Prevalence and incidence of liver enzyme elevations in a pooled oncology clinical trial cohort.

Few epidemiologic studies describe longitudinal liver chemistry (LC) elevations in cancer patients. A population-based retrospective cohort was identified from 31 Phase 2-3 oncology trials (excluding targeted therapies) conducted from 1985 to 2005 to evaluate background rates of LC elevations in patients (n = 3998) with or without liver metastases. Patients with baseline liver metastases (29% of patients) presented with a 3% prevalence of alanine transaminase (ALT) ≥ 3x upper limits normal (ULN) and 0.2% prevalence of bilirubin ≥ 3xULN. During follow-up, the incidence (per 1000 person-months) of new onset ALT elevations ≥3xULN was 6.1 (95% CI: 4.5, 8.0) and 2.2 (95% CI: 0.9, 4.5) in patients without and with liver metastases, respectively. No new incident cases of ALT and bilirubin elevations suggestive of severe liver injury occurred among those with liver metastases; a single case occurred among those without metastasis. Regardless of the presence of liver metastases, LC elevations were rare in cancer patients during oncology trials, which may be due to enrollment criteria. Our study validates uniform thresholds for detection of LC elevations in oncology studies and serves as an empirical referent point for comparing liver enzyme abnormalities in oncology trials of novel targeted therapies. These data support uniform LC stopping criteria in oncology trials.

Statistical approaches for conducting network meta-analysis in drug development.

We introduce health technology assessment and evidence synthesis briefly, and then concentrate on the statistical approaches used for conducting network meta-analysis (NMA) in the development and approval of new health technologies. NMA is an extension of standard meta-analysis where indirect as well as direct information is combined and can be seen as similar to the analysis of incomplete-block designs. We illustrate it with an example involving three treatments, using fixed-effects and random-effects models, and using frequentist and Bayesian approaches. As most statisticians in the pharmaceutical industry are familiar with SAS® software for analyzing clinical trials, we provide example code for each of the methods we illustrate. One issue that has been overlooked in the literature is the choice of constraints applied to random effects, and we show how this affects the estimates and standard errors and propose a symmetric set of constraints that is equivalent to most current practice. Finally, we discuss the role of statisticians in planning and carrying out NMAs and the strategy for dealing with important issues such as heterogeneity.

Detection and kinetics of persistent neutralizing anti-interferon-beta antibodies in patients with multiple sclerosis. Results from the ABIRISK prospective cohort study.

Two validated assays, a bridging ELISA and a luciferase-based bioassay, were compared for detection of anti-drug antibodies (ADA) against interferon-beta (IFN-ß) in patients with multiple sclerosis. Serum samples were tested from patients enrolled in a prospective study of 18 months. In contrast to the ELISA, when IFN-ß-specific rabbit polyclonal and human monoclonal antibodies were tested, the bioassay was the more sensitive to detect IFN-ß ADA in patients' sera. For clinical samples, selection of method of ELISA should be evaluated prior to the use of a multi-tiered approach. A titer threshold value is reported that may be used as a predictor for persistently positive neutralizing ADA.

Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe: A descriptive study of test results.

Antibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta (IFNß) and natalizumab have been pooled and characterized through collaboration within a European consortium. The aim of this study was to report on the clinical practice of ADA testing in Europe, considering the number of ADA tests performed and type of ADA assays used, and to determine the frequency of ADA testing against the different drug preparations in different countries. A common database platform (tranSMART) for querying, analyzing and storing retrospective data of MS cohorts was set up to harmonize the data and compare results of ADA tests between different countries. Retrospective data from six countries (Sweden, Austria, Spain, Switzerland, Germany and Denmark) on 20,695 patients and on 42,555 samples were loaded into tranSMART including data points of age, gender, treatment, samples, and ADA results. The previously observed immunogenic difference among the four IFNß preparations was confirmed in this large dataset. Decreased usage of the more immunogenic preparations IFNß-1a subcutaneous (s.c.) and IFNß-1b s.c. in favor of the least immunogenic preparation IFNß-1a intramuscular (i.m.) was observed. The median time from treatment start to first ADA test correlated with time to first positive test. Shorter times were observed for IFNß-1b-Extavia s.c. (0.99 and 0.94 years) and natalizumab (0.25 and 0.23 years), which were introduced on the market when ADA testing was already available, as compared to IFNß-1a i.m. (1.41 and 2.27 years), IFNß-1b-Betaferon s.c. (2.51 and 1.96 years) and IFNß-1a s.c. (2.11 and 2.09 years) which were available years before routine testing began. A higher rate of anti-IFNß ADA was observed in test samples taken from older patients. Testing for ADA varies between different European countries and is highly dependent on the policy within each country. For drugs where routine monitoring of ADA is not in place, there is a risk that some patients remain on treatment for several years despite ADA positivity. For drugs where a strategy of ADA testing is introduced with the release of the drug, there is a reduced risk of having ADA positive patients and thus of less efficient treatment. This indicates that potential savings in health cost might be achieved by routine analysis of ADA.

Designing and incorporating a real world data approach to international drug development and use: what the UK offers.

Assessments of the safety, efficacy and appropriate use of new medicines lie at the heart of treatment development and subsequent adoption in clinical practice. Highly controlled randomised clinical trials routinely inform decisions on the approval, coverage and use of a medicine. Researchers and decision makers have become increasingly aware that these experimental data alone are insufficient to address those decisions fully. Real world data recorded from routine healthcare delivery by healthcare professionals and patients help provide a more complete picture of care. The UK, with its connectivity and rich longitudinal patient records, accumulated research and informatics experience and National Health Service, provides an exemplar of how real world data address a wide range of challenges across drug development.

Detecting Data Quality Issues in Clinical Trials: Current Practices and Recommendations.

BACKGROUND: Data quality issues in clinical trials can be caused by a variety of behaviors including fraud, misconduct, intentional or unintentional noncompliance, and significant carelessness. Regardless of how these behaviors are defined, they may compromise the validity of the study results. Reliable study results and quality data are needed to evaluate products for marketing approval and for decisions that are made on the use of medicine. This article focuses on detecting data quality issues, irrespective of origin or motive. Early detection of data quality issues are important so that corrective actions taken can be implemented during the conduct of the trial, recurrence can be prevented, and data quality can be preserved. METHODS: A survey was distributed to TransCelerate member companies to assess current strategies for detecting and mitigating risks involving fraud and misconduct in clinical trials. A review of literature across many industries from 1985 to 2014 was conducted using multiple platforms. RESULTS: Eighteen TransCelerate member companies anonymously responded to the survey. All of the respondents had one or more existing strategies for fraud and misconduct detection. The literature search identified current practices and methodologies across many industries. CONCLUSIONS: TransCelerate recommends the creation of an integrated, multifaceted approach to proactively detect data quality issues. Detection methods should include a strategy tailored to the characteristics of the study. Some sponsors are taking advantage of more advanced methods and integrated processes and systems to proactively detect and address issues, relying on advances in technology to more efficiently review data in real time. Further research is underway to assess statistical data quality detection methodology in clinical trials.

Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis.

Immunogenicity of biopharmaceutical products in multiple sclerosis is a frequent side effect which has a multifactorial etiology. Here we study associations between anti-drug antibody (ADA) occurrence and demographic and clinical factors. Retrospective data from routine ADA test laboratories in Sweden, Denmark, Austria and Germany (Dusseldorf group) and from one research study in Germany (Munich group) were gathered to build a collaborative multi-cohort dataset within the framework of the ABIRISK project. A subset of 5638 interferon-beta (IFNß)-treated and 3440 natalizumab-treated patients having data on at least the first two years of treatment were eligible for interval-censored time-to-event analysis. In multivariate Cox regression, IFNß-1a subcutaneous and IFNß-1b subcutaneous treated patients were at higher risk of ADA occurrence compared to IFNß-1a intramuscular-treated patients (pooled HR = 6.4, 95% CI 4.9-8.4 and pooled HR = 8.7, 95% CI 6.6-11.4 respectively). Patients older than 50 years at start of IFNß therapy developed ADA more frequently than adult patients younger than 30 (pooled HR = 1.8, 95% CI 1.4-2.3). Men developed ADA more frequently than women (pooled HR = 1.3, 95% CI 1.1-1.6). Interestingly we observed that in Sweden and Germany, patients who started IFNß in April were at higher risk of developing ADA (HR = 1.6, 95% CI 1.1-2.4 and HR = 2.4, 95% CI 1.5-3.9 respectively). This result is not confirmed in the other cohorts and warrants further investigations. Concerning natalizumab, patients older than 45 years had a higher ADA rate (pooled HR = 1.4, 95% CI 1.0-1.8) and women developed ADA more frequently than men (pooled HR = 1.4, 95% CI 1.0-2.0). We confirmed previously reported differences in immunogenicity of the different types of IFNß. Differences in ADA occurrence by sex and age are reported here for the first time. These findings should be further investigated taking into account other exposures and biomarkers.

Evaluating Source Data Verification as a Quality Control Measure in Clinical Trials.

TransCelerate has developed a risk-based monitoring methodology that transforms clinical trial monitoring from a model rooted in source data verification (SDV) to a comprehensive approach leveraging cross-functional risk assessment, technology, and adaptive on-site, off-site, and central monitoring activities to ensure data quality and subject safety. Evidence suggests that monitoring methods that concentrate on what is critical for a study and a site may produce better outcomes than do conventional SDV-driven models. This article assesses the value of SDV in clinical trial monitoring via a literature review, a retrospective analysis of data from clinical trials, and an assessment of major and critical findings from TransCelerate member company internal audits. The results support the hypothesis that generalized SDV has limited value as a quality control measure and reinforce the value of other risk-based monitoring activities.

Defining a Central Monitoring Capability: Sharing the Experience of TransCelerate BioPharma's Approach, Part 1.

Central monitoring, on-site monitoring, and off-site monitoring provide an integrated approach to clinical trial quality management. TransCelerate distinguishes central monitoring from other types of central data review activities and puts it in the context of an overall monitoring strategy. Any organization seeking to implement central monitoring will need people with the right skills, technology options that support a holistic review of study-related information, and adaptable processes. There are different approaches actively being used to implement central monitoring. This article provides a description of how companies are deploying central monitoring, as well as samples of the workflows that illustrate how some have implemented it. The desired outcomes include earlier, more predictive detection of quality issues. This paper describes the initial implementation steps designed to learn what organizational capabilities are necessary.