Date Published: March 13, 2019
Publisher: Public Library of Science
Author(s): Rishi J. Desai, Ameet Sarpatwari, Sara Dejene, Nazleen F. Khan, Joyce Lii, James R. Rogers, Sarah K. Dutcher, Saeid Raofi, Justin Bohn, John G. Connolly, Michael A. Fischer, Aaron S. Kesselheim, Joshua J. Gagne, Sanjay Basu
Abstract: BackgroundTo the extent that outcomes are mediated through negative perceptions of generics (the nocebo effect), observational studies comparing brand-name and generic drugs are susceptible to bias favoring the brand-name drugs. We used authorized generic (AG) products, which are identical in composition and appearance to brand-name products but are marketed as generics, as a control group to address this bias in an evaluation aiming to compare the effectiveness of generic versus brand medications.Methods and findingsFor commercial health insurance enrollees from the US, administrative claims data were derived from 2 databases: (1) Optum Clinformatics Data Mart (years: 2004–2013) and (2) Truven MarketScan (years: 2003–2015). For a total of 8 drug products, the following groups were compared using a cohort study design: (1) patients switching from brand-name products to AGs versus generics, and patients initiating treatment with AGs versus generics, where AG use proxied brand-name use, addressing negative perception bias, and (2) patients initiating generic versus brand-name products (bias-prone direct comparison) and patients initiating AG versus brand-name products (negative control). Using Cox proportional hazards regression after 1:1 propensity-score matching, we compared a composite cardiovascular endpoint (for amlodipine, amlodipine-benazepril, and quinapril), non-vertebral fracture (for alendronate and calcitonin), psychiatric hospitalization rate (for sertraline and escitalopram), and insulin initiation (for glipizide) between the groups. Inverse variance meta-analytic methods were used to pool adjusted hazard ratios (HRs) for each comparison between the 2 databases. Across 8 products, 2,264,774 matched pairs of patients were included in the comparisons of AGs versus generics. A majority (12 out of 16) of the clinical endpoint estimates showed similar outcomes between AGs and generics. Among the other 4 estimates that did have significantly different outcomes, 3 suggested improved outcomes with generics and 1 favored AGs (patients switching from amlodipine brand-name: HR [95% CI] 0.92 [0.88–0.97]). The comparison between generic and brand-name initiators involved 1,313,161 matched pairs, and no differences in outcomes were noted for alendronate, calcitonin, glipizide, or quinapril. We observed a lower risk of the composite cardiovascular endpoint with generics versus brand-name products for amlodipine and amlodipine-benazepril (HR [95% CI]: 0.91 [0.84–0.99] and 0.84 [0.76–0.94], respectively). For escitalopram and sertraline, we observed higher rates of psychiatric hospitalizations with generics (HR [95% CI]: 1.05 [1.01–1.10] and 1.07 [1.01–1.14], respectively). The negative control comparisons also indicated potentially higher rates of similar magnitude with AG compared to brand-name initiation for escitalopram and sertraline (HR [95% CI]: 1.06 [0.98–1.13] and 1.11 [1.05–1.18], respectively), suggesting that the differences observed between brand and generic users in these outcomes are likely explained by either residual confounding or generic perception bias. Limitations of this study include potential residual confounding due to the unavailability of certain clinical parameters in administrative claims data and the inability to evaluate surrogate outcomes, such as immediate changes in blood pressure, upon switching from brand products to generics.ConclusionsIn this study, we observed that use of generics was associated with comparable clinical outcomes to use of brand-name products. These results could help in promoting educational interventions aimed at increasing patient and provider confidence in the ability of generic medicines to manage chronic diseases.
Partial Text: Generic drugs are a critical component of the healthcare system, accounting for approximately 90% of all US prescriptions dispensed . Generic drugs contain equivalent amounts of the same active ingredient(s) as their brand-name counterparts, but usually cost far less . Some prior studies have demonstrated improved adherence with generic drugs compared to brand-name drugs, likely due to price [3,4]. Generics are approved by regulators based on evidence of pharmaceutical equivalence and bioequivalence with the brand-name product, even though they may contain different inactive ingredients. Still, many patients and providers perceive generics to be less effective and less safe than their brand-name counterparts [5–11]. Some patients explicitly express concerns about the effectiveness of generic drugs to treat their serious illnesses . Negative expectations with generic products may lead patients to experience negative clinical outcomes due to a complex neurobiological phenomenon often described as the nocebo effect [13,14].
This study was undertaken as a part of a Cooperative Agreement (U01) with the FDA Office of Generic Drugs. As part of the funding proposal (S1 Text), we specified the study hypotheses, the pool of drugs of interest, the clinical outcomes of interest, and the analytic techniques to be used. Changes in the study methods to strengthen the study design, and for practical purposes, are detailed below. This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (S1 STROBE checklist).
In this study conducted using 2 large US commercial insurance databases, we used AGs—generic versions of brand-name products that are chemically identical and identical in appearance to the branded product—to account for potential bias due to negative perceptions towards generics in comparing the effectiveness of brand-name versus generic products. We observed equivalent or better clinical outcomes among patients who used generic versus AG products in 15 out of 16 comparisons across 8 drug products. When directly comparing individuals who initiated treatment with generic versus brand-name products, we used AGs versus brand-name products as a negative control comparison. For the 2 drugs for which we observed higher rates of hospitalization with a psychiatric condition with the generic version compared to the brand-name version—escitalopram and sertraline—the negative control comparisons also tended towards higher rates with AG use compared to brand-name use, suggesting that the differences observed between brand-name and generic users in these outcomes were likely explained by residual confounding or generic perception bias.
In this study of 8 drug products conducted using 2 large US commercial insurance databases, we observed that use of generics provided comparable clinical outcomes as the brand products. These results could be used in educational interventions aimed at increasing patient and physician confidence in the ability of generic medicines to manage chronic diseases.