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Non-medical Switching from Originator Tumor Necrosis Factor Inhibitors to Their Biosimilars: Systematic Review of Randomized Controlled Trials and Real-World Studies.

ABSTRACT: Tumor necrosis factor (TNF) inhibitors are widely used biologics for the treatment of several chronic inflammatory diseases. The launch of anti-TNF biosimilars has introduced the possibility of non-medical switching between originator biologics and their biosimilars. However, the potential clinical and patient-reported consequences of non-medical switching remain largely unknown, as much of the evidence comes from poorly or uncontrolled real-world evidence (RWE) studies that often have an element of bias and nonstandardized outcome measures. To appropriately evaluate the safety, efficacy, and immunogenicity of non-medical switching from an originator to its biosimilar, we propose that seven key study design elements should be considered when assessing the existing evidence: studies should be (1) randomized and double-blind, (2) adequately controlled, and (3) adequately powered; include (4) multiple switching, (5) an assessment of immunogenicity, and (6) adequate follow-up duration; and (7) report individual patient-level outcomes. This systematic review assessed the robustness and consistency of the current non-medical switching evidence, with a focus on TNF inhibitors. A comprehensive literature search (January 2012-February 2018) identified 98 publications corresponding to 91 studies (17 randomized controlled trials and 74 RWE studies) describing non-medical switching from a TNF inhibitor originator to its biosimilar. When assessing the totality of this evidence, none of the non-medical switching studies conducted to date were found to use all seven of the key design elements, and the absence of these elements dilutes the robustness of the data. Furthermore, discontinuation rates varied widely among studies (0-87%), suggesting heterogeneity and inconclusiveness of the current efficacy, safety, and immunogenicity evidence, particularly at an individual patient level. Therefore, patients should not be indiscriminately switched from an originator TNF inhibitor to its biosimilar for non-medical reasons. Switching decisions should remain between the treating physicians and their patients and be made on a case-by-case basis, relying upon robust scientific evidence.

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AbbVie.Plain Language Summary: Plain language summary available for this article.

SUBMITTER: Numan S

PROVIDER: S-EPMC6133136 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionTo examine the prevalence rates of biosimilar discontinuation and switchback to the originator tumor necrosis factor alpha (TNF) inhibitors following non-medical switch (NMS) in patients.MethodsReal-world studies reporting biosimilar discontinuation and switchback rates following NMS published between January 2012 and August 2018 were identified through a systematic literature review. A meta-analysis estimated the annualized discontinuation and switchback rates. A subsequent meta-analysis assessed annualized incremental discontinuation rate among studies reporting both discontinuation rates in patients who underwent an NMS (switchers) and patients who remained on originators (non-switchers).ResultsA total of 66 publications were identified: 31 in gastroenterology, 32 in rheumatology, and 3 in both. Half of the studies reported switchback rates; only 9 studies reported discontinuation rates for both switchers and non-switchers. Across studies, the mean/range sample size of the NMS patient population was 136/9-1641; mean/range follow-up was 10/3-24 months. Annualized biosimilar discontinuation rate was 21% (95% confidence interval [CI] 18%, 25%). Switchback rate was 14% (95% CI 10%, 17%) among all NMS patients and 62% (95% CI 44%, 80%) among discontinuers. The mean/range sample size of switchers and non-switchers was 344/89-1621 and 768/19-2870, respectively; mean/range follow-up was 11/6-18 and 12/6-8 months, respectively. Annualized incremental biosimilar discontinuation rate was 18% (95% CI 4%, 31%).ConclusionBiosimilar discontinuation was found to be prevalent among patients who underwent an NMS from an originator TNF inhibitor to its biosimilar(s) in the real world. In addition, switchback to the originator TNF inhibitors was common following biosimilar discontinuation. Careful consideration is necessary when switching patients already on an originator TNF inhibitor to its biosimilar(s). Main limitations included the heterogeneity of the studies and the limited comparability of the data.

Project description:IntroductionA systematic literature review was conducted to review and summarize the economic impact of non-medical switching (NMS) from biologic originators to their biosimilars (i.e., switching a patient's medication for reasons irrelevant to the patient's health).MethodsEnglish publications reporting healthcare resource utilization (HRU) or costs associated with biosimilar NMS were searched in PubMed and EMBASE over the past 10 years and from selected scientific conferences over the past 3 years, along with gray literature for all biologics with an approved biosimilar (e.g., tumor-necrosis factor inhibitors, erythropoiesis-stimulating agents, insulin and hormone therapies).ResultsA total of 1311 publications were retrieved, where 54 studies met the selection criteria. Seventeen studies reported increased real-world HRU or costs related to biosimilar NMS, e.g., higher rates of surgery (11%), steroid use (13%) and biosimilar dose escalating (6-35.4%). Among the studies that the estimated cost impact associated with NMS, 33 reported drug costs reduction, 12 reported healthcare costs post-NMS without a detailed breakdown, and 5 reported NMS setup and managing costs. Cost estimation/simulation studies demonstrated the cost reduction associated with NMS. However, variation across studies was substantial because of heterogeneity in study designs and assumptions (e.g., disease areas, scenarios of drug price discount rates, cost components, population size, study period, etc.).ConclusionReal-world studies reporting the economic impact of biosimilar NMS separately from drug costs are emerging, and those that reported such results found increased HRU in patients with biosimilar NMS. Studies of cost estimation have been largely limited to drug prices. Comprehensive evaluation of the economic impact of NMS should incorporate all important elements of healthcare service needs such as drug price, biologic rebates, HRU, NMS program setup, administration and monitoring costs.FundingAbbVie.

Project description:IntroductionTo save costs to the healthcare system, forced non-medical switch (NMS) policies that cut drug coverage for originator biologics and fund only less expensive biosimilars are being implemented. However, costs related to the impact of NMS on healthcare resource utilization (HCRU) must also be considered. This study aims to summarize the evidence on the economic impact of an originator-to-biosimilar NMS.MethodsA systematic literature review (SLR) was conducted. Publications reporting on HCRU or costs associated with originator-to-biosimilar NMS in the real-world setting were searched in MEDLINE and EMBASE from January 2008 to February 2020. In addition to hand searching the reference lists of relevant publications and SLRs, key conference websites, PubMed, and various government sites were also searched for the 2 years preceding the search (2018-2020).ResultsA total of 1845 citations were identified, of which 49 were retained for data extraction. Most studies reporting on the HCRU associated with NMS reported on post-NMS HCRU alone without a comparison pre-NMS. However, four studies described a difference in HCRU (i.e., investigations pre- vs post-switch or between non-switchers vs switchers), all of which reported a relative increase in HCRU, including laboratory testing, imaging, medical visits, and hospitalizations, amongst patients who underwent an originator-to-biosimilar NMS. Most studies reporting on the costs associated with NMS reported significant savings following NMS on the basis of drug costs alone. However, four studies specifically reporting on the difference of costs following originator-to-biosimilar NMS all demonstrated an increase in HCRU-related costs associated with NMS (increase in HCRU-related costs of 4-37% or 148-2234 2020 Canadian dollars).ConclusionAmongst the studies that reported on the difference in HCRU pre- vs post-switch or between non-switchers and switchers, all showed an increase in HCRU and related costs associated with NMS, suggesting that the expected overall savings due to less costly drug prices may be reduced as a result of an increase in HCRU and its associated costs post-switch. Nevertheless, more real-world studies that include NMS-related healthcare costs in addition to drug costs are needed.

Project description:BackgroundIn recent years, several biosimilar drugs, including those of infliximab, have obtained marketing authorization from the European Medicines Agency (EMA). Given the peculiarity of the safety profile of biological medical products (originator and biosimilars), the evaluation of their tolerability represents an important component of pre-marketing and post-marketing clinical development. For example, infliximab products may cause adverse drug reactions (ADRs) including acute infusion reactions, delayed hypersensitivity reactions, and loss of efficacy, as a direct consequence of immunogenicity. Therefore, specific contraindications, special warnings and precautions have been introduced in the infliximab Summary of Product Characteristics (SPC).ObjectiveThe aim was to assess the magnitude of preventable ADRs in individual case safety reports (ICSRs) having infliximab as a suspected drug across Italy (using the spontaneous reporting systems), and the probability of reporting infections, infusion reactions, lack of efficacy, and hypersensitivity for originator and biosimilars of infliximab.MethodsWe analyzed ADRs reported across the 2015-2017 period in the databases of five Italian regions: Campania, Lombardy, Sicily, Tuscany, and Veneto. Preventability of ADRs was assessed using the P-method. To compare the probability of reporting infections, infusion reactions, lack of efficacy, and hypersensitivity as ADRs as opposed to other types of ADRs between originator and biosimilars of infliximab, we used the reporting odds ratio (ROR). For descriptive purposes, the number of ICSRs involving infliximab, the number of infliximab vials distributed in the aforementioned Italian regions and the relative reporting rate stratified by semester were reported.ResultsFrom October 2015 to October 2017, 459 ICSRs reported infliximab as a suspected drug (222 ICSRs related to infliximab originator and 237 to infliximab biosimilars). In the same period, 81,906 vials of infliximab were distributed, resulting in a reporting rate of six ICSRs/1000 vials. Overall, 34 cases (7.41%) were categorized as preventable. The most frequently detected critical criteria were "documented hypersensitivity to administered drug or drug class," "inappropriate prescription for patient's underlying medical condition" and "incorrect dose." Biosimilars had, in adjusted analyses, an increased probability of being reported as suspected in ICSRs reporting infusion reactions (ROR 4.09; 95% confidence interval [CI] 1.26-13.32) when compared to Remicade®. On the contrary, they had a decreased probability of being reported as suspected in ICSRs reporting infections or lack of efficacy (ROR 0.33; 95% CI 0.12-0.89; ROR 0.35; 95% CI 0.20-0.61).ConclusionOur study demonstrates that, along with a rapid increase in the utilization of infliximab biosimilars across Italy, there was also an increase in reporting ADRs induced by infliximab biosimilars. Of the reported ADRs, 7.4% were considered preventable. In adjusted analyses, infliximab biosimilars were shown to have an increased probability of being reported as suspected drugs in infusion reactions and a decreased probability of being reported as suspected drugs in cases of lack of efficacy or infection. Considering the potential advantages offered by the utilization of biosimilars in clinical practice, we believe that the use of biosimilars, including those of infliximab, should be supported. In order to achieve this aim, increased knowledge on safety and efficacy of biosimilar drugs should be obtained from real world clinical practice.

Project description:IntroductionControlled clinical studies have shown that the efficacy of tocilizumab (TCZ) monotherapy is superior to that of tumor necrosis factor inhibitor (TNFi) monotherapy and comparable to that of TCZ plus methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). This study compared the real-world effectiveness of TCZ monotherapy vs. TNFis plus MTX in US patients with RA.MethodsTCZ-naïve patients from the Corrona RA registry with prior exposure to ≥ 1 TNFi who initiated TCZ monotherapy or TNFi + MTX were included. Outcomes included mean change in Clinical Disease Activity Index (CDAI), achievement of low disease activity (LDA; CDAI ≤ 10), achievement of modified American College of Rheumatology (mACR) 20/50 responses, and mean change in modified Health Assessment Questionnaire (mHAQ) at 6 months. Patients initiating TNFi + MTX were grouped by MTX dose (≤ 10 mg; > 10 to ≤ 15 mg; > 15 to ≤ 20 mg; > 20 mg); outcomes in each group were compared with TCZ monotherapy using trimmed populations (excluding patients outside the propensity score distribution overlap).ResultsPatients in all groups experienced improvement in CDAI at 6 months (mean change, - 6.9 to - 9.7), with no significant differences between the TCZ monotherapy and TNFi + MTX groups. Achievement of LDA and mACR responses at 6 months were comparable between the TCZ monotherapy and TNFi + MTX groups; overall, 26.8-38.0% of patients achieved LDA, 24.3-37.6% achieved mACR20 response and 13.2-20.8% achieved mACR50 response. The mean change in mHAQ at 6 months was - 0.1 in all groups.ConclusionsIn this real-world population of US patients with RA who had prior TNFi exposure, there was no evidence of a difference in the effectiveness of TCZ monotherapy compared with that of TNFi + MTX, regardless of MTX dose, at 6 months for improving RA disease activity.FundingCorrona, LLC. Plain language summary available for this article.

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Non-medical Switching from Originator Tumor Necrosis Factor Inhibitors to Their Biosimilars: Systematic Review of Randomized Controlled Trials and Real-World Studies.

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