

What makes clinical research and clinical trials so important?

While basic research provides us with hypotheses about potential new treatments and diagnostic methods, clinical trials are the only way to find out if the findings of basic research can be translated into positive effects for humans. Unfortunately, treatments which are effective in mice or other animals often do not have the same effect in humans. Toxicities or side effects other than those expected may occur, and the drugs may also be less effective.

The COVID pandemic has provided us with some very good examples of how dangerous it is to assume that treatments that appear to be effective in the lab will also work in human patients. Hydroxychloroquine, for example, was touted as an effective treatment for COVID, until well-designed clinical trials showed that it actually had no effect. Similarly, ivermectin was also commended as a treatment – until clinical studies showed that it was not effective. This underlines how naive we are sometimes when it comes to drawing conclusions from basic research findings for applications in humans, and why we must explore the safety, toxicity and use of treatments in well-designed trials overseen by ethics review committees and official regulatory authorities.

How are the findings of basic research translated into clinical trials?

The ideas for clinical trials mainly come from two sources. The first is the translation of the results from working with lab models of diseases. However, before a new treatment can be administered to patients, lab studies have to be carried out to prove its safety in animals and determine the dosage. The production of a new drug also has to comply with international regulations. After all the data have been collected, a protocol for clinical trials in patients can be drawn up.

The second source of ideas for clinical trials is the clinic itself. Clinicians and other people working in patient care may make observations or come up with questions based on what they see in practice. As an example, for many years we were convinced that the treatment of breast cancer required removal of the entire breast, parts of the chest wall and the axillary lymph nodes. But many doctors – and patients too – started to wonder if this was really necessary in the light of new findings about how breast cancer spreads. So the question was: is it possible to perform less drastic surgery and still achieve the same results? This resulted in a big clinical trial in which the former “standard” surgery was compared to a less aggressive surgical procedure. And it turned out that the less aggressive procedure was just as effective. This result has fundamentally changed the way we treat breast cancer. Clinicians and patients often voice misgivings or wonder if there might be different treatment approaches – and this results in trials to answer questions such as: What if we combine two drugs? Or what if we performed less surgery? Or what if we complemented an existing drug with another drug that is already available? These are the kind of questions that are raised in the clinical setting.

What kinds of funding systems are there and what are their respective pros and cons?

The way clinical trials are funded varies greatly around the world. In some disciplines, and particularly in oncology, it became evident some decades ago that research programmes which fund a group or network for clinical studies are very efficient. Groups or networks of this kind can conduct research projects or trials year after year, in contrast to repeatedly financing individual projects. Financing individual clinical studies on a project-by-project basis can help create an efficient network, but as soon as a project is over, the participants part ways and you have to establish a new network for the next project. Programme-based funding of academic clinical research networks allows these networks to attract and retain highly qualified personnel. In many countries, the government provides basic funding for such networks to support the research infrastructure. These groups then raise additional funds from the private sector or charitable foundations to support individual projects.

Private sector funding will always be important for certain trials. The industry has an intrinsic interest in ensuring that high-level studies are conducted using its products. This is why they sometimes cooperate with academic research groups and networks. In such cases, it is still the academics who oversee the studies. Alternatively, companies can conduct trials themselves on a project-by-project basis by recruiting institutions and clinicians to carry out the trial, while overseeing it themselves.

All these funding mechanisms have their pros and cons. Currently, at least in the field of oncology, many more clinical studies are supported and/or sponsored by the pharmaceutical industry than by government or the charitable sector. This is unfortunate, because much of the progress in the treatment of diseases is based on the reflections of clinicians on how things could be improved. But if no pharmaceutical company gets involved, they often simply don’t have the money for research.

Are there any additional, systemic benefits of clinical trials?

I think that publicly financed health systems should invest in clinical trials, especially to find solutions which would benefit the whole system. There are many questions around how we can better use current treatments or diagnostic methods, for example. This could lead to better results for patients, and help save costs as well.

Besides what I have just mentioned, there are also data suggesting that the outcomes of patients who are treated in a hospital with active clinical research are better than those of patients treated in institutions without active research programmes. And this is not because all patients at hospitals with research programmes take part in clinical trials. Only a minority of patients participate in trials. Research has also shown that participating in a trial does not necessarily lead to a better outcome for the individual. If they do achieve better outcomes, it is mainly due to the selection criteria for the trials. What makes clinical institutions with intensive research programmes better for all patients is that, as a “side effect” of their research work, they have management protocols in place that provide for the highest standards of care and perhaps also for better clinical processes. Studies have documented this phenomenon for patients suffering from heart disease, ovarian cancer, intestinal cancer, myeloma and breast cancer. This is another important argument in favour of making clinical research part of a clinic’s normal daily business and part of our treatment culture.