“And the dose for the next cohort will be…”
Interim analysis for CNS first in human single ascending dose studies at CHDR
Being member of the interim safety committees is one of the most enjoyable parts of my work as the determination of the next dose level in a clinical trial unites both science and clinical operations at its best. The speed with which such ascending dose trails are performed, the close operations with colleagues and sponsor, and the excitement to find out details of the interim report content are a good recipe for pleasure.
Routinely, as single ascending dose phase 1 studies have a limited cohort size (e.g. 8-12 healthy volunteers), the clinical phase of a single cohort is often performed in one or two days, and subsequent cohorts are commonly carried out with one week intervals1. This allows 3-4 working days or so to produce the interim report, although we recently applied even shorter time lines during a frog leap designed study for which 2 cohorts were dosed each weak requiring the production of the interim report during the weekends.
In order to prevent possible delay in the production of the study medication at the LUMC pharmacy, we tend to predict a range for the most likely dose levels for the next two cohorts, allowing the pharmacy to prepare the medication well in advance.
For CNS studies, the interim report not only contains information on subject characteristics, adverse events and graphs for safety parameters. Pharmacodynamic (PD) parameters, we often use the most sensitive tests on our CNS test battery, have proven to be an indispensible part of interim analysis as information of the compound’s penetration of the brain often predicts side effects.
Often the dose escalation steps are provided in the protocol, but deviating from these predefined dose levels, but within regulatory limitations, is not uncommon. Sound determination of the first dose level is the most delicate step is in my opinion. In addition to FDA’s NOAEL conversion table for animal to human equivalence doses2, we routinely prepare a structured overview of all preclinical data available and use this as a tool for dose escalation as it has proven to predict safety and pharmacodynamics in many trials.
However, sometimes the compound behaves differently from what was predicted, e.g. unexpected nonlinear pharmacokinetics due to slow absorption, or side effects emerge before a clear efficacy-related CNS effect is observed. Therefore, in addition to clinical common sense, strategies for early stopping are essential. These stopping rules, e.g. occurrence of severe adverse events, are typically described in protocol as well as the highest allowed dose level. If no formal stopping events are encountered during the study, the pharmacodynamic effects can still provide sound reasons to stop dose escalation, for instance if the effects seem to max out with the highest two or three doses.
This PD-based approach towards dose escalation studies is appreciated by sponsors for its speed, accuracy and concomitant scientific advice. An approach to be proud off.
1 Zuiker RG, Chen X, Østerberg O, Mirza NR, Muglia P, de Kam M, Klaassen ES, van Gerven JM. NS11821, a partial subtype-selective GABAA agonist, elicits selective effects on the central nervous system in randomized controlled trial with healthy subjects. J Psychopahramcol. 2016 Mar;30(3): 253-62.
2 Guidance for Industry. Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) July 2005