The perils of paediatric research

Abstract

Researchers wishing to study paediatric disease face formidable practical and ethical difficulties. Yet it is rare for investigators to appear on the front pages of national newspapers because of their work. Last week that was the unfortunate fate for Prof David Southall, head of the academic paediatrics department at the UK North Staffordshire Hospital Trust. He found that his research has been made the subject of a Government inquiry. Concern quickly gave way to suspicion and ended with personal vilification. Trust in doctors was again under attack. A group of parents claim that they were not informed that their preterm children were to receive an experimental treatment in intensive care. The trial at the centre of the complaints compared the effectiveness of continuous negative extrathoracic pressure (CNEP) with standard positive pressure ventilation in matched pairs of 244 preterm babies between October, 1989, and November, 1993, at two neonatal intensive-care units. Media reports indicate that, of the 122 infants who received CNEP, 28 died and 15 have some form of brain damage. The inquiry will be led by Prof Rod Griffiths, regional director of public health for the West Midlands. At the centre of his inquiry will be the final report of the Southall study, which was published in Pediatrics more than 3 years after the trial had stopped (1996; 98: 1154–60). The paper raises important issues, some of which pose fundamental questions about research into neonatal illness. First, the study's result—namely, that “CNEP may have beneficial effects in neonates with respiratory distress syndrome”—can be taken only as a preliminary indication of the safety and efficacy of CNEP. Clinical progress among neonates entered into the trial was assessed by an unvalidated and arbitrarily constructed clinical outcomes score. The authors state, “Although it [the score] had not been previously validated in its accuracy to measure an infant's clinical outcome, it provided an objective and ethical means of monitoring the use of CNEP and determining when the trial should end”. A question for the inquiry to answer will be on what grounds the investigators and ethics committee members were satisfied that the outcome scale, and so the trial itself, were objective and ethically sound, given that the scoring system had not been validated. The complications that arose in infants who received CNEP were severe—a high rate of pneumothorax early in the trial, neck excoriations, hypothermia and hyperthermia, unexplained non-specific abdominal distension, and a higher frequency of cranial ultrasound abnormalities. There were 28 deaths in the CNEP group compared with 22 in neonates receiving standard treatment. Although this difference was not statistically significant, the investigators expressed surprise at the trend towards higher mortality: “CNEP was hoped to improve the infants' respiratory disease and result in a decrease in mortality”, they wrote. Despite this warning, together with the clear finding of no difference between CNEP and standard treatment according to the clinical outcome score, investigators concluded that “CNEP improves the respiratory outcome”. The inquiry must consider the validity of this conclusion in the light of the published evidence. The issue of informed consent will be a further matter for the inquiry to consider. In the present case, “parental consent was obtained between 2 and 4 hours of age”. The inquiry must consider how likely it was that informed consent could be achieved during this difficult time for parents. Certainly, some parents—those of 36 infants—did feel able to refuse consent. Inquiry investigators will need to interview the parents of those 36 children to judge how effective the consent procedures were. The inquiry panel will be aware that there has been a sea-change in attitudes towards the ethics of clinical research during the decade since this trial was designed and started. Indeed, when researchers from North Staffordshire Hospital first reported the results of uncontrolled trials of the CNEP apparatus, neither ethical approval nor informed consent were mentioned (BMj 1989; 299: 1253–57). In that year, informed consent in clinical trials involving adults was the subject of fierce debate in the lay and medical press, with many researchers arguing against. We have learned lessons and moved on since then. Similar lessons must be learned from the Griffiths inquiry so that essential neonatal research can proceed without personal vilification replacing careful peer review. The parents at the centre of this inquiry have experienced a tragic loss that cannot be reversed. A further tragedy for tomorrow's children would be a climate in which research into neonatal care has become impossible.