CHDR has devoted much of its own research to drug development methodology. Through systematic reviews, dedicated studies, academic networks, and its own expertise and collected database of 30 years of drug studies, CHDR has validated and optimized a unique set of methods and biomarkers, aimed to address every major question in early drug development.

At a glance

At 10% of our annual revenue a dedicated research budget is large enough to accommodate an ambitious research programme, which will facilitate CHDR's methodology development programme as well as Ready-4-Research and Trial@home.



In-house Medical Research Council

CHDR is an independent foundation without shareholders, and we have always used part of our revenue to finance research projects, in addition to conducting sponsored studies,’ says Prof Adam Cohen, CHDR’s CEO. ‘But now that our organisation ‒ and our annual revenue ‒ has grown, it has become important to structure this self-financed research. Most importantly, having a dedicated research budget gives us the freedom to decide which projects we want to fund.

Structure

The R&D Fund was created to serve as an incentive for driving innovation and the realisation of new ideas. Each staff member at CHDR is eligible to apply for an R&D Fund grant through his/her Research Director.The application should discuss how the project is relevant to drug development projects and how it will serve our core strategic priorities. In their review of each application, the Scientific Advisory Board determines whether the project is likely to contribute to the following strategic priorities:

- Biomarker development in a broad sense, including ‘wet’ biomarkers in the laboratory and other measurements to quantify pharmacological activity such as electrophysiology, challenge models, and/or behavioural measures;

- Trial@home, CHDR’s innovative programme for conducting entire studies on an outpatient basis by monitoring study subjects through the use of wearable devices, smartphone apps, and other tools;

- CHDR’s monocentre approach, in which all study participants are brought to one central study site, where all of the tests and measurements are performed; and

- Ready-for-Research, our extensive database of well-characterised patients who have indicated their willingness to participate in research studies and have been clinically evaluated and pre-screened.

Neuronal hyperexcitability

In neurology, neuronal hyperexcitability is a clinically important factor in various disorders, including epilepsy and amyotrophic lateral sclerosis (ALS). Until recently, the standard method used to measure neuronal hyperexcitability focused on peripheral motor neurons. With this method, two electrical stimuli are applied to the neuron, and the effect is measured using EMG. The first stimulus affects the response to the second stimulus depending on various parameters such as stimulus intensity and refractory time. In addition to these peripheral measurements, researchers at CHDR and Twente University also use transcranial magnetic stimulation (TMS) in combination with EEG and EMG to study excitability in the motor cortex of the brain. In this test, a magnetic coil placed over the motor cortex induces a change in the electric field. Above a specific threshold, the coil induces a motor response comparable to the response induced by directly stimulating the motor neuron. By using a similar dual-stimuli approach, this method can be used to quantify the effects of test drugs on excitability in the cerebral cortex. The aim of one such ongoing study is to demonstrate the concentration-dependent effects of three anti-epileptic compounds on cortical excitability and other variables measured using TMSEMG and TMS-EEG.

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Test car

The effect of a drug on driving performance is extremely important from a safety perspective. Driving also presents the CNS with an interesting challenge, as it requires the integrated efforts of various parts of the brain. In addition to our driving simulator from Green Dino, CHDR has obtained and is now validating a test car that can be used to measure driving performance in real-life traffic conditions. Researchers at CHDR have already used this new car to study the baseline driving patterns of both beginning and experienced drivers. They are now using this advanced tool to study the effects of sleep deprivation and pharmacological compounds on driving performance.

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Measuring the QT interval

CHDR’s Cardiology Services has also invested in developing a new method for measuring the QT interval in an ECG, which serves a major indicator of a drug’s safety. This novel approach is more sensitive and specific than other methods, providing a better understanding of the drug’s safety profile and decreasing the risk of wrongly terminating the development of a compound that is actually safe. The standard approach used to measure a compound’s effects on the corrected QT interval is to perform a single measurement at fixed times during the clinical experiment; these time points are usually based on the compound’s plasma concentration. At each time point, a 10-second ECG trace is recorded and analysed. Unfortunately, however, this sampling method is not particularly accurate in terms of assessing the compound’s effects on the corrected QT interval, which can easily be overestimated and can have dire consequences on the compound’s development. At CHDR’s Cardiology Services, we developed and validated a new sampling method that provides much higher sensitivity and specificity than standard ECG sampling, allowing us to detect — or exclude — an increase in the QT interval.

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Keeping track of immunosuppression

We recently launched a new project to develop, apply, and validate a battery of functional tests designed to measure immunosuppression in kidney transplant patients. This test battery will measure general immune status, patient-specific and antigen-specific responses, and the relationship between these responses and the drug’s concentration in the plasma. This project will result in a panel of diagnostic tests to help guide the pharmacological treatment of individual kidney transplant recipients, thereby minimising kidney damage, graft rejection, and the risk of immunodeficiency and/or drug toxicity. This multi-disciplinary project will capitalise on close collaboration between several research groups. CHDR will coordinate the project and will be responsible for the clinical pharmacology, and the Leiden University Medical Centre (LUMC) Pharmacy and the departments of Immunology, Nephrology, and Clinical Chemistry will be indispensable. Moreover, the Leiden Academic Centre for Drug Research (LACDR) will develop pharmacometrics models to correlate drug concentration with drug effects, and EMC will provide expert advice regarding transplantation immunology.

Responsible staff: Dr Matthijs Moerland and Prof Koos Burggraaf.

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Mitochondrial function and hip fractures

Another new study at CHDR is designed to measure mitochondrial dysfunction as a prognostic factor for predicting patient recovery following surgical hip fracture repair in elderly patients. This project will provide a detailed picture of the recovery process by measuring physical parameters on a daily basis using CHDR's Trial@Home. The measurements include the patient’s weight, body-mass index, physical activity, and metabolism. This project will be performed in collaboration with the LUMC’s Department of Orthopaedic Surgery, and local hospitals (e.g. Bronovo Hospital and Alrijne Hospital) will help recruit patients for the study.

Responsible staff: Dr Geert Jan Groeneveld.

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