What Are the Differences Between Dose Escalation and Dose Expansion in Clinical Trials?

The dose escalation and dose expansion both relate to clinical trials, important in assessing efficacy and safety of drugs. Dose escalation is a method of gradual increase in drug doses with a purpose to establish MTD. In this phase, a small number of participants, usually 20 to 50, take part, and the research has been directed toward elucidation of dose-related adverse effects and optimization of dosing. One striking statistic from this is that roughly 40% of early-phase trials go via this methodology for effectively establishing MTD.

In contrast, dose expansion involves the administration of a drug at MTD to a larger population after its determination. This stage is for further gathering data on efficacy and safety in a better-defined patient population. Studies indicate that the dose expansion cohorts can have 100 or more participants and, therefore, very significantly improve statistical power in trial results. For example, the FDA has indicated that robust data from such cohorts may call the shots in regulatory decisions on approvals.

The rationale for dose escalation is based on its safety and pharmacodynamic focus. For example, a historic trial of a new oncology drug demonstrated increased adverse effects after higher doses were reached, therefore, the researchers identified a safe dosage range. In contrast, during the period when the same trial was in the phase of dose expansion, the response rate of 30% among the patients provided a glimpse into the potential efficacy in selected subjects.

As pointed out by famous experts in this field, such as Dr. Scott Gottlieb, former Commissioner of the FDA, “Understanding dose-response relationships is essential to developing safe and effective therapies.” This should give an idea about the crucial role both dose escalation and expansion have in a drug development pipeline.

The answer to the question of when to use either dose escalation or dose expansion lies with the objectives of the trial. If the aim is the identification of a dosage level that is safe, dose escalation is pursued. On the contrary, if the investigators intend to study the drug’s therapeutic effect, dose expansion follows. Recently, it was also established in a study that dose escalation for the establishment of MTD followed by dose expansion ensues with the development of the most complete profile of a drug.

Ultimately, both dose escalation and dose expansion contribute to but also complement each other in clinical trials. Certain case studies or even trial reports that have demonstrated this more concretely might be worthy to consider in understanding the subtle difference between dose escalation vs dose expansion.

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