How CHDR improves and changes the clinical trial

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Naturalistic drug effect studies. Trial@Home

Traditional relationships between doctors and patients have changed. Patients are better educated than ever before, and want to take responsibility for their own lives. Although most patients value the relationship with their doctor, many now want to be informed and coached about health issues, rather than ‘treated’ by a benevolent and knowledgeable, yet somewhat paternalising physician. These changes will also affect clinical research.

Many patients with untreatable conditions are looking for alternative therapies. From the patient’s perspective, the risks associated with an unproven treatment understandably become less important if the disease is severe enough. The internet is a ready source of all types of compounds, often of dubious origin and quality. Access to experimental therapies is subject to strict regulations, and it is still difficult for a patient to be entered into a trial. Some patients now claim their right to decide for themselves, how much (unknown) risk they are willing to take with new unproven treatments. Organizations like MyTomorrows offer experimental drugs to patients who cannot be helped with regular treatments – outside of a clinical trial. Unfortunately  it is not in the patients’ benefit if new therapies are used in practice, without first being properly studied. Nonetheless, it is understandable that patients are looking for ways to accelerate the availability of new treatments – and researchers will have to respond.

Patients and healthy people are also taking responsibility for monitoring of their own health. An increasing number of genetic screens and laboratory diagnostics are offered to patients, often with medical advice. Miniature medical applications are increasingly sensitive, and large companies like Apple already offer apps and portable devices, which are able to constantly monitor physiological or behavioural indicators of healthy and performance in daily life. Unfortunately, the reliability of many of these applications is still unclear.

Over the decades, CHDR has devoted much of its time and resources to the development of tests for drug effects and disease. We use this experience in the collaboration with a number of technical parties in the joint development and validation of applications that patients can use at home, during the conduct of a clinical trial. Some examples include smartphone apps to photograph skin lesions, for new drugs in dermatology; small portable devices that continuously measure vital functions, like the Vital Connec®; and the Mini-NeuroCart®, which is based on CHDR’s drug-sensitive multimodal CNS test battery, made suitable for studies ‘in the field’. In addition, CHDR also develops tablet-based apps for ambulant patient instructions and effect measurements. And this is just part of our Trial@Home initiative, which aims to perform highly informative, data intensive studies under naturalistic conditions – during attacks of recurrent diseases, or for chronic drug effects in the comfort of the patient’s home, in their own bed at night, in the office, or any other situation that is affected by the compound – not just in the clinical research unit. The time has come that patients and researchers can team up to improve clinical research.

by Joop van Gerven

Cars & Clinical trials: driving simulators Vs. on-the-road-driving-tests

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For many of us, driving a car represents freedom and independence and economical power. What has this to do with CHDR, you might ask? Well, many pharmacological agents that affect the central nervous system are of concern when it comes to driving safety. Those medications (and also drugs of abuse) can induce fatigue, impair vision and reduce vigilance leading to periods of inattention. This poses a risk for the operation of dangerous equipment like a car. Although those risks are often already known at a drug-group level, for clinical pharmacologists like us, it is important to estimate the dose response relationship for an individual investigative drug early in its development. Additionally there may be certain groups, like the elderly or the young drivers, which are much more at risk when impaired by medicines, alcohol or drugs.

The effect of investigative drugs on driving performances is often assessed by using a standardized on-the-road-driving-test, which was developed in the 1980s and has been applied extensively in over 50 studies since. In short, subjects are instructed to drive a car over a 100 km highway. The car is equipped with two camera’s that constantly monitor the position of the car within the traffic lane. The outcome is mainly measured by the alterations in the standard deviation of lateral position (SDLP), which has proven to be a suitable parameter for vehicle control and traffic safety.

However, the on-the-road-driving-test is inflexible, labor intensive and therefore costly, it may take weeks to complete a full study while testing a single dose only, making the test less suitable for the assessment of dose response effects and certainly not suitable for a quick adaption in the study design. Nevertheless, the on-the-road-driving-test is often required for registration purposes, but a negative study outcome may cause a significant restriction in its indication as specified in the SMPC. Therefore, an on-the-road-driving-test may not be the single most suitable tool for drug-induced driving risks.

Luckily, the SDLP can also be measured in an in- house driving simulator in a much more practical and reproducible manner. Other parameters that are of importance in driving a car safely -, i.e. alertness, memory, coordination amongst others – can be added effortlessly. Also, driving simulation makes it possible to study the temporal relationship between medication and driving performance and work out the pharmacokinetic dynamic relationships. Of course all tests are surrogate endpoints for the occurrence of accidents but this ‘real’ endpoint can never be assessed. The current generation of driving simulators have, however, been validated positively against real driving behavior.

At CHDR we are currently studying the sensitivity of a driving simulator test battery to the effects of ethanol and a benzodiazepine, trying to compare these results with those of the NeuroCart™, a validated and established test battery developed by CHDR that quantifies a large range of drug-sensitive CNS-functions that are also relevant for every-day performance. Results from this study will allow us to determine whether a driving simulator is suitable to assess impairment in performance due to investigative drugs in a laboratory setting. This will set the standard for future studies in the important area of drug effects on real life performance.

Rob Zuiker