Real-world evidence for regulatory decision-making: updated guidance from around the world.

Leveraging the value of real-world evidence (RWE) to make informed regulatory decisions in the field of health care continues to gain momentum. Improving clinical evidence generation by evaluating the outcomes and patient experiences at the point-of-care would help achieve the ultimate aim of ensuring that effective and safe treatments are rapidly approved for patient use. In our previous publication, we assessed the global regulatory landscape with respect to RWE and provided a review of the regional availability of frameworks and guidance through May 2021 on the basis of 3 key regulatory elements: regulatory RWE frameworks, data quality guidance, and study methods guidance. In the current review, we have updated and elaborated upon recent developments in the regulatory RWE environment from a regional perspective under the same 3 regulatory elements stated above. In addition, we have also included a new category on procedural guidance. The review also discusses the perceived gaps and potential opportunities for future development and harmonization in this field to support framework establishment in regions without pre-existing RWE policies. Additionally, the article reviews current developments of health technology assessment (HTA) bodies pertaining to RWE and discusses the status of evidentiary alignment among regulators and HTA agencies.

External Control Arms in Idiopathic Pulmonary Fibrosis Using Clinical Trial and Real-World Data Sources.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease for which novel therapies are needed. External controls (ECs) could enhance IPF trial efficiency, but the direct comparability of ECs versus concurrent controls is unknown. Objectives: To develop IPF ECs by fit-for-purpose data standards to historical randomized clinical trial (RCT), multicenter registry (Pulmonary Fibrosis Foundation Patient Registry), and electronic health record (EHR) data and to evaluate endpoint comparability among ECs and the phase II RCT of BMS-986020. Methods: After data curation, the rate of change in FVC from baseline to 26 weeks among participants receiving BMS-986020 600 mg twice daily was compared with the BMS-placebo arm and ECs using mixed-effects models with inverse probability weights. Measurements and Main Results: At 26 weeks, the rates of change in FVC were -32.71 ml for BMS-986020 and -130.09 ml for BMS-placebo (difference, 97.4 ml; 95% confidence interval [CI], 24.6-170.2), replicating the original BMS-986020 RCT. RCT ECs showed treatment effect point estimates within the 95% CI of the original BMS-986020 RCT. Pulmonary Fibrosis Foundation Patient Registry ECs and EHR ECs experienced a slower rate of FVC decline compared with the BMS-placebo arm, resulting in treatment-effect point estimates outside of the 95% CI of the original BMS-986020 RCT. Conclusions: IPF ECs generated from historical RCT placebo arms result in comparable primary treatment effects to that of the original clinical trial, whereas ECs from real-world data sources, including registry or EHR data, do not. RCT ECs may serve as a potentially useful supplement to future IPF RCTs.

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.

Real-World Evidence for Regulatory Decision-Making: Guidance From Around the World.

PURPOSE: Interest in leveraging real-world evidence (RWE) to support regulatory decision making for product effectiveness has been increasing globally as evident by the increasing number of regulatory frameworks and guidance documents. However, acceptance of RWE, especially before marketing for regulatory approval, differs across countries. In addition, guidance on the design and conduct of innovative clinical trials, such as randomized controlled registry studies, pragmatic trials, and other hybrid studies, is lacking. METHODS: We assessed the global regulatory environment with regard to RWE based on regional availability of the following 3 key regulatory elements: (1) RWE regulatory framework, (2) data quality and standards guidance. and (3) study methods guidance. FINDINGS: This article reviews the available frameworks and existing guidance from across the globe and discusses the observed gaps and opportunities for further development and harmonization. IMPLICATIONS: Cross-country collaborations are encouraged to further shape and align RWE policies and help establish frameworks in countries without current policies with the goal of creating efficiencies when considering RWE to support regulatory decision-making globally.

Overall survival in the real-world and clinical trials: a case study validating external controls in advanced melanoma.

Aims: We assessed the suitability of real-world data (RWD) as an external control for analysis of overall survival (OS) compared with clinical trial data (CTD) in advanced melanoma. Methods: OS among adults receiving ipilimumab for advanced melanoma was compared between trials (CTD group) and the Flatiron Health database (RWD group) using Cox models. Adjusted analyses accounted for differences in baseline factors; missing data were addressed through multiple imputation. Results: After adjusting for baseline factors and accounting for missingness, OS was similar in the CTD (n = 241) versus RWD groups (n = 816; hazard ratio: 0.98; 95% CI: 0.75-1.26). Conclusion: Flatiron Health data is suitable to construct external control groups for OS in advanced melanoma trials after adjusting for baseline factors and missing data.

Clinical trials are the gold standard for measuring the efficacy and safety of new treatments. Comparisons between clinical trials and external controls drawn from real-world data are potentially valuable ­ especially when randomized trials are not available or feasible ­ but carry important risks of bias stemming from differences across populations, care settings and measurement of patient characteristics and outcomes. As a case study, we assessed the suitability of a particular real-world database (the Flatiron Health Database) for analyzing overall survival among patients in clinical trials of treatments for metastatic melanoma. Challenges included differences in patient baseline prognostic factors across populations, including high proportions with missing information in real-world data. After accounting for these differences, we observed similar survival between patients receiving ipilimumab monotherapy in clinical trials and in real-world data. We conclude that real-world external controls can be suitable for metastatic melanoma.

An update on drug-drug interactions between antiretroviral therapies and drugs of abuse in HIV systems.

INTRODUCTION: While considerable progress has been made in the fight against HIV/AIDS, to date there has not been a cure, and millions of people around the world are currently living with HIV/AIDS. People living with HIV/AIDS have substance abuse disorders at higher rates than non-infected individuals, which puts them at an increased risk of drug-drug interactions. AREAS COVERED: Potential drug-drug interactions are reviewed for a variety of potential drugs of abuse, both licit and illicit. These drugs include alcohol, cigarettes or other nicotine delivery systems, methamphetamine, cocaine, opioids, and marijuana. Potential interactions include decreased adherence, modulation of drug transporters, or modulation of metabolic enzymes. We also review the relative incidence of the use of these drugs of abuse in People living with HIV/AIDS. EXPERT OPINION: Despite considerable improvements in outcomes, disparities in outcomes between PLWHA who use drugs of abuse, vs those who do not still exist. It is of critical necessity to improve outcomes in these patients and to work with them to stop abusing drugs of abuse.

Economic and Clinical Burden of Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes in the U.S.

OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) and is strongly associated with type 2 diabetes mellitus (T2DM). Patients with both T2DM and NASH have increased risk for adverse clinical outcomes, leading to higher risk for mortality and morbidity. We built a Markov model with 1-year cycles and 20-year horizon to estimate the economic burden of NASH with T2DM in the U.S. RESEARCH DESIGN AND METHODS: Cohort size was determined by population size, prevalence of T2DM, and prevalence and incidence of NASH in 2017. The model includes 10 health states-NAFL, NASH fibrosis stages F0 through F3, compensated and decompensated cirrhosis, hepatocellular carcinoma, 1 year post-liver transplant, and post-liver transplant-as well as liver-related, cardiovascular, and background mortality. Transition probabilities were calculated from meta-analyses and literature. Annual costs for NASH and T2DM were taken from literature and billing codes. RESULTS: We estimated that there were 18.2 million people in the U.S. living with T2DM and NAFLD, of which 6.4 million had NASH. Twenty-year costs for NAFLD in these patients were $55.8 billion. Over the next 20 years, NASH with T2DM will account for 65,000 transplants, 1.37 million cardiovascular-related deaths, and 812,000 liver-related deaths. CONCLUSIONS: This model predicts significant clinical and economic burden due to NASH with T2DM over the next 20 years. In fact, this burden may be greater since we assumed conservative inputs for our model and did not increase costs or the incidence of T2DM over time. It is highly likely that interventions reducing morbidity and mortality in NASH patients with T2DM could potentially reduce this projected clinical and economic burden.

The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis.

BACKGROUND & AIMS: Although non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and NASH with advanced fibrosis are closely associated with type 2 diabetes mellitus (T2DM), their global prevalence rates have not been well described. Our aim was to estimate the prevalence of NAFLD, NASH, and advanced fibrosis among patients with T2DM, by regions of the world. METHODS: We searched for terms including NAFLD, NASH and T2DM in studies published from January 1989 to September 2018, using PubMed, Ovid MEDLINE®, EMBASE and Web of Science. Strict exclusion criteria were applied. Regional and global mean prevalence weighted by population size in each country were estimated and pooled using random-effects meta-analysis. Potential sources of heterogeneity were investigated using stratified meta-analysis and meta-regression. RESULTS: Among 80 studies from 20 countries that met our inclusion criteria, there were 49,419 individuals with T2DM (mean age 58.5 years, mean body mass index 27.9 kg/m2, and males 52.9%). The global prevalence of NAFLD among patients with T2DM was 55.5% (95% CI 47.3-63.7). Studies from Europe reported the highest prevalence (68.0% [62.1-73.0%]). Among 10 studies that estimated the prevalence of NASH, the global prevalence of NASH among individuals with T2DM was 37.3% (95% CI 24.7-50.0%). Seven studies estimated the prevalence of advanced fibrosis in patients with NAFLD and T2DM to be 17.0% (95% CI 7.2-34.8). Meta-regression models showed that geographic region and mean age (p <0.5) were associated with the prevalence of NAFLD, jointly accounting for 63.9% of the heterogeneity. CONCLUSIONS: This study provides the global prevalence rates for NAFLD, NASH, and advanced fibrosis in patients with T2DM. These data can be used to estimate the clinical and economic burden of NASH in patients with T2DM around the world. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) is now recognized as the most prevalent chronic liver disease worldwide. Type 2 diabetes mellitus (T2DM) is an important risk factor for NAFLD. Additionally, T2DM seems to accelerate the progression of liver disease in NAFLD. Despite the high prevalence and serious clinical implications of NAFLD in patients with T2DM, it is usually overlooked in clinical practice. This meta-analysis provides evidence of the high prevalence of NAFLD and NASH in patients with T2DM. In this context, increasing awareness about the importance of NAFLD in patients with T2DM among all important stakeholders (primary care physicians, specialists, and health policy makers) must be prioritized.

Effectiveness and Safety of Apixaban versus Warfarin as Outpatient Treatment of Venous Thromboembolism in U.S. Clinical Practice.

In the AMPLIFY clinical trial, apixaban was non-inferior to warfarin plus subcutaneous enoxaparin bridge therapy in the treatment of acute venous thromboembolism (VTE) and was associated with significantly less bleeding. This study evaluated their comparative effectiveness and safety in routine clinical practice. A matched-cohort design and data from four U.S. private health care claims databases were employed. Study population comprised patients who initiated outpatient treatment with apixaban versus warfarin (plus parenteral anticoagulant bridge therapy) within 30 days of their initial VTE episode; apixaban and warfarin patients were matched on age, characteristics of VTE episode, study database and propensity score. Major bleeding, clinically relevant non-major (CRNM) bleeding and recurrent VTE during the 180-day (maximum) follow-up period were compared using shared frailty models. During mean follow-up of 143 days among apixaban patients (n = 17,878) and 152 days among warfarin patients (n = 17,878), incidence proportions for apixaban versus warfarin, respectively, were 1.7% versus 2.3% for major bleeding, 7.0% versus 9.4% for CRNM bleeding and 2.3% versus 2.9% for recurrent VTE. In shared frailty models, risks of major bleeding (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.64-0.87), CRNM bleeding (HR = 0.77, 95% CI = 0.71-0.83) and recurrent VTE (HR = 0.80, 95% CI = 0.70-0.91) were lower for apixaban versus warfarin. In this large-scale evaluation of VTE patients receiving outpatient treatment with apixaban or warfarin in U.S. clinical practice, risks of major bleeding, CRNM bleeding and recurrent VTE were significantly lower among patients who received apixaban.

Incidence of type 2 diabetes mellitus and hyperlipidemia in patients prescribed dasatinib or nilotinib as first- or second-line therapy for chronic myelogenous leukemia in the US.

OBJECTIVE: Evaluate the incidence of type 2 diabetes mellitus (T2DM) and hyperlipidemia (HLD) in CML patients initiating therapy with dasatinib or nilotinib. METHODS: Retrospective study using MarketScan claims from January 2006 to December 2014. The first analysis evaluated occurrence of T2DM, defined as ≥2 claims with a T2DM ICD-9 code or 1 diagnosis claim and an antidiabetic medication. The second analysis evaluated occurrence of HLD, defined as ≥2 claims with an HLD ICD-9 code, or 1 diagnosis claim and an anti-HLD medication. Incidence rates were computed as number of events divided by sum of person years (PY) at risk for all subjects. Multivariate Cox proportional hazards models estimated hazard ratios (HRs) for T2DM or HLD. RESULTS: There were 2004 and 1280 patients who met the criteria for the T2DM analysis (n = 1272 dasatinib, n = 732 nilotinib) and HLD analysis (n = 845 dasatinib, n = 435 nilotinib). The incidence rate of T2DM was 40.4 per 1000 PY (95% CI: 27.60, 56.98) for nilotinib and 17.6 per 1000 PY (95% CI: 11.14, 26.38) for dasatinib. HR for occurrence of T2DM was 2.77 (95% CI: 1.58, 4.86), indicating that patients on nilotinib had a significantly higher adjusted risk for incident T2DM. The incidence rate of HLD was 74.6 per 1000 PY (95% CI: 50.70, 105.94) for nilotinib and 46.4 per 1000 PY (95% CI: 33.00, 63.45) for dasatinib. HR for occurrence of HLD was 1.75 (95% CI: 1.07, 2.87) indicating that patients on nilotinib had a significantly higher adjusted risk for incident HLD. CONCLUSIONS: Patients receiving nilotinib had significantly higher rates of incident T2DM or HLD than patients on dasatinib.

Comparison of "Word" vs. "Picture" Version of the Free and Cued Selective Reminding Test (FCSRT) in Older Adults.

BACKGROUND: This study examined the psychometric relationship between the Word and Picture versions of the Free and Cued Selective Reminding Test (FCSRT) and developed an equation for score conversion. METHODS: 187 participants were administered the FCSRT-Picture and FCSRT-Word on two visits using a randomized counterbalanced design. RESULTS: Participants had a mean age of 82.1 (sd=5.4) and mean education of 14.5 (sd=3.3) years. Mean FCSRT-Picture Free Recall score (mean 33.0, range: 17-44) was 7.9 points higher than the Word score (mean 25.1, range: 3-43). The Picture and Word FCSRT correlations for Free Recall and Total Recall were r=0.56, p<0.01 and r=0.46, p<0.01, respectively. DISCUSSION: The Picture and Word versions of the FCSRT were moderately associated in a sample of cognitively normal older adults. The score mean differences and variability between FCSRT-Picture and FCSRT-Word indicate that their scores should not be considered equivalent.

Value-based assessment of pharmacodiagnostic testing from early stage development to real-world use.

Disease etiology may be regarded as a consequence of both genotypic and biochemical phenomena, which impact individual patients in different ways. Disease prognosis, beneficial treatment response, and susceptibility to adverse drug effects are often intimately tied to individual biology. Clinical and genetic biomarkers applied individually or in concert are increasingly used to stratify patient populations in terms of prognosis, therapeutic benefit, or safety. As a result, clinical trialists are challenged to design studies that reflect these determinants of outcome, to optimize the patient's eventual clinical course both in the trial and in actual practice. These designs are informed both by preclinical studies and by real-world research that can establish proof of concept for a novel biomarker and provide a basic understanding of the relationship between biomarker and clinical outcome. As clinical and real-world studies unfold, a deeper understanding of the nature of the biomarker and its potential uses in drug development is gained. Specifically, one can eventually define the biomarker as prognostic (i.e., predicts disease progression), predictive (predicts treatment response or adverse outcome(s)), or exhibiting both prognostic and predictive properties. One must further validate the performance of these emerging biomarkers, again in both the trial and real-world environments. The eventual adoption of the biomarker as a useful pharmacodiagnostic test is premised upon this early translational research. In this article, the development and validation of predictive and prognostic biomarkers is discussed by using selected examples that highlight factors contributing to the valuation of biomarkers and their application to personalized medicine in the real world.

Measurements of medial temporal lobe atrophy for prediction of Alzheimer's disease in subjects with mild cognitive impairment.

Our aim was to compare the predictive accuracy of 4 different medial temporal lobe measurements for Alzheimer's disease (AD) in subjects with mild cognitive impairment (MCI). Manual hippocampal measurement, automated atlas-based hippocampal measurement, a visual rating scale (MTA-score), and lateral ventricle measurement were compared. Predictive accuracy for AD 2 years after baseline was assessed by receiver operating characteristics analyses with area under the curve as outcome. Annual cognitive decline was assessed by slope analyses up to 5 years after baseline. Correlations with biomarkers in cerebrospinal fluid (CSF) were investigated. Subjects with MCI were selected from the Development of Screening Guidelines and Clinical Criteria for Predementia AD (DESCRIPA) multicenter study (n = 156) and the single-center VU medical center (n = 172). At follow-up, area under the curve was highest for automated atlas-based hippocampal measurement (0.71) and manual hippocampal measurement (0.71), and lower for MTA-score (0.65) and lateral ventricle (0.60). Slope analysis yielded similar results. Hippocampal measurements correlated with CSF total tau and phosphorylated tau, not with beta-amyloid 1-42. MTA-score and lateral ventricle volume correlated with CSF beta-amyloid 1-42. We can conclude that volumetric hippocampal measurements are the best predictors of AD conversion in subjects with MCI.

Screening for predementia AD: time-dependent operating characteristics of episodic memory tests.

OBJECTIVE: Data from the Einstein Aging Study (EAS) were used to prospectively evaluate the free recall score from the free and cued selective reminding test (FCSRT-FR) and logical memory I immediate recall (LM-IR) subtest of the Wechsler memory scale-revised for prediction of incident Alzheimer disease (AD) dementia among individuals from a community-based cohort with memory complaints. METHODS: Analyses included 854 participants, age ≥70 years, who initially had no dementia, and had memory complaints. Clinic evaluations were completed annually and AD dementia was diagnosed using standard criteria (n = 86 cases; average follow-up 4.1 years). Time-dependent receiver operating characteristic analysis was used to evaluate the prognostic ability of FCSRT-FR and LM-IR for incident AD over various durations of follow-up. RESULTS: For identifying those with memory complaints who will develop incident AD dementia over 2-4 years, the FCSRT-FR had better operating characteristics than LM-IR. APOE ε4 status, age, and education did not affect cut points; however, positive predictive values were higher among APOE ε4-positive individuals. CONCLUSIONS: For follow-up intervals of 2-4 years, the FCSRT-FR is more predictive than the LM-IR for identifying individuals with memory complaints who will develop incident AD. APOE ε4 status improves positive predictive value, but does not affect the choice of optimal cuts.

Injury markers predict time to dementia in subjects with MCI and amyloid pathology.

OBJECTIVES: Alzheimer disease (AD) can now be diagnosed in subjects with mild cognitive impairment (MCI) using biomarkers. However, little is known about the rate of decline in those subjects. In this cohort study, we aimed to assess the conversion rate to dementia and identify prognostic markers in subjects with MCI and evidence of amyloid pathology. METHODS: We pooled subjects from the VU University Medical Center Alzheimer Center and the Development of Screening Guidelines and Criteria for Predementia Alzheimer's Disease (DESCRIPA) study. We included subjects with MCI, an abnormal level of ß-amyloid(1-42) (Aß(1-42)) in the CSF, and at least one diagnostic follow-up visit. We assessed the effect of APOE genotype, CSF total tau (t-tau) and tau phosphorylated at threonine 181 (p-tau) and hippocampal volume on time to AD-type dementia using Cox proportional hazards models and on decline on the Mini-Mental State Examination (MMSE) using linear mixed models. RESULTS: We included 110 subjects with MCI with abnormal CSF Aß(1-42) and a mean MMSE score of 26.3 ± 2.8. During a mean follow-up of 2.2 ± 1.0 (range 0.4-5.0) years, 63 subjects (57%) progressed to AD-type dementia. Abnormal CSF t-tau (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.1-4.6, p = 0.03) and CSF p-tau (HR 3.5, 95% CI 1.3-9.2, p = 0.01) concentration and hippocampal atrophy (HR 2.5, 95% CI 1.1-5.6, p = 0.02) predicted time to dementia. For subjects with both abnormal t-tau concentration and hippocampal atrophy, HR was 7.3 (95% CI 1.0-55.9, p = 0.06). Furthermore, abnormal CSF t-tau and p-tau concentrations and hippocampal atrophy predicted decline in MMSE score. CONCLUSIONS: In subjects with MCI and evidence of amyloid pathology, the injury markers CSF t-tau and p-tau and hippocampal atrophy can predict further cognitive decline.

The epidemiology of Alzheimer's disease: laying the foundation for drug design, conduct, and analysis of clinical trials.

Epidemiological studies increasingly inform Alzheimer's disease (AD) public health impact, prevention strategies, drug targets, therapeutic interventions, and clinical trial design. For this reason, the Alzheimer's Association Research Roundtable convened an international group of AD experts with experience in conducting both observational and clinical trials for a meeting on October 19 and 20, 2010, in Washington, DC, to discuss the role of epidemiologic studies in AD research and therapeutic advances. Topics included wellness markers and risk factors, with a focus on special populations such as those at elevated risk, super agers, and underserved populations. Discussions also highlighted lessons learned from observational studies of aging, cardiovascular disease, and other disease areas, as well as how new technologies have enabled the gathering of data relevant to drug development and clinical trial conduct.

Test sequence of CSF and MRI biomarkers for prediction of AD in subjects with MCI.

Our aim was to identify the best diagnostic test sequence for predicting Alzheimer's disease (AD)-type dementia in subjects with mild cognitive impairment (MCI) using cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) biomarkers. We selected 153 subjects with mild cognitive impairment from a multicenter memory clinic-based cohort. We tested the CSF beta amyloid (Aß)1-42/tau ratio using enzyme-linked immunosorbent assay (ELISA) and hippocampal volumes (HCVs) using the atlas-based learning embeddings for atlas propagation (LEAP) method. Outcome measure was progression to AD-type dementia in 2 years. At follow-up, 48 (31%) subjects converted to AD-type dementia. In multivariable analyses, CSF Aß1-42/tau and HCV predicted AD-type dementia regardless of apolipoprotein E (APOE) genotype and cognitive scores. Test sequence analyses showed that CSF Aß1-42/tau increased predictive accuracy in subjects with normal HCV (p < 0.001) and abnormal HCV (p = 0.025). HCV increased predictive accuracy only in subjects with normal CSF Aß1-42/tau (p = 0.014). Slope analyses for annual cognitive decline yielded similar results. For selection of subjects for a prodromal AD trial, the best balance between sample size and number of subjects needed to screen was obtained with CSF markers. These results provide further support for the use of CSF and magnetic resonance imaging biomarkers to identify prodromal AD.

Impact of early intervention and disease modification in patients with predementia Alzheimer's disease: a Markov model simulation.

BACKGROUND: Early screenings involving biomarkers and use of potential disease-modifying therapies (DMTs) may have significant humanistic implications for treatment strategies in Alzheimer's disease. METHODS: Markov models simulated transitions of patient cohorts beginning in predementia, a hypothetical early stage of Alzheimer's disease marked by objective cognitive impairment/memory complaints without functional impairment, and followed for 10 years. Hypothetical cohorts of 10,000 patients included those who were treated with standard of care (donepezil) upon reaching mild-moderate Alzheimer's disease, a DMT in predementia, and a DMT in mild-moderate Alzheimer's disease. Transition probabilities were based on data from the Alzheimer's Disease Neuroimaging Initiative and published clinical data, and estimated for the hypothetical DMT. In each disease stage (predementia, mild, moderate, or severe), time was computed and costs were estimated using literature review and published data, and published data provided mortality rates. The impact of screening was evaluated using positive predictive value (patients identified as predementia truly at risk for transition to dementia). RESULTS: Earlier treatment yielded modest gains in total life-years; however, the distribution was skewed towards milder disease. Assuming a 25% reduction in the annual risk of progression, treating predementia patients with DMT increased life-years in predementia to mild states on average from 3.2 to 4.2, while life-years spent in moderate-to-severe Alzheimer's disease decreased from 2.6 to 2.2. Average time in the community increased from 4.4 to 5.4 years, while time in long-term care declined from 1.3 to 0.9 years. This impact grows as the advantage of the novel agent increases. Screening accuracy had significant implications for cost-effectiveness. CONCLUSION: If screening can accurately identify predementia patients at risk for progression, earlier treatment with DMTs has the potential benefit to patients of prolonging time in milder disease, reducing time spent with more severe disease, increasing time in the community, and reducing time in long-term care.

Treatment patterns in patients with advanced breast cancer who were exposed to an anthracycline, a taxane, and capecitabine: a descriptive report.

OBJECTIVE: The aim of this work was to analyze chemotherapy treatment patterns in patients with advanced breast cancer who had been previously exposed to an anthracycline, a taxane, and capecitabine. METHODS: This retrospective cohort study used medical and pharmacy administrative claims with health-plan enrollment data and medical-record review from a large, US-based health insurer database, the HealthCore Integrated Research Database. Women were included if they were aged > or =18 years at the initial breast cancer diagnosis between January 1999 and July 2005 and had received all 3 drug classes of interest, as well as an initial diagnosis of American Joint Committee on Cancer stage I to III breast cancer with metastatic recurrence or an initial diagnosis of stage IV disease. Information about demographics, clinical and pathologic characteristics, survival, and treatments were obtained from computerized data and medical record review. Descriptive analyses were conducted to characterize the treatment patterns. RESULTS: One hundred forty-four women with advanced breast cancer were identified. Patients ranged in age from 28 to 76 years, with a mean (SD) age of 48.2 (9.1) years, and with 54 patients (37.5%) aged 40 to 49 years and 48 patients (33.3%) aged 50 to 59 years at the time of initial diagnosis. Ninety-three patients (64.6%) were white, 15 (10.4%) were black, 7 (4.9%) were Hispanic, and 4 (2.8%) were Asian. Overall, 89 patients (61.8%) received > or =1 additional chemotherapy regimen after exposure to all 3 chemotherapy agents of interest; 55 (38.2%) received > or =2 additional regimens. A variety of chemotherapeutic regimens were prescribed; 14 monotherapy regimens and 37 combination therapy regimens were used. The most common regimens (both as single agents and combination therapy) included gemcitabine, vinorelbine, or retreatment with a taxane. Of the 89 patients who received > or =1 retreatment, 7 (7.9%) were retreated with anthracycline, 12 (13.5%) with a taxane, and 9 (10.1%) with capecitabine. For first and second treatment after exposure to all 3 agents of interest, the most common single-agent regimens were gemcitabine (first: 17 patients [19.1%]; second: 9 patients [16.4%]) and vinorelbine (first: 14 patients [15.7%]; second: 9 patients [16.4%]). The most common combination therapies for first retreatment were carboplatin based (6 patients [6.7%]). CONCLUSIONS: Of these patients with advanced breast cancer, 61.8% received > or =1 additional chemotherapy regimen after previous treatment with an anthracycline, a taxane, and capecitabine. The variety of agents prescribed suggests a lack of standard of care. Rigorous clinical effectiveness studies of common regimens in heavily pretreated and chemotherapy-resistant populations with breast cancer are warranted.