Failures in Phase III: Causes and Consequences

Abstract

Phase III randomized controlled trials (RCT) in oncology fail to lead to registration of new therapies more often than RCTs in other medical disciplines. Most RCTs are sponsored by the pharmaceutical industry, which reflects industry's increasing responsibility in cancer drug development. Many preclinical models are unreliable for evaluation of new anticancer agents, and stronger evidence of biologic effect should be required before a new agent enters the clinical development pathway. Whenever possible, early-phase clinical trials should include pharmacodynamic studies to demonstrate that new agents inhibit their molecular targets and demonstrate substantial antitumor activity at tolerated doses in an enriched population of patients. Here, we review recent RCTs and found that these conditions were not met for most of the targeted anticancer agents, which failed in recent RCTs. Many recent phase III RCTs were initiated without sufficient evidence of activity from earlyphase clinical trials. Because patients treated within such trials can be harmed, they should not be undertaken. The bar should also be raised when making decisions to proceed from phase II to III and from phase III to marketing approval. Many approved agents showed only better progression-free survival than standard treatment in phase III trials and were not shown to improve survival or its quality. Introduction of value-based pricing of new anticancer agents would dissuade the continued development of agents with borderline activity in early-phase clinical trials. When collaborating with industry, oncologists should be more critical and better advocates for cancer patients.

Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?

“…This is in line with the concept that tumor angiogenesis is a hallmark of cancer. However, the benefits are limited and there is no method of selection of patients likely to respond to this therapy [198,199]. Moreover, treatment resistance to anti-angiogenic drugs may be mediated by increased hypoxia, which can also aggravate immunosuppression.…”

Overcoming obstacles in the design of cancer anorexia/weight loss trials

“…We can only speculate on why pharmaceutical company-sponsorship is associated with success; this positive association may hinge on a desire to seek more pragmatic outcomes that drive a business model or perhaps on better financial support for the development plan. In the absence of compelling phase 2 data, the success of phase 3 trials in cancer therapeutics with targeted agents is much lower [22]. Similar findings as those from Chan and others have been reported by others, although the clinical value of the endpoint that defined the success of the phase 3 trials at times seems debatable [21].…”

Imatinib treatment of poor prognosis mesenchymal-type primary colon cancer: a proof-of-concept study in the preoperative window period (ImPACCT)

“…Up to 60 % of phase III trials have negative outcomes [14, 15]. This high failure rate underscores the need for optimization of trial design, including better patient selection.…”

“…In ImPACCT we aim to deliver proof-of-concept that PDGFR/KIT inhibition with imatinib reduces the aggressive phenotype of newly diagnosed primary CMS4 colon tumours. Delivering proof-of-concept for drug activity in early stages of drug development is pivotal to prevent unfounded trial phase transition [14, 15]. …”