Electrophysiological Monitoring in Clinical Trials

Electrophysiological testing remains an important efficacy parameter in clinical neuropathy trials. The quality of nerve conduction studies in reported trials varies greatly, and may be responsible for negative results. We report the utilization of an expert core lab for electrophysiological testing. With the core lab, the variability of repeat testing is comparable to that of a single, excellent laboratory. Motor conduction velocities demonstrated a coefficient of variation of 3% and sensory conduction velocities 4% across 60 study sites. The distal motor evoked potential amplitudes varied by 13% at the ankle, and 10% at the wrist. The sensory potential amplitudes varied by 16% at the ankle, and 11% at the wrist in 60 sites. The overall monitoring rate in all submitted nerve conduction tracings was 36.6%. Our results show that an expert core lab can improve the electrophysiological quality of clinical trial data with the potential to show small changes in nerve conduction velocities and in both motor and sensory potential amplitudes. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1368–1373, 1998 ELECTROPHYSIOLOGICAL MONITORING IN CLINICAL TRIALS VERA BRIL, MD, FRCP(C), RUSSELL ELLISON, MD, MYLAN NGO, RT, BENGT BERGSTROM, MD, DONNA RAYNARD, RT, HUGO GIN, and the Roche Neuropathy Study Group 1 University of Toronto, The Toronto Hospital, General Division, EN11-209, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4, Canada 2 Hoffmann-LaRoche, Toronto, Canada Accepted 16 February 1998 Electrophysiological testing (nerve conduction studies, NCS) remains an essential technique for quantifying peripheral nerve function in peripheral neuropathy trials due to its inherent reliability, reproducibility, and objectivity. Nerve conduction studies measure peripheral nerve function directly without subjective bias and without contamination by central nervous system pathways. In research trials, neuropathy is defined currently on the basis of two out of five possible areas of abnormality: symptoms, signs, NCS, quantitative sensory testing (QST), and autonomic tests. The least variable and most reliable is the NCS. In addition, regulatory bodies have stated the requirement of more than one parameter showing positive change in order to accept a compound’s efficacy. Clinical measures of symptoms and signs as used routinely are highly variable. Quantitative clinical scales have been developed, but are cumbersome, and not widely employed as they too are variable, particularly for symptoms. QST has drawbacks as to reliability, reproducibility, and site of pathology. In early studies, uncontrolled nerve conduction evaluations were undertaken. Those responsible for analyses had little appreciation of the technical limitations of electrophysiology. A high degree of variability in parameters was observed: a much greater degree than repeat studies in a single laboratory. Consequently, the power of these studies to detect any meaningful change was severely limited. An advance in NCS was the institution of a central expert monitoring facility to provide quality control of the nerve conduction studies. The expert reviewer improved the variability of repeat measures and the power of studies. This function was still limited in its ability to evaluate data, and ensure rigorous protocol adherence and technical competence. We report a method of optimizing electrophysiological testing in large-scale, multicenter trials. The reproducibility of NCS achieved in 60 sites is that observed in a single, excellent laboratory when strict Abbreviations: EMG, electromyographic; HLR, Hoffmann-LaRoche; NCS, nerve conduction studies; QST, quantitative sensory testing; SOM, standard operating manual