Recommendations for the design of therapeutic trials for neonatal seizures

Although seizures have a higher incidence in neonates than any other age group and are associated with significant mortality and neurodevelopmental disability, treatment is largely guided by physician preference and tradition, due to a lack of data from welldesigned clinical trials. There is increasing interest in conducting trials of novel drugs to treat neonatal seizures, but the unique characteristics of this disorder and patient population require special consideration with regard to trial design. The Critical Path Institute formed a global working group of experts and key stakeholders from academia, the pharmaceutical industry, regulatory agencies, neonatal nurse associations, and patient advocacy groups to develop consensus recommendations for design of clinical trials to treat neonatal seizures. The broad expertise and perspectives of this group were invaluable in developing recommendations addressing: (1) use of neonate-specific adaptive trial designs, (2) inclusion/exclusion criteria, (3) stratification and randomization, (4) statistical analysis, (5) safety monitoring, and (6) definitions of important outcomes. The guidelines are based on available literature and expert consensus, pharmacokinetic analyses, ethical considerations, and parental concerns. These recommendations will ultimately facilitate development of a Master Protocol and design of efficient and successful drug trials to improve the treatment and outcome for this highly vulnerable population

International variations in application of the best-interest standard across the age spectrum

OBJECTIVE: Ethically and legally, assertions that resuscitation is in a patient's best interest should be inversely correlated with willingness to forego intensive care (and accept comfort care) at the surrogate's request. Previous single country studies have demonstrated a relative devaluation of neonates when compared with other critically ill patients. STUDY DESIGN: In this international study, physicians in Argentina, Australia, Canada, Ireland, The Netherlands, Norway and the United States were presented with eight hypothetical vignettes of incompetent critically ill patients of different ages. They were asked to make assessments about best interest, respect for surrogate autonomy and to rank the patients in a triage scenario. RESULTS: In total, 2237 physicians responded (average response rate 61%). In all countries and scenarios, participants did not accept to withhold resuscitation if they estimated it was in the patient's best interest, except for scenarios involving neonates. Young children (other than neonates) were given high priority for resuscitation, regardless of existing disability. For neonates, surrogate autonomy outweighed assessment of best interest. In all countries, a 2-month-old-infant with meningitis and a multiply disabled 7-year old were resuscitated first in the triage scenario, with more variable ranking of the two neonates, which were ranked below patients with considerably worse prognosis. CONCLUSIONS: The value placed on the life of newborns is less than that expected according to predicted clinical outcomes and current legal and ethical theory relative to best interests. Value assessments on the basis of age, disability and prognosis appear to transcend culture, politics and religion in this domain.Journal of Perinatology advance online publication, 13 October 2016; doi:10.1038/jp.2016.168