Real World-Evidence for Regulatory Use Decision Aid: An Interactive Tool To Inform Clinical Development and Regulatory Strategies.

Real-world evidence (RWE) is increasingly used to complement clinical trial data for regulatory decision-making and in certain cases utilized to establish the clinical effectiveness of a therapy. However, the use of RWE is not applicable for all regulatory submissions, and it can be challenging to identify appropriate use cases. An interactive tool was developed ("Decision Aid," https://sn.pub/TpDjZx ) to assist researchers, industry, and other stakeholders in identifying regulatory situations that can benefit from leveraging RWE by organizing precedent cases based on a given regulatory objective (new product approval, labeling expansion for new indication or additional clinical data, post-marketing requirement) and type of RWE study design (external control, observational study, pragmatic trial). Key success factors ensuring fit-for-purpose data and rigorous methods (e.g., clear endpoints, minimizing bias, data completeness) are also described. The tool allows the user to navigate through the precedent cases by selecting certain regulatory objectives and/or study designs. The Decision Aid supports regulatory activities in the RWE space and encourages further use of RWE in regulatory decision-making.

ENERGIZE: a Phase III study of neoadjuvant chemotherapy alone or with nivolumab with/without linrodostat mesylate for muscle-invasive bladder cancer.

Immune checkpoint inhibitors have revolutionized the treatment of patients with metastatic urothelial carcinoma. In cisplatin-eligible muscle-invasive bladder cancer (MIBC), cisplatin-based neoadjuvant chemotherapy (NAC) before radical cystectomy improves overall survival. Tumor PD-L1 expression increases in MIBC after NAC, suggesting potential synergy in combining PD1/PD-L1 inhibitors with NAC. IDO1 is overexpressed in bladder cancer and is associated with poor outcomes. Linrodostat mesylate (BMS-986205) - a selective, potent, oral IDO1 inhibitor - combined with nivolumab has demonstrated safety and preliminary evidence of clinical activity in metastatic urothelial carcinoma. Here, we discuss the rationale and trial design of the ENERGIZE, a Phase III trial investigating the efficacy of NAC in combination with nivolumab with or without linrodostat followed by postsurgery nivolumab or nivolumab with linrodostat in cisplatin-eligible patients with MIBC. Clinical trial registration number: NCT03661320.

Evaluation of bone marrow reticulin formation in chronic immune thrombocytopenia patients treated with romiplostim.

Romiplostim is a thrombopoietin receptor agonist that increases platelet counts in patients with chronic immune thrombocytopenia (ITP). Thrombopoietin receptor agonists are reported to increase the risk for reticulin fiber deposition within bone marrow. This report describes bone marrow findings from romiplostim-treated rats, a retrospective analysis of reticulin observed in romiplostim ITP clinical trials, and a prospective clinical study of the effects of romiplostim on bone marrow morphology. In rats, romiplostim produced a dose-dependent increase in bone marrow fibrosis that resolved after treatment withdrawal. Of 271 ITP patients in romiplostim clinical trials, 10 were reported to have reticulin deposition; reticulin grade was increased in 4 of 5 patients with both pretreatment and on-treatment bone marrow results. Reticulin grade often decreased soon after romiplostim discontinuation. In the prospective study, reticulin grade during romiplostim treatment remained within the normal range for all patients and was increased in only 1 of 6 patients with pretreatment and on-treatment bone marrow results. This report suggests that romiplostim produces reversible, dose-dependent bone marrow changes in rats and produces modest increases in bone marrow reticulin in some ITP patients that decrease when therapy is discontinued. These studies were registered at www.clinicaltrials.gov as #NCT00102323, #NCT00102336, #NCT00861224, and #NCT00116688.

Evaluating clinically meaningful change on the ITP-PAQ: preliminary estimates of minimal important differences.

OBJECTIVE: Interpretation of data from health-related quality of life (HRQoL) questionnaires can be enhanced with the availability of minimally important difference (MID) estimates. This information will aid clinicians in interpreting HRQoL differences within patients over time and between treatment groups. The Immune Thrombocytopenic Purpura (ITP)-Patient Assessment Questionnaire (PAQ) is the only comprehensive HRQoL questionnaire available for adults with ITP. RESEARCH DESIGN AND METHODS: Forty centers from within the US and Europe enrolled ITP patients into one of two multicenter, randomized, placebo-controlled, double-blind, 6-month, phase III clinical trials of romiplostim. Patients enrolled in these studies self-administered the ITP-PAQ and two items assessing global change (anchors) at baseline and weeks 4, 12, and 24. Using data from the ITP-PAQ and these two anchors, an anchor-based estimate was computed and combined with the standard error of measurement and standard deviation to compute a distribution-based estimate in order to provide an MID range for each of the 11 scales of the ITP-PAQ. RESULTS: A total of 125 patients participated in these clinical trials and provided data for use in these analyses. Combining results from anchor- and distribution-based approaches, MID values were computed for 9 of the 11 scales. MIDs ranged from 8 to 12 points for Symptoms, Bother, Psychological, Overall QOL, Social Activity, Menstrual Symptoms, and Fertility, while the range was 10 to 15 points for the Fatigue and Activity scales of the ITP-PAQ. These estimates, while slightly higher than other published MID estimates, were consistent with moderate effect sizes. CONCLUSIONS: These MID estimates will serve as a useful tool to researchers and clinicians using the ITP-PAQ, providing guidance for interpretation of baseline scores as well as changes in ITP-PAQ scores over time. Additional work should be done to finalize these initial estimates using more appropriate anchors that correlate more highly with the ITP-PAQ scales.

Epidemiology of immune thrombocytopenic purpura in the General Practice Research Database.

The epidemiology of immune thrombocytopenic purpura (ITP) is not well-characterised in the general population. This study described the incidence and survival of ITP using the UK population-based General Practice Research Database (GPRD). ITP patients first diagnosed in 1990-2005 were identified in the GPRD. Overall incidence rates (per 100,000 person-years) and rates by age, sex, and calendar periods were calculated. Survival analysis was conducted using the Kaplan-Meier and proportional hazard methods. A total of 1145 incident ITP patients were identified. The crude incidence was 3.9 (95% confidence interval [CI]: 3.7-4.1). Overall average incidence was statistically significantly higher in women (4.4, 95% CI: 4.1-4.7) compared to men (3.4; 95% CI: 3.1-3.7). Among men, incidence was bimodal with peaks among ages under 18 and between 75-84 years. The hazard ratio for death among ITP patients was 1.6 (95% CI: 1.3-1.9) compared to age- and sex-matched comparisons. During follow-up 139 cases died, of whom 75 had a computerised plausible cause of death. Death was related to bleeding in 13% and infection in 19% of these 75. In conclusion, ITP incidence varies with age and is higher in women than men. This potentially serious medical condition is associated with increased mortality in the UK.

Pharmacoepidemiology of anemia in kidney transplant recipients.

ABSTRACT. Anemia has long been known to be a complication of end-stage renal disease (ESRD), and it has been linked to cardiovascular morbidity and mortality. Although kidney transplant recipients (KTR) are prone to experiencing cardiovascular outcomes, little is known about the epidemiology of anemia in this population. With few exceptions, studies to date have not fully evaluated the associations between posttransplant anemia (PTA) and medications commonly used in KTR, particularly immunosuppressant drugs, angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB). The authors aimed to specifically investigate possible associations between these drugs and PTA. Detailed medical information was retrospectively collected on 374 consecutive KTR from our transplant clinic. Univariate/multivariate linear regression models were used to test for associations between hematocrit (HCT) and other covariates, and logistic regression models were used to detect independent predictors of PTA, defined as HCT <33%. The mean time since transplantation was 7.7 yr, and mean creatinine was 2.2 mg/dl. The prevalence of PTA was 28.6%. Ten percent of all patients were on erythropoietin therapy, but only 41.6% of patients whose HCT was <30 received this treatment. From multivariate analyses, the authors found that female gender and lower renal function were associated with lower HCT (both P < 0.001). Patients on ACEI had significantly lower HCT (P = 0.005) compared with patients without such treatment. In addition, a significant curvilinear dose-response relationship was found between ACEI dose and HCT. Among the immunosuppressant drugs, mycophenolate mofetil (P = 0.05) and tacrolimus (P = 0.02) were associated with a lower HCT. The authors conclude that PTA is prevalent and undertreated in KTR. Several medications that are possibly modifiable correlates of PTR deserve further study.