Early Decision-Making in Drug Development: The Potential Role of Pharmaco-EEG and Pharmaco-Sleep

Abstract

The pharmaceutical industry has been suffering from low clinical success rates of new drugs for some time with particularly high attrition in early clinical development, especially for drugs aimed at central targets. Both pharmaco-electroencephalography (EEG) and pharmaco-sleep, along with other biomarker techniques, have significant potential to assist with this problem by enabling early decisions to be made about the likelihood of a compound proving successful in the clinic. This paper discusses the role and points of application of biomarker techniques in early drug development. It proposes a framework for the use of pharmaco-EEG and pharmaco-sleep in drug development that (i) relies on the combination of preclinical data and an understanding of translatability to generate robust hypotheses for testing in early clinical studies and (ii) is backed up by a clear decision-making process. The areas that need further development before this framework can be put fully into practice are discussed, along with some possible routes by which this could be achieved through precompetitive co-operation within the industry.

The effects of roflumilast, a phosphodiesterase type-4 inhibitor, on EEG biomarkers in schizophrenia: A randomised controlled trial

“…This study was a proof-of-concept study and should be followed up by more research using a larger sample size. The fact that significant changes in EEG measures with a small number of subjects has been observed reinforces the usefulness of EEG in pharmacological studies as a marker of potential for efficacy (Wilson and Danjou, 2015). More importantly, these results support the proposition that PDE4 inhibitors have therapeutic potential in patients with schizophrenia.…”

“…Improved task performance can be the result of changes at any point in a task process from sensory detection to response selection and motor output and it is unclear whether PDE4 leads to improvements across the processing chain or at specific processing stages. One way to explore this issue is through the measurement of electroencephalogram (EEG) biomarkers, increasingly used in psychiatric and pharmacological studies (Light et al, 2012; Wilson and Danjou, 2015) and used previously to examine PDE4 inhibition in a preclinical hyperdopaminergic model of schizophrenia (Halene and Siegel, 2008; Maxwell et al, 2004). This approach offers valuable utility in identifying early indicators for prediction of potential efficacy (Light et al, 2012).…”

The “rights” of precision drug development for Alzheimer’s disease

“…Assessment of DMN integrity may be an important biomarker with predictive value for the impact of the intervention on clinical outcomes [112]. EEG is dependent on the intact network function and may have applications in AD drug development similar to, but more robustly, than those of fMRI [108, 118, 119]. Both EEG and fMRI require procedural and interpretative standardization to be implemented in multi-site trials.…”

Interacting Influences of Sleep, Pain, and Analgesic Medications on Sleep Studies in Rodents

“…41 The prevalence of drug-induced changes in both human and rodent EEG has led to the suggestion that carefully controlled collection and assessment of drug-induced changes in the rodent EEG and sleep could provide a useful biomarker for making early decisions about moving drugs from preclinical into clinical development, particularly for centrally acting drugs. 7,18,19,57,79 In most preclinical studies, sleep and its stages are scored based largely based on the EEG. However, some drugs can dissociate the EEG from its normal relationship to sleep-waking behavior, confounding the interpretation of sleep studies.…”