M. Parmar

Designing phase II trials in cancer: a systematic review and guidance

Background:Literature reviews of cancer trials have highlighted the need for better understanding of phase II statistical designs. Understanding the key elements associated with phase II design and knowledge of available statistical designs is necessary to enable appropriate phase II trial design.Methods:A systematic literature review was performed to identify phase II trial designs applicable to oncology trials. The results of the review were used to create a library of currently available designs, and to develop a structured approach to phase II trial design outlining key points for consideration.Results:A total of 122 papers describing new or adapted phase II trial designs were obtained. These were categorised into nine levels, reflecting the practicalities of implementation, and form a library of phase II designs. Key design elements were identified by data extraction. Along with detailed description of the key elements and the library of designs, a structured thought process was developed to form a guidance document for choice of phase II oncology trial design.Conclusion:The guidance offers researchers a structured and systematic approach to identifying phase II trial designs, highlighting key issues to be considered by both clinicians and statisticians and encouraging an interactive approach to more informed trial design.

A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

Background:Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies.Patients and Methods:Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients’ tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload.Results:A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15u2009w.d. in 91% and 20u2009w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival.Conclusions:Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.

Research-intensive cancer care in the NHS in the UK

In the late 1990 s, in response to poor national cancer survival figures, government monies were invested to enhance recruitment to clinical cancer research. Commencing with England in 2001 and then rolling out across all four countries, a network of clinical cancer research infrastructure was created, the new staff being linked to existing clinical care structures including multi-disciplinary teams. In parallel, a UK-wide co-ordination of cancer research funders driven by the virtual National Cancer Research Institute, combined to create a whole-system approach linking research funders, researchers and NHS clinicians all working to the same ends. Over the next 10 years, recruitment to clinical trials and other well-designed studies, increased 4-fold, reaching 17% of the incident cancer population, the highest national rate world-wide. The additional resources led to more studies opened, and more patients recruited across the country, for all types of cancers and irrespective of additional clinical research staff in some hospitals. In 2006, a co-ordinated decision was made to increasingly focus on randomized trials, leading to increased recruitment, without any fall-off in accrual to non-randomized and observational studies. The National Cancer Research Network has supported large successful trials which are changing clinical practice in many cancers.

Future research and methodological approaches

This supplement has explored the evidence for benefits from the participation of healthcare institutions and their patients in clinical research. The questions have been clarified. There is some encouragement that research active healthcare institutions may deliver improved outcomes compared to less research-active or research-inactive institutions but there is a pressing need for further research. In this chapter we explore the methodological challenges to evaluating the impact of the process of clinical research on hospitals and other healthcare organizations. The postulated mechanisms by which benefits may be accrued are important drivers of the types of research needed and these are emphasized. Study designs are explored including formal randomized trials, the stepped wedge randomized design, approaches to the design and analysis of observational studies particularly to examine whether a temporal or spatial relationship exists between changes in research activity and patients outcomes. It is acknowledged that in most future studies the data available will be cross-sectional and observational, and such studies are susceptible to many types of bias. The importance of identifying and addressing such biases in multivariate analysis is discussed and examples of successful studies are given.