Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials

Stein, Donald G.

doi:10.3109/02699052.2015.1065344

Cited by 249Traumatic Brain Injury and Neurovascular DisturbancesTraumatic Brain Injury ResearchEthics in Clinical Research

Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials

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Stein, Donald G.·2015·Brain Injury

DOI 10.3109/02699052.2015.1065344PMC PMC4667711

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Abstract

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.

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The failure of pre-clinical TBI therapies to translate has been attributed in part to inadequate preclinical efforts to recapitulate the complexity of the human injury.
“This has been attributed in part to inadequate preclinical efforts to recapitulate the complexity of the human injury.”
From Sex Differences in Traumatic Brain Injury: What We Know and What We Should Know (2019) · cites this paper as [19]
Results of TBI clinical trials are not always analyzed by sex.
“Moreover, results are not always analyzed by sex.”
From Sex Differences in Traumatic Brain Injury: What We Know and What We Should Know (2019) · cites this paper as [19]

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Authors: Stein, D. G.
Affiliations: Emory University (US)
Corresponding author: Stein, Donald G.
Venue: Brain Injury
Publisher: Informa UK Limited
Published: 2015-08-14
Volume: 29
Issue: 11
Pages: 1259-1272
ISSN: 0269-9052 (ISSN-L)
1362-301X
DOI: 10.3109/02699052.2015.1065344
PMC: PMC4667711
OpenAlex: W1757695926
Cited by: 249
References: 102
Citations by year: 2026: 17 · 2025: 16 · 2024: 19 · 2023: 26 · 2022: 14 · 2021: 20 · 2020: 25 · 2019: 25 · 2018: 30 · 2017: 24 · 2016: 27 · 2015: 5
FWCI: 3.77
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Brain Injury (publishedVersion)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ethics in Clinical Research
Keywords: traumatic brain injury, progesterone, clinical trial failure, drug development, outcome measures, preclinical to clinical translation, stroke, sepsis
MeSH terms: Brain Injuries, Humans, Progestins, Progesterone, Treatment Outcome, Outcome Assessment, Health Care, Treatment Failure, Clinical Trials, Phase III as Topic

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Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials

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