Abstract ED02-02: Phasing out phase III trials: How much evidence do we need if the target is clearly hit?
Authors: Verweij Jaap 
Published: June 2012

Recent successes in the development of targeted therapies for cancer have lead to a discussion on design of studies that should provide definitive evidence of antitumor activity. Such activity can be evident even in early phase clinical trials, and in some instances the data have even been reason to question the ethics of subsequent randomized phase III trials, particularly for those drugs that deal with diseases with a high unmet medical need. And the enormous increase of the subsequent costs of drugs has also stimulated a reconsideration of study design, questioning the realism and relevance of showing tiny differences with statistical power. In the era of cytotoxic drugs, they moved from Phase I studies (to establish safety and the maximum tolerated dose), through Phase II studies (to screen for an early signal of anti-tumor activity), to Phase III studies that compared the novel treatment the existing standard of care to determine if it provided clinical benefit. Shortening and narrowing of this cascade of events seems important.

Since 1992, drug approval by the FDA has already been possible without data from confirmatory clinical trials as part of the accelerated approval process. This has had different levels of success. In Europe EMA does not provide this option. It therefor remains important to continuously reassess how drug trials can be optimized as far as the designs required for registration are concerned. In that respect the question is if there would be circumstances conceivable that would allow avoidance randomized phase III study data, or design of smaller size phase III studies.

In all examples of recent success there were common themes that were likely contributing to that success. Perhaps most importantly, in every case the preclinical studies identified the biological functionality of the drug's putative target as a driver of tumor growth. In all cases this driver was present in the tumor cell itself, and was not a tumor environment target. Also, assays of the targets could be used as predictive biomarkers to select patients with sensitive tumors for the early clinical studies. Regardless of whether this biomarker was present in a larger population of patients with the disease (CML, GIST, BCC), or only in a sub-population (Melanoma, NSCLC).

All drugs involved showed substantial evidence of antitumor activity in either non-randomized trials (when compared to historical data) or in randomized phase II studies. In such circumstances we should consider changing the current common approach of a large phase III study, into either randomized phase II trials, or (preferably) smaller size phase III studies looking for larger increments of effect. The major advantage of foregoing large randomized phase III trials is that effective new drugs can sooner be made available to patients. This way one could also circumvent the problem of poor accrual in pivotal phase III studies due to parallel availability of named patient programs. And one could decrease costs for drug development. The obvious disadvantage of working with smaller trials would be having less data regarding the safety of the new drug.

Yet, certainly for targets in or at the tumor cell itself, it seems possible to set some criteria for changing the usual flow of studies, merging study designs into one another, and obtain data on clinical relevance without doing large randomized phase III studies

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr ED02-02.