Process evaluation of a behaviour change approach to improving clinical practice for detecting hereditary cancer.

BACKGROUND: This retrospective process evaluation reports on the application of a 1-year implementation program to increase identification and management of patients at high risk of a hereditary cancer syndrome. The project used the Theoretical Domains Framework Implementation (TDFI) approach, a promising implementation methodology, used successfully in the United Kingdom to address patient safety issues. This Australian project run at two large public hospitals aimed to increase referrals of patients flagged as being at risk of Lynch syndrome on the basis of a screening test to genetic services. At the end of the project, the pathologists' processes had changed, but the referral rate remained inconsistent and low. METHODS: Semi-structured interviews explored participants' perceptions of the TDFI approach and Health services researchers wrote structured reflections. Interview transcripts and reflections were coded initially against implementation outcomes for the various TDFI approach activities: acceptability, appropriateness, feasibility, value for time cost, and adoption. On a second pass, themes were coded around challenges to the approach. RESULTS: Interviews were held with nine key project participants including pathologists, oncologists, surgeons, genetic counsellors and an administrative officer. Two health services researchers wrote structured reflections. The first of two major themes was 'Theory-related challenges', with subthemes of accessibility of theory underpinning the TDFI, commitment to that theory-based approach, and the problem of complexity. The second theme was 'Practical challenges' with subthemes of stakeholder management, navigating the system, and perceptions of the problem. Health services researchers reflected on the benefits of bridging professional divides and facilitating collective learning and problem solving, but noted frustrations around clinicians' time constraints that led to sparse interactions with the team, and lack of authority to effect change themselves. CONCLUSIONS: Mixed success of adoption as an outcome was attributed to the complexity and highly nuanced nature of the setting. This made identifying the target behaviour, a key step in the TDFI approach, challenging. Introduced changes in the screening process led to new, unexpected issues yet to be addressed. Strategies to address challenges are presented, including using an internal facilitator with a focus on applying a theory-based implementation approach.

Discovery of GS-9669, a thumb site II non-nucleoside inhibitor of NS5B for the treatment of genotype 1 chronic hepatitis C infection.

Investigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of cell culture medium binding, revealed the structure-activity relationships for intrinsic cellular potency. The pharmacokinetic profile was enhanced through incorporation of heterocyclic ethers on the N-alkyl substituent. Hydroxyl groups were incorporated to modulate protein binding. Intrinsic potency was further improved through enantiospecific introduction of an olefin in the N-acyl motif, resulting in the discovery of the phase 2 clinical candidate GS-9669. The unexpected activity of this compound against the clinically relevant NS5B M423T mutant, relative to the wild type, was shown to arise from both the N-alkyl substituent and the N-acyl group.