Demystifying the estimand framework: a case study using patient-reported outcomes in oncology.

Patient-reported outcome (PRO) measures describe how a patient feels or functions and are increasingly being used in benefit-risk assessments in the development of cancer drugs. However, PRO research objectives are often ill-defined in clinical cancer trials, which can lead to misleading conclusions about patient experiences. The estimand framework is a structured approach to aligning a clinical trial objective with the study design, including endpoints and analysis. The estimand framework uses a multidisciplinary approach and can improve design, analysis, and interpretation of PRO results. On the basis of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use E9(R1) addendum, we provide an overview of the estimand framework intended for a multistakeholder audience. We apply the estimand framework to a hypothetical trial for breast cancer, using physical function to develop specific PRO research objectives. This Policy Review is not an endorsement of a specific study design or outcome; rather, it is meant to show the application of principles of the estimand framework to research study design and add to ongoing discussion. Use of the estimand framework to review medical products and label PROs in oncology can improve communication between stakeholders and ultimately provide a clearer interpretation of patient experience in the development of oncological drugs.

Registration trials of antibacterial drugs for the treatment of nosocomial pneumonia.

Since 1989, 12 registration trials have been submitted to the US Food and Drug Administration to support the clinical efficacy of 8 antibacterial drugs for the treatment of nosocomial pneumonia. Six trials used noninferiority designs, whereas the others were equivalence trials or lacked a prespecified hypothesis. Patients with nosocomial pneumonia and ventilator-associated pneumonia were frequently enrolled in the same clinical trials. Enrolled patients were predominantly male and had mean Acute Physiology and Chronic Health Evaluation II scores of 12-18. The investigator's assessment of clinical response was the primary end point, which was usually measured 7-14 days after study drug completion. Clinical cure rates among the intent-to-treat population for nosocomial pneumonia and ventilator-associated pneumonia ranged from 37% to 69% and 25% to 58%, respectively. All-cause mortality ranged from 8% to 28%. Pseudomonas aeruginosa, Acinetobacter species, and methicillin-resistant Staphylococcus aureus were common bacterial pathogens. The design, implementation, and limitations of the clinical trials and implications for future clinical research are discussed.

Memory Self-Appraisal and Cerebral Glucose Metabolism in Age-Associated Memory Impairment.

The authors used positron emission tomography to measure cerebral glucose metabolism in 43 people with age-associated memory impairment to determine relationships between memory self-appraisal and brain function. People with lower frontal metabolism during a resting state reported more frequent prior mnemonics usage, a measure of memory self-appraisal. A multiple regression analysis indicated that reported mnemonics usage was the most significant predictor of left (P = 0.0004) and right (P = 0.0014) frontal metabolism. These models indicated that mnemonics usage, along with depression ratings, accounted for 39% of left frontal lobe function and, along with visual spatial memory, accounted for 40% of right frontal metabolism. These results suggest that mnemonics usage may compensate for subtle frontal dysfunction or reflect greater efficiency of memory processing.

Statistical challenges in drug approval trials that use patient-reported outcomes.

This article describes challenging aspects of the use of patient-reported outcome instruments in clinical trials for drug approval, in our perspective as statistical reviewers at the US Food and Drug Administration. We discuss aspects of planning and interpreting results in clinical trials (1) adapting an existing patient-reported outcome instrument for use in clinical trials, (2) using multi-item patient-reported outcomes and (3) missing patient-reported outcome values from many subjects over time. These challenges are illustrated with multiple examples from different clinical trials for different indications. We finally discuss important considerations in labeling.

Social communication in children with epilepsy.

BACKGROUND: This study examined measures of social communication that involve the use of language in formulating and organizing thoughts and its relationship with seizure-related, developmental, cognitive, and behavioral variables in 92 children with complex partial seizure disorder (CPS), 51 with primary generalized epilepsy (PGE), and 117 normal children, aged 5.1-16.9 years. METHODS: Coding the children's speech samples with the Kiddie Formal Thought Disorder Rating Scale (Caplan et al., 1989) and Halliday and Hasan's (1976) analysis of cohesion demonstrated social communication deficits in both seizure disorder groups. RESULTS: The CPS patients had both formal thought disorder and cohesion deficits and the PGE group had mild cohesion deficits. IQ, as well as fronto-temporal and bilateral spike and wave activity were associated with the severity of the social communication deficits of the CPS group. The social communication deficits of the PGE group, however, were related to IQ and seizure control. CONCLUSIONS: Recurrent CPS and PGE and fronto-temporal localization of epileptic activity might impair the development of children's communication skills.