Introduction 1 2 emergency nature of the research incapacity of the patients to consent short therapeutic time windows risk/benefit ratio based on the concept that in relation to the seriousness of the injury, significant adverse side effects may be acceptable for treatments with possible benefit. The importance of implications of these issues is not fully recognized outside, and even within, the expert field of treatment of severe TBI. Therapeutic trials to evaluate the efficacy and safety of pharmacological agents are subject to the ethical and juridical principles of Good Clinical Practice, national legislation and European and international regulations. The guiding ethical principles underlying these investigations of treatment are respect for autonomy of the subjects, protection against discomfort, harm, risk and exploitation and the prospect of benefit. The prospect of benefit is almost always complicated by the equipoise underpinning the statistical null hypothesis of pharmacological trials: the hope that an individual patient will benefit, but that this is not more certain than the chance of non benefit. 3 4 6 7 19 The Directive made no direct exception for emergency and critical care situations, and therefore threatened to prevent all emergency trials involving patients with acute catastrophic illness causing loss of decision-making capacity and facing (very) short therapeutic time windows, such as severe shock, circulatory arrest, acute myocardial infarction, severe stroke and other acute neurological conditions, and moderate and severe traumatic brain injury. 20 9 21 The Directive was conceived in part to ensure that participants enrolled in research projects are given adequate information about the nature of the trials and the associated risks. Legislation to protect the interests of patients was necessary and timely. The research community welcomed most of the Articles in the Directive; they offer guidance and will help to maintain confidence in the probity of medical research. Unfortunately, however, neither those responsible for the Directive, nor many who drafted enabling legislation within Member States, considered the special problems relating to research in emergency nor critical care situations, where consent cannot be obtained from subjects and where the need for emergency treatment does not allow time for contact with relatives or other legal representatives. Moreover, in the United States, in 1996, the FDA had published a waiver of informed consent for certain types of emergency and critical care research after earlier strict provisions had brought to a halt important progress in some critical clinical situations. ‘Vienna Initiative to save European Research Wiener Klinische Wochenschrift 6 Consent Procedures 22 23 24 12 25 26 With deferred (proxy) consent patients are included into the research without prior consent. After inclusion, the patient (deferred consent) or his/her representatives (deferred proxy consent) should be informed as soon as possible and subsequent informed consent should be requested. 27 28 27 19 29 30 31 23 26 31 32 12 33 35 36 37 38 39 The Emergency Nature of Research in TBI Traumatic Brain Injury is by definition an acute condition. The emergency nature of pharmacological research in TBI is reflected by the fact that experimental and clinical studies have shown that patho-physiological cascades are initiated within minutes to hours following primary injury. Time windows for treatment modalities are therefore considered to be short. Experimental studies have shown the efficacy of many neuroprotective agents, if these were administered before, or within 15 min after injury; others have shown a window of efficacy of 3–6 h. 40 41 42 sustained TBI within the past 6 h 40 43 the time between injury and admission in a neuro-trauma center; the time between admission in a neuro-trauma center and first head CT scan; the time between the first head CT scan and proxy consent for inclusion in the trial; the time between proxy consent and study drug administration. after 44 1 1 1 1 1 1 Table 1 Time windows per country (median + IQR) Country (N) Hours between injury and admission NTC median (IQR) Hours between injury and CT scan median (IQR) Hours between injury and obtained consent median (IQR) Hours between injury and SDA median (IQR)  Belgium (23) 0.93 (0.65–1.27) 1.80 (1.28–2.27) 3.75 (2.75–4.75) 4.60 (3.98–5.42) Netherlands (73) 1.00 (0.75–1.33) 1.65 (1.32–2.00) 4.53 (3.95–5.05) 5.53 (5.07–5.75) Israel (116) 0.93 (0.72–1.40) 1.91 (1.58–2.47)  4.01 (3.20–4.83) 4.67 (4.00–5.33) Spain (75) 1.33 (0.97–1.67)  2.07 (1.65–2.53) 4.17 (3.33–5.00) 5.17 (4.30–5.58) Germany (109) 1.20 (0.88–2.00) 1.65 (1.30–2.13) 4.08 (3.42–4.98) 5.25 (4.25–5.67) Italy (146) 1.25 (0.83–2.60) 1.77 (1.40–2.35) 4.92 (4.08–5.28) 5.50 (4.98–5.75) France (34) 2.17 (1.42–3.00) 3.08 (1.97–3.53) 5.00 (4.50–5.38) 5.75 (5.17–5.83) Other countries* (55)  1.47 (1.00–2.67) 1.82 (1.33–2.50) 4.00 (3.08–4.75) 5.25 (4.33–5.75) *Countries with small patient populations (United Kingdom, Denmark, Austria, Poland, and Turkey) were combined Fig. 1 43  40 1 Risk-Benefit Ratio 45 46 Conclusions Specific ethical issues pertaining in clinical testing of pharmacological neuroprotective agents in TBI include the emergency nature of the research, the incapacity of the patients to informed consent before inclusion, short therapeutic time windows, and a risk-benefit ratio based on concept that in relation to the severity of the trauma, significant adverse side effects may be acceptable for treatments with possible benefit. 12 3 6 15 ‘treat first, ask later’ 4