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.
Introduction: There is no widely used method for communicating the possible need for surgical intervention in patients with traumatic brain injury (TBI). This study describes a scoring system designed to communicate the potential need for surgical decompression in TBI patients. The scoring system, named the Surgical Intervention for Traumatic Injury (SITI), was designed to be objective and easy to use. Methods: The SITI scale uses radiographic and clinical findings, including the Glasgow Coma Scale Score, pupil examination, and findings noted on computed tomography. To examine the scale, we used the patient database for the Progesterone for the Treatment of Traumatic Brain Injury III (ProTECT III) trial, and retrospectively applied the SITI scale to these patients. Results: Of the 871 patients reviewed, 164 (18.8%) underwent craniotomy or craniectomy, and 707 (81.2%) were treated nonoperatively. The mean SITI score was 5.1 for patients who underwent surgery and 2.5 for patients treated nonoperatively (P<0.001). The area under the receiver operating characteristic curve was 0.887. Conclusion: The SITI scale was designed to be a simple, objective, clinical decision tool regarding the potential need for surgical decompression after TBI. Application of the SITI scale to the ProTECT III database demonstrated that a score of 3 or more was well associated with a perceived need for surgical decompression. These results further demonstrate the potential utility of the SITI scale in clinical practice.