Gillis Carrigan

The Xolair Pregnancy Registry (EXPECT): The safety of omalizumab use during pregnancy

BACKGROUND For many asthma medications, pregnancy safety data remains insufficient. OBJECTIVE The omalizumab pregnancy registry, EXPECT, evaluates maternal, pregnancy, and infant outcomes after exposure to omalizumab, including incidence of congenital anomalies. METHODS EXPECT is a prospective, observational study of pregnant women exposed to ≥1 dose of omalizumab within 8 weeks prior to conception or at any time during pregnancy. Primary outcome measures include rates of live births, elective terminations, stillbirths, and congenital anomalies. Data were collected at enrollment, each trimester, birth, and every 6 months up to 18 months post-delivery. RESULTS As of November 2012, 188 of 191 pregnant women were exposed to omalizumab during their first trimester. Of 169 pregnancies with known outcomes (median exposure during pregnancy, 8.8 months), there were 156 live births of 160 infants (4 twin pairs), 1 fetal death/stillbirth, 11 spontaneous abortions, and 1 elective termination. Among 152 singleton infants, 22 (14.5%) were born prematurely. Of 147 singleton infants with weight data, 16 (10.9%) were small for gestational age. Among 125 singleton full-term infants, 4 (3.2%) had low birth weights. Overall, 20 infants had congenital anomalies confirmed, 7 (4.4%) of whom had 1 major defect. No pattern of anomalies was observed. CONCLUSIONS To date, proportions of major congenital anomalies, prematurity, low birth weight, and small size for gestational age observed in the EXPECT registry are not inconsistent with findings from other studies in this asthma population. Recognizing the small sample size available, no apparent increased birth prevalence of major anomalies or patterns of major anomalies has been observed.

Cardiovascular and cerebrovascular events among patients receiving omalizumab: Results from EXCELS, a prospective cohort study in moderate to severe asthma

Background: EXCELS, a postmarketing observational cohort study, was a commitment to the US Food and Drug Administration to assess the long‐term safety of omalizumab in an observational setting, focusing predominantly on malignancies. Objective: The aim of this study was to examine a potential association between omalizumab and cardiovascular (CV)/cerebrovascular (CBV) events in EXCELS. Methods: Patients (≥12 years of age) with moderate to severe allergic asthma and who were being treated with omalizumab (n = 5007) or not (n = 2829) at baseline were followed up for ≤5 years. Analyses included overall CV/CBV events, but focused on the subset of arterial thromboembolic events (ATEs), comprising CV death, myocardial infarction, ischemic stroke, transient ischemic attack, and unstable angina. A prespecified analysis of the end point of ATE was conducted to control for available potential confounders. A blinded independent expert panel adjudicated all events. Results: At baseline, the 2 cohorts had similar demographic characteristics, but severe asthma was more common in the omalizumab versus the non‐omalizumab group (50% vs 23%). Omalizumab‐treated patients had a higher rate of CV/CBV serious adverse events (13.4 per 1,000 person years [PYs]) than did non–omalizumab‐treated patients (8.1 per 1,000 PYs). The ATE rates per 1,000 PYs were 6.66 (101 patients/15,160 PYs) in the omalizumab cohort and 4.64 (46 patients/9,904 PYs) in the non‐omalizumab cohort. After control for available confounding factors, the hazard ratio was 1.32 (95% CI, 0.91–1.91). Conclusion: This observational study demonstrated a higher incidence rate of CV/CBV events in the omalizumab versus the non‐omalizumab cohort. Differences in asthma severity between cohorts likely contributed to this imbalance, but some increase in risk cannot be excluded.

Development and Validation of a High-Quality Composite Real-World Mortality Endpoint

Objective To create a high‐quality electronic health record (EHR)–derived mortality dataset for retrospective and prospective real‐world evidence generation. Data Sources/Study Setting Oncology EHR data, supplemented with external commercial and US Social Security Death Index data, benchmarked to the National Death Index (NDI). Study Design We developed a recent, linkable, high‐quality mortality variable amalgamated from multiple data sources to supplement EHR data, benchmarked against the highest completeness U.S. mortality data, the NDI. Data quality of the mortality variable version 2.0 is reported here. Principal Findings For advanced non‐small‐cell lung cancer, sensitivity of mortality information improved from 66 percent in EHR structured data to 91 percent in the composite dataset, with high date agreement compared to the NDI. For advanced melanoma, metastatic colorectal cancer, and metastatic breast cancer, sensitivity of the final variable was 85 to 88 percent. Kaplan–Meier survival analyses showed that improving mortality data completeness minimized overestimation of survival relative to NDI‐based estimates. Conclusions For EHR‐derived data to yield reliable real‐world evidence, it needs to be of known and sufficiently high quality. Considering the impact of mortality data completeness on survival endpoints, we highlight the importance of data quality assessment and advocate benchmarking to the NDI.

Potential for using external control arms derived from electronic health records to replace control arms from randomized controlled trials

Background: Non-inferiority trials are associated with methodological challenges. The European Medicines Agency (EMA) does not have a guideline on designing non-inferiority trials and recommend to define the non-inferiority margin based on clinical and statistical considerations. However, they do not recommend a specific method to determine the margin. Objectives: To assess the challenges in designing non-inferiority trials for drugs intended to be marketed in Europe. Methods: Using the database of the Dutch Medicines Evaluation Board (MEB), a search in recent (2014 and 2015) final EMA scientific advice letters was conducted to identify design proposals that were sent by pharmaceutical companies to the EMA about non-inferiority trials. Each scientific letter is for one drug, and it includes proposals for different aspects of the trial with a response from the EMA to each proposal. The proportion of the accepted proposals by the EMA was assessed taking into account the therapeutic class and the type of the drug application (orphan vs other drugs) using generalized estimating equations with an exchangeable correlation matrix to account for clustering of proposals within letters. Results: The EMA accepted 142 of 232 (61%) of the total proposals. Almost 65% of the proposals were for three therapeutic classes: anti-infectives (most common), drugs for endocrine disorders (mainly anti-diabetics), and oncology drugs. The EMA acceptance did not differ between proposals for endocrine drugs vs anti-infectives (OR: 1.30, 95%CI 0.52 to 3.24) and between oncology drugs vs anti-infectives (OR: 0.54, 95%CI 0.12 to 2.47). The EMA acceptance also did not differ between orphan vs other drug applications (OR: 0.47 95%CI 0.19 to 1.14). The non-inferiority margin was the main challenge, only 25 of 61 (41%) proposals for the choice of the margin were accepted. There was no common approach proposed by pharmaceutical companies to define the margin (the recommended approach by the EMA was proposed for only 18 of 61 margins) nor a common method of the recommended approach. Conclusions: There are many questions about the design of non-inferiority trials with the choice of the inferiority margin as the main challenge. We did not find that the challenge was related to one of the three most common therapeutic classes or to a type of drug applications. This study shows that more explicit guidance from the EMA on the rationale for choosing different approaches to define the margin is needed.against myocardial infarction in UK adults aged at least 65y Background A recent investigation using routinely collected health records found the influenza vaccine to be effective against heart failure. However, treatment of overt myocardial infarction (MI) events is important in preventing progression to heart failure, especially in older adults, yet evidence for the association between respiratory disease and subsequent MI is from observational data and subject to confounding bias.Background: Cough and angioedema are well-known adverse effects of angiotensin-converting enzyme (ACE) inhibitors. Some observational studies in patients using ACE inhibitors have observed that women have a higher incidence of cough and angioedema than men. Objectives: To evaluate based on randomized controlled trials (RCTs), whether the risks of developing cough and angioedema with ACE inhibitors are modified by sex. Methods: We searched PubMed and Cochrane databases for all years to August 2016. We included RCTs that contain information about the incidence of cough and angioedema in users of ACE inhibitors and controls (active/placebo) in men and women. We performed meta-analyses using the random effects model. Pooled risk ratios (RRs) for cough and angioedema associated with ACE inhibitors in women and men were estimated and tested for interaction. Results: We included four RCTs in our analysis (three studies for cough and two studies for angioedema). We found that there was no difference in the RR to develop cough or angioedema for ACE inhibitors versus controls between women and men. For cough in women, the RR was 3.70; 95% CI (2.55-5.35) and for men, 2.61; 95% CI (1.30-5.27) (P value for interaction 0.39). For angioedema, these RRs were 5.56; 95% CI (2.45-12.62) and 6.35; 95% CI (1.81-22.36), respectively (P-value for interaction 0.86). Conclusions: Our meta-analyses show that the risks of developing cough and angioedema associated with ACE inhibitors are not modified by sex. However, these findings should be interpreted cautiously due to limited number of studies involved.