We are planning a phase Ib trial of an unlicensed product in combination with two other licensed medicines. The study will have a dose escalation phase and then a secondary, expanded phase at a study established dose where we will look for evidence of efficacy when we combinine the unlicensed product with the two licensed drugs compared to the two licensed drugs on thier own.

Dosing and the potential for dosing errors are a concern and we are planning to have all dosing errors (if they occur) referred to and independent clinician (as well as the trial management structures - TSC etc) for review as part of any reporting process. This would cover both instances of overdosing and underdosing and be irresepctive of whether or not there was an associated SAE.

Our concerns are around pateint safety and how any dosing errors may affect the outcomes of both the dose escalation phase and the expansion phase of the study.

There seems acceptance that any overdoses would need a full indepnedent clinical review for both patient safety perspective and to offer assurance on any dosing alterations decisions to the trial management team. However a view has been put forward that for an instance of underdosing this would not be needed. That in these cases the trail TSC would be suffient to review the incident.

My questions are;

1. Should dosing errors in a phase Ib trial all be treated the same irrespective of whether or not they are over- or underdoses? If not why not?

2. Is this overall strategy a good one or is it potentially overly cautious?

3. Might we only do this full independent review of dosing errors in the dose escalation phase and then only for overdoses in the expansion phase?

Any advice appreciated.