Marking 2-Years of New Thinking in Clinical Trials: The Estimand Journey.

The ICH E9(R1) addendum on Estimands and Sensitivity Analyses in Clinical Trials has introduced a new estimand framework for the design, conduct, analysis, and interpretation of clinical trials. We share Pharmaceutical Industry experiences of implementing the estimand framework in the first two years since the final guidance became available with key lessons learned and highlight what else needs to be done to continue the journey in embedding the estimand framework in clinical trials. Emerging best practices and points to consider on strategies for implementing a new estimand thinking process are provided. Whilst much of the focus of implementing ICH E9(R1) to date has been on defining estimands, we highlight some of the important aspects relating to the choice of statistical analysis methods and sensitivity analyses to ensure estimands can be estimated robustly with minimal bias. In particular, we discuss the implications if complete follow-up is not possible when the treatment policy strategy is being used to handle intercurrent events. ICH E9(R1) was introduced just before the start of the COVID-19 pandemic, but a positive outcome from the pandemic has been an acceleration in the adoption of the estimand framework, including differentiating intercurrent events related or not related to the pandemic. In summary, much has been learned on the estimand journey and continued sharing of case studies will help to further advance the understanding and increase awareness across all clinical researchers of the estimand framework.

No evidence of increased risk of malignancies in patients with diabetes treated with insulin detemir: a meta-analysis.

AIMS/HYPOTHESIS: Recent epidemiological studies suggest that treatment with insulin glargine (A21Gly,B31Arg,B32Arg human insulin) may promote cancer growth. The present meta-analysis was performed to assess the risk of cancer during treatment with insulin detemir (B29Lys(epsilon-tetradecanoyl),desB30 human insulin), another long-acting insulin analogue. METHODS: This meta-analysis was performed in a population of 8,693 patients with type 1 or type 2 diabetes, who were included in Novo Nordisk-sponsored, randomised and controlled diabetes trials of at least 12 weeks in duration that compared insulin detemir with NPH insulin or insulin glargine. In a blinded manner, the adverse events with suspected treatment-emergent malignant tumours were obtained from these studies under three system-organ classes: 'Neoplasms benign, malignant and unspecified (including cysts and polyps)', 'Neoplasm' and 'Surgical and medical procedures'. Conditional ORs were estimated applying both the Mantel-Haenzel and Peto methods to ensure robustness of results. RESULTS: Separate analyses were performed for trials comparing insulin detemir with NPH insulin and insulin detemir with insulin glargine. In the first analysis, 16 studies were included with a total of 3,983 patients treated with insulin detemir and 2,661 patients treated with NPH insulin. In the second analysis, five studies were included with a total of 1,219 patients treated with insulin detemir and 830 patients treated with insulin glargine. The estimated OR for a cancer diagnosis between NPH insulin and insulin detemir was statistically significantly >1, with the ratio favouring insulin detemir. There was a more than twofold higher cancer occurrence in the NPH insulin-treated population. For the insulin detemir comparison with insulin glargine, there was a non-significant difference in ORs in favour of insulin detemir. CONCLUSIONS/INTERPRETATION: In these randomised controlled diabetes trials, patients treated with insulin detemir had a lower or similar occurrence of a cancer diagnosis compared with patients treated with NPH insulin or insulin glargine, respectively.

Biphasic insulin aspart given thrice daily is as efficacious as a basal-bolus insulin regimen with four daily injections: a randomised open-label parallel group four months comparison in patients with type 2 diabetes.

AIMS: To show that a thrice daily meal-time biphasic insulin aspart (BIAsp) treatment regimen is as efficacious as a 4 times daily basal-bolus regimen with human isophane insulin (NPH) and insulin aspart (IAsp). METHODS: A multinational, randomised, open-label parallel-group trial in 394 patients with type 2 diabetes on a once or twice daily insulin regimen. Patients were randomised 1:1 to BIAsp or IAsp+NPH for 16 weeks. The BIAsp group was treated according to individual needs using BMI as a surrogate index of insulin resistance. Subjects administered BIAsp 70 (BMI< or =30 kg/m (2)) or BIAsp 50 (BMI>30 kg/m (2)) with breakfast and lunch and BIAsp 30 with dinner. The IAsp+NPH group injected IAsp at meals and NPH at bedtime as basal insulin. HbAlc levels after 16 weeks were compared between treatments using a predefined non-inferiority criterion of 0.4%. The incidence of hypoglycaemic episodes and adverse events was evaluated. RESULTS: Mean HbAlc (+/-SD) decreased from 9.1+/-0.7% to 7.8+/-1.0% with both treatments. Glycaemic control provided by BIAsp was non-inferior to that obtained by the IAsp+NPH (intention to treat ITT) population: diff, HbAlc -0.05%; 95% CI (-0.24; 0.14); per protocol (PP) population: diff, HbAlc -0.03%; 95% CI (-0.23; 0.16). Similar improvements in glycaemic control in both groups were confirmed by self-measured 8-point plasma glucose (PG) profiles, average and fasting PG concentrations, and average prandial PG increments. The incidence of adverse events and hypoglycaemic episodes was similar in the two treatment groups. CONCLUSIONS: A thrice daily meal-time BIAsp regimen is a suitable alternative to an intensified insulin regimen in people with inadequately controlled type 2 diabetes mellitus, and requires fewer daily injections than a basal-bolus therapy without compromising efficacy and safety.

Good metabolic control is associated with better quality of life in 2,101 adolescents with type 1 diabetes.

OBJECTIVE: It is unclear whether the demands of good metabolic control or the consequences of poor control have a greater influence on quality of life (QOL) for adolescents with diabetes. This study aimed to assess these relations in a large international cohort of adolescents with diabetes and their families. RESEARCH DESIGN AND METHODS: The study involved 2,101 adolescents, aged 10-18 years, from 21 centers in 17 countries in Europe, Japan, and North America. Clinical and demographic data were collected from March through August 1998. HbA(1c) was analyzed centrally (normal range 4.4-6.3%; mean 5.4%). Adolescent QOL was assessed by a previously developed Diabetes Quality of Life (DQOL) questionnaire for adolescents, measuring the impact of diabetes, worries about diabetes, satisfaction with life, and health perception. Parents and health professionals assessed family burden using newly constructed questionnaires. RESULTS: Mean HbA(1c) was 8.7% (range 4.8-17.4). Lower HbA(1c) was associated with lower impact (P < 0.0001), fewer worries (P < 0.05), greater satisfaction (P < 0.0001), and better health perception (P < 0.0001) for adolescents. Girls showed increased worries (P < 0.01), less satisfaction, and poorer health perception (P < 0.01) earlier than boys. Parent and health professional perceptions of burden decreased with age of adolescent (P < 0.0001). Patients from ethnic minorities had poorer scores for impact (P < 0.0001), worries (P < 0.05), and health perception (P < 0.01). There was no correlation between adolescent and parent or between adolescent and professional scores. CONCLUSIONS: In a multiple regression model, lower HbA(1c) was significantly associated with better adolescent-rated QOL on all four subscales and with lower perceived family burden as assessed by parents and health professionals.

Persistent differences among centers over 3 years in glycemic control and hypoglycemia in a study of 3,805 children and adolescents with type 1 diabetes from the Hvidøre Study Group.

OBJECTIVE: Twenty-one international pediatric diabetes centers from 17 countries investigated the effect of simple feedback about the grand mean HbA(1c) level of all centers and the average value of each center on changes in metabolic control, rate of severe hypoglycemia, and insulin therapy over a 3-year period. RESEARCH DESIGN AND METHODS: Clinical data collection and determination of HbA(1c) levels were conducted at a central location in 1995 (n = 2,780, age 0-18 years) and 1998 (n = 2,101, age 11-18 years). RESULTS: Striking differences in average HbA(1c) concentrations were found among centers; these differences remained after adjustment for the significant confounders of sex, age, and diabetes duration. They were apparent even in patients with short diabetes duration and remained stable 3 years later (mean adjusted HbA(1c) level: 8.62 +/- 0.03 vs. 8.67 +/- 0.04 [1995 vs. 1998, respectively]). Three centers had improved significantly, four centers had deteriorated significantly in their overall adjusted HbA(1c) levels, and 14 centers had not changed in glycemic control. During the observation period, there were increases in the adjusted insulin dose by 0.076 U/kg, the adjusted number of injections by 0.23 injections per day, and the adjusted BMI by 0.95 kg/m(2). The 1995 versus 1998 difference in glycemic control for the seven centers could not be explained by prevailing insulin regimens or rates of hypoglycemia. CONCLUSIONS: This study reveals significant outcome differences among large international pediatric diabetes centers. Feedback and comparison of HbA(1c) levels led to an intensification of insulin therapy in most centers, but improved glycemic control in only a few.

Does a photographic cue facilitate false belief performance in subjects with autism?

The posting manipulation, which Mitchell and Lacohée (1991) successfully employed to facilitate false belief (FB) task performance in normally developing 3-year-olds, was employed with subjects with autism. There was no autism-specific impairment on the standard FB task, compared to mental handicap and normal controls: All groups performed poorly, with the autism and normal groups performing significantly worse than chance and the mental handicap group performing at chance. However, a facilitative effect was found on the posting FB task for all subject groups. On the posting task the mental handicap and normal controls groups performed significantly better than chance and the autism group performed at chance. The facilitative effect reached significance for the autism and normal groups. The lack of an autism-specific deficit on the standard task is discussed in relation to the somewhat variable findings of past studies of FB performance in autism. The facilitative effect of the posting manipulation may tell us something about the task demands required to pass a false belief task itself, and suggestions are made for future research to clarify how the facilitative effect operates.