Questioning assent: how are children's views included as families make decisions about clinical trials?

BACKGROUND: Assent is used to take children's wishes into account when they are invited into clinical trials, but the concept has attracted considerable criticism. We investigated children's accounts of decision-making with the aim of informing practice in supporting children when invited to join a clinical trial. METHODS: We audio-recorded qualitative, semi-structured interviews with 22 children aged 8-16 years about being invited to take part in a clinical trial. Most children were interviewed with their parents. Analysis of the transcribed interviews examined the content of participants' accounts thematically, whilst also drawing on principles of discourse analysis, which examines how individuals use talk to achieve certain effects or social practices. RESULTS: It was not possible to separate children's knowledge of the clinical trial, or their decision-making processes from that of their parents, with parents taking a substantial mediating role in producing their children's decisions. Decision-making gradually unfolded across time and events and was interwoven within the family context, rather than happening in one moment or in the clinical setting. Whilst children valued their parents' role, a case study of child-parent disagreement indicated how children can struggle to be heard. CONCLUSIONS: Decisions happen within a process of family dynamics, in contrast to ideas of assent that isolate it from this context. Parents have a substantial role in children's decisions, and thus how families come to provide consent. Reflecting this we argue that assent practices need to focus on supporting parents to support their children in learning and deliberating about trials. However, this needs to be accompanied by practitioners being alert to the possibility of divergence in child and parent views and enabling children's perspectives to be heard.

Processes in recruitment to randomised controlled trials of medicines for children (RECRUIT): a qualitative study.

OBJECTIVES: To investigate recruitment processes across a range of clinical trials and from the perspective of parents, young people and practitioners to identify strategies to improve recruitment and its conduct across the spectrum of trials of medicines for children. DESIGN: Qualitative interview and observational study. SETTING: Eleven paediatric clinical trial centres recruiting to four trials. PARTICIPANTS: Members of 60 families approached to consider entry to one of the participating trials and 31 practitioners. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Data were verbatim transcripts of (1) audio-recorded trial recruitment discussions between practitioners and families (n = 41) and (2) semi-structured interviews with parents (n = 62), young people (n = 22) and practitioners (19 doctors and 12 research nurses). Analyses were interpretive, following the general principles of the constant comparative method. RESULTS: Practitioners were concerned to avoid overburdening parents and some indicated that they found approaching families about trials to be aversive. By contrast, even in the most difficult situations, parents did not mind being asked about trials and they did not describe the approach as burdensome. Some parents viewed the trial approach as a positive or exciting opportunity. Parents and young people took little active part in the trial discussions and asked few questions. Despite this, they were satisfied with how they had been approached, and spoke of how they had felt involved, valued, cared for and comfortable to interject during the discussion. However, we identified several parents who had important misunderstandings about the trial. There were few differences between parents who consented and those who declined a trial. Regardless of whether they consented or declined, parents' trial decisions were influenced by their perceptions of the trial in relation to their child's safety and well-being, potential benefits to the child and family, potential benefits to others and the practicality of participation. Of these, parents' paramount consideration was safety. Parents', young people's and practitioners' views of what was important when considering a trial were broadly convergent, although families gave greater importance than practitioners to the trial's practical requirements. All parties valued the face-to-face trial discussion highly and wanted shorter and less complex written information. Parents did not feel pressured by the trial team to participate, but some described how their personal values made them reluctant to decline, and several parents who did decline described a passing sense of discomfort. CONCLUSIONS: The concerns of some practitioners that families would be overburdened were unfounded, as parents did not object to being asked about research. Practitioners may benefit from support that helps them feel personally more at ease in approaching families about trials. Parents and young people often described the trial discussions in strongly positive terms and emphasised the importance of the social and emotional aspects of these encounters. Informed consent training could be enhanced if it similarly emphasised these aspects of recruitment; the misunderstandings we identified indicate how this training could also help practitioners to improve the clarity of their trial discussions with families. Guidelines on informed consent documents should take account of findings that all groups thought that these documents should be shorter and more straightforward. FUNDING: This research was commissioned by the National Institute for Health Research Health Technology Assessment programme.

Heterogeneity of mutant versus wild-type Ki-ras in primary and metastatic colorectal carcinomas, and association of codon-12 valine with early mortality.

The point mutations occurring in codons 12 and 13 of Ki-ras in 78 patients with colorectal carcinoma (31 Dukes' A and B, 21 Dukes' C, and 26 Dukes' D) have been determined by allele-specific oligonucleotide hybridization and sequencing. Duplicate samples of invasive primary carcinoma, adjacent normal tissue, and available lymph node and liver metastases from the same patients were microdissected from paraffin sections. There were no differences in the mutation rate between primary carcinomas and secondary deposits: 26 of 78 (33 per cent) primary carcinomas, 10 of 32 (31 per cent) lymph node metastases, and 10 of 26 (38 per cent) liver metastases. Multiple sampling revealed frequent heterogeneity within carcinomas: 9 of 26 primaries with Ki-ras mutations also contained areas of carcinoma with only the wild-type gene, implying that Ki-ras mutation, even when present in a colonic carcinoma, may not have been necessary for establishing the malignant phenotype. Also, 2 of 26 (8 per cent) Dukes' D patients had a mutation in their primary carcinoma but none in liver metastases and 6 of 47 (13 per cent) Dukes' C and D patients had mutations in liver or lymph node metastases but none in the primary carcinoma. Such heterogeneity may modify the effectiveness of novel therapies targeting mutant Ki-ras function, such as farnesyltransferase inhibition. Mutation of codon 12 from GGT (glycine) to GTT (valine) was more prevalent in primary and metastatic deposits of Dukes' C/D carcinomas (P = 0.01) than in primary carcinomas from Dukes' A/B patients. Mutations of codon 12 to GAT, AGT, GCT and codon 13 GGC to GAC were also found, but no correlation with carcinoma aggressiveness was apparent. Follow-up of 71/78 patients (up to 12 years) revealed decreased overall survival (P = 0.001) in patients with the GGT to GTT transversion in codon 12, even when the analysis was restricted to Dukes' D cases, supporting the suggestion that this mutation may confer a more aggressive phenotype in colorectal carcinoma.