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In this section, we will highlight the key high-impact studies, updates, and analyses published in medicine during the past week.
Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer’s Disease
Alzheimer’s disease is associated with the accumulation of aggregated amyloid-beta (Aβ) peptide in the cerebral cortex and hippocampus. A humanized monoclonal antibody, Solanezumab, binds soluble forms of amyloid and putatively promotes its clearance from the brain. In these two Phase 3 double-blind randomized control trial, a total of 2052 patients with mild-to-moderate Alzheimer’s were randomly assigned to receive placebo or solanezumab every 4 weeks for 18 months. Neither subgroup showed significant improvement in changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog11) [−0.8 points, 95% CI −2.1 to 0.5; P=0.24], the Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale (ADCS-ADL)[ −0.4 points, 95% CI, −2.3 to 1.4; P=0.64], or on the Alzheimer’s Disease Assessment Scale (ADAS-cog14)[ −1.7 point, 95% CI, −3.5 to 0.1; P=0.06]. Thus, Solanezumab failed to improve cognition or functional ability.
Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia
Patients with relapsed chronic lymphocytic leukemia (CLL), the most prevalent leukemia among adults, who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy, creating a need for effective therapies for this patient population. The B-cell–receptor signaling pathway, which plays a key role in the pathogenesis of CLL, is mediated in part by the activation of the delta isoform of phosphatidylinositol 3-kinase (PI3Kδ). Idelalisib is a potent, oral, selective small-molecule inhibitor of PI3Kδ. In this Phase 3 randomized control trial, 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses were randomly assigned to receive rituximab and either idelalisib or placebo twice daily. The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P=0.02), compared to those receiving placebo. Thus, the combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy.
Given the fact that resubmission of failed FDA approval applications is costly and delays the availability of new drugs to patients, it is important to understand whether most new drug applications fail because of inadequate drug performance or because the information submitted to the FDA is unsatisfactory to make that determination. In this retrospective review of FDA documents, all drug applications submitted to the FDA between 2000 and 2012 for new molecular entities (NMEs), active ingredients never before marketed in the US in any form, were reviewed. Of the 302 identified NME applications, 151 (50%) were approved when first submitted and 222 (73.5%) were ultimately approved. Of the unsuccessful first-time applications, 24 (15.9%) included uncertainties related to dose selection, 20 (13.2%) choice of study end points that failed to adequately reflect a clinically meaningful effect, 20 (13.2%) inconsistent results when different end points were tested, 17 (11.3%) inconsistent results when different trials or study sites were compared, and 20 (13.2%) poor efficacy when compared with the standard of care. Thus, failure to select optimal drug doses and suitable study end points accounted for significant delays in the approval of new drugs. Both of these can be prevented with more thorough study designs, ultimately decreasing costs.
There is ongoing controversy regarding whether access to firearms in the home increases the risk for violent death. In this meta-analysis, data were pooled from 15 observational studies that assessed the odds of suicide or homicide, yielding pooled odds ratios (ORs) of 3.24 (95% CI, 2.41 to 4.40) and 1.94 (CI, 1.44 to 2.93), respectively. When only studies that used interviews to determine firearm accessibility were considered, the pooled OR for suicide was 3.14 (CI, 2.29 to 4.43). Thus, this review concluded that access to firearms is associated with increased risk for completed suicide and being the victim of homicide.
The FDA evaluates safety and effectiveness of high-risk Cardiac Implantable Electronic Devices (CIEDs) such as pacemakers, implantable cardioverter-defibrillators, and cardiac resynchronization therapy devices, via the premarket approval (PMA) process. Subsequent changes to approved high-risk devices are implemented via “supplements,” which may not require additional clinical testing. This review of FDA’s PMA database reveals that of all the CIEDs approved from 1979 through 2012, 77 were original while 5829 were supplement PMA applications. Thirty-seven percent of approved supplements involved a change to the device’s design. Among 180-day supplements approved from 2010-2012, 23% (15/64) included new clinical data to support safety and effectiveness. Thus, it is important to realize that many CIEDs are approved via the PMA supplement process, not as original PMAs. Most of these new device models are deemed safe and effective without requiring new clinical data, reinforcing the importance of rigorous postapproval surveillance of these devices.
By Annick Aubin-Pouliot and David Ouyang
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