CLINICAL OPERATIONS
A hypothetical dose escalation study To understand the importance of scenario planning as a risk management tool within study designs, we can make several assumptions regarding a hypothetical first-in-human dose-escalation study that will utilise a traditional 3+3 trial design: • five dose levels will be investigated • a 14-day screening period will apply • study drug to be administered every 14 days • a 28-day dose limiting toxicity (DLT) window will apply from first study drug administration
• dose escalation requires the approval of a safety review committee (SRC)
• data entry and preparation for the SRC meeting is seven days
• first subject should be observed for 16 days (ie, 48 hours after the second dose of study drug) for the occurrence of DLTs prior to the second subject being administered the study drug
• subsequent subjects in dose escalation must be dosed at least 48 hours apart, with an average recruitment rate of one subject per week (recruitment pauses during DLT window and during SRC adjudication)
• no screen failures • no modification of dose escalation based on DLT observations
To keep things simple, let’s just consider the two scenarios in the table below.
The first scenario assumes that no DLTs are
observed during the dose escalation, and therefore the study progresses quickly, with three subjects treated at each dose level for a total of 15 subjects. The second scenario assumes that one DLT is
observed in one of the three subjects treated at each dose level in the last week of the DLT window. As required by the rules of the 3+3 schema, each
dose level is therefore required to expand to a total of six subjects. We have also assumed that no further DLTs are observed in the additional subjects recruited at each dose level, thereby allowing dose escalation to complete with six subjects at each of the five dose levels, for a total of 30 subjects. While some may argue that the likelihood of
every dose level experiencing a DLT in the last week of the DLT window is an extreme example, it is nonetheless a great illustration of the importance of scenario planning.
Primary implications It doesn’t take much more than a curious glance to identify the primary implications of the study delivery between the two identified scenarios. Firstly, the dose escalation timeline has increased from 44 to 84 weeks; secondly, the number of subjects has increased from 15 to 30; and lastly, although not identified in this simplified model, a significant increase to costs (both investigator grants and CRO change orders) is very likely. While your consultant/CRO will be able to assist
you to quantify the primary implications (ie, time and cost) between multiple scenarios (such as recruitment rates, number of sites, incidence of DLTs, etc), the consultant/CRO are not well placed to the scenario plan’s secondary implications. These secondary implications are often internal to the small and emerging biotech and not as well considered or characterised in the risk management plan. While this article is unable to reference all possible secondary implications, a number of key secondary implications are discussed below.
Secondary implications
A fully costed project budget would include overhead recovery – the largest component would
Scenario 1
Week 1
Week 11 Week 21 Week 31 Week 41 Week 44
40 weeks | 17 Scenario 2
Week 1
Week 19 Week 37 Week 55 Week 73 Week 84
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