As part of the Food and Drug Administration drug approval process, a study is conducted to assess the clinical benefit and toxicity of a new drug that is intended to be used in combination with current standard chemotherapy for patients with recurrent glioblastoma. Fifty patients with recurrent glioblastoma enroll in the trial and are randomized to receive standard chemotherapy plus either placebo or 1 of 3 possible doses of the new drug. Study results show a dose-dependent reduction in tumor size with all 3 doses of the new drug, along with a significant increase in adverse drug effects, including hypertension, muscle weakness, lymphopenia, and hypophosphatemia. The researchers conclude that the middle dose of the new drug offers the greatest ratio of benefit to toxicity. Which of the following best describes this type of study?
Show Explanatory Sources
Efficacy and safety of new drugs are established during the clinical trials process. New drugs are approved by a regulatory body (eg, Food and Drug Administration) following review of phase I to III trials. Phases differ in size, objective, and participant selection.
Phase I: small trials usually conducted with healthy participants to assess safety and pharmacokinetics, often performed in a strictly controlled environment with extensive biochemical and physiologic monitoring. Although some phase I chemotherapy trials may involve subjects with cancer due to the inherent toxicity of treatment, drug efficacy (eg, tumor size reduction) is not assessed during a phase I trial (Choice A).
Phase II: small- to medium-sized trials conducted with participants having the condition of interest to assess treatment efficacy, toxicity, adverse effects, and optimal dosing strategies. These studies may or may not have a control group and can be called pilot studies.
Phase III: large trials (typically >300 patients) that are adequately powered to fully assess treatment response and safety, often including analysis of treatment effects in selected subsets of the target patient population. These trials must show adequate effectiveness and safety compared to standard treatment for the drug to obtain regulatory approval.
(Choice C) This trial enrolled a small number of participants with recurrent glioblastoma and compared multiple drug doses with respect to treatment efficacy and toxicity. The results were reported to advise optimal drug dosing (ie, dose-finding); although drug dose correlated with a decrease in tumor size, effectiveness and safety outcomes were not compared with the standard treatment (eg, absolute/relative risks). Therefore, this study is best characterized as a phase II trial.
(Choice D) Phase IV trials are performed after a new drug has obtained regulatory approval for clinical use. These trials are typically performed to assess long-term benefits and risks or identify uncommon adverse effects that were not fully characterized in phase III studies.
(Choice E) In contrast to phase I, II, III, and IV trials, which include human subjects, preclinical studies do not involve human subjects.
Educational objective:
Phase II studies are small- to medium-sized trials conducted with participants having the condition of interest to assess treatment efficacy, toxicity, adverse effects, and optimal dosing strategies; they are sometimes called pilot studies.