A New Approach to Clinical Trials
This is a thoughtful editorial from the Journal of Clinical Oncology about a different approach to clinical trials. Our current system of Phase I, II, and III trials for cancer agents was developed in the 1960s and has worked out pretty well. However, progress (blesssedly) has been made, and research continues to directions that could not have been imagined fifty years ago. The suggestion here is that the development of targeted therapies needs to be considered and tested in a different way. Here is the beginning and then a link to read more:
Cracking Open Window of Opportunity Trials
Kevin Kalinsky and Dawn L. Hershman, Columbia University Medical Center, New York, NY
Despite an increase in investment, only one in every 10 new molecular therapeutic agents that enters clinical development receives US Food and Drug Administration approval.1 The sequential phase I/II/III model that was developed in the 1960s for cytotoxic chemotherapy2 remains a common pathway for drug development, with anticancer agents often being investigated in metastatic disease before operable disease. However, with many new targeted therapies, there are limitations in measuring response
by traditional methods, such as response rate defined by RECIST criteria, which may lead to erroneous conclusions about a drug's benefit. Evaluating molecular end points can be hindered by difficulties in procuring tumor tissue before and after drug administration and by heterogeneity in previous exposure to cancer therapies. A method to circumvent this issue is to assess novel agents in presurgical (window of opportunity or phase 0) trials. In this model, women with newly diagnosed breast cancer, for instance, receive a study drug between the diagnostic breast biopsy and planned surgical resection. The goals of these trials include evaluation of target modulation after drug exposure and pharmacokinetic assessment of a potential anticancer agent. This is in comparison to neoadjuvant trials, in which an investigational agent iscommonlygiven preoperatively along with cytotoxicchemotherapy or hormonal therapy for a longer period of time than in a presurgical trial, and the primary end point is often, but not always, pathologic or clinical response. The ultimate hope is that presurgical studies can expedite the drug development process by improving the understanding of an agent's biologic effect early in its development, validating markers that may predict subsets of patients who will benefit, and targeting select patients in subsequent clinical trials that are powered to detect changes in clinical outcome.