Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials.
BACKGROUND
Despite positive preclinical studies and two positive Phase II clinical trials, two large Phase III clinical trials of progesterone treatment of acute traumatic brain injury (TBI) recently ended with negative results, so a 100% failure rate continues to plague the field of TBI trials.


METHODS
This paper reviews and analyses the trial structures and outcomes and discusses the implications of these failures for future drug and clinical trial development. Persistently negative trial outcomes have led to disinvestment in new drug research by companies and policy-makers and disappointment for patients and their families, failures which represent a major public health concern. The problem is not limited to TBI. Failure rates are high for trials in stroke, sepsis, cardiology, cancer and orthopaedics, among others.


RESULTS
This paper discusses some of the reasons why the Phase III trials have failed. These reasons may include faulty extrapolation from pre-clinical data in designing clinical trials and the use of subjective outcome measures that accurately reflect neither the nature of the deficits nor long-term quantitative recovery.


CONCLUSIONS
Better definitions of injury and healing and better outcome measures are essential to change the embrace of failure that has dominated the field for over 30 years. This review offers suggestions to improve the situation.
a Department of Emergency Medicine , Emory University , Atlanta , GA , USA.
Donald G
DG
Stein
D001930:Brain Injuries / Q000188:drug therapy*; D017326:Clinical Trials, Phase III as Topic / Q000379:methods*; D006801:Humans; D017063:Outcome Assessment, Health Care; D011374:Progesterone / Q000627:therapeutic use*; D011372:Progestins / Q000627:therapeutic use*; D017211:Treatment Failure; D016896:Treatment Outcome
D011372:Progestins; D011374:Progesterone
Clinical trials; ProTECT III; SyNAPSe; progesterone; traumatic brain injury