Relevance of Adalimumab Product Attributes to Patient Experience in the Biosimilar Era: A Narrative Review.

Adalimumab (ADL, Humira®, reference product), an anti-TNF-α biologic, has transformed the treatment of chronic, immune-mediated inflammatory diseases. However, the high cost of ADL therapy has driven the development of more affordable ADL biosimilars, agents with no clinically meaningful differences from the reference product. This review summarizes the product attributes of reference ADL and the nine ADL biosimilars approved and available in the USA in relation to patient experience of injection-site pain (ISP). Product formulation, delivery volume and device features (e.g., type and needle gauge size) influence patient experience of ISP with potential clinical consequences. Citrate-free formulations generally cause less ISP; injection volumes of > 1.5 ml may be associated with increased ISP. Reference ADL and all ADL biosimilars offer a citrate-free formulation, and reference ADL and four ADL biosimilars offer a high-concentration solution that allows a smaller injection volume. All available ADL products are injected subcutaneously using either a pre-filled pen (PFP) or pre-filled syringe (PFS). Patients prefer the PFP, but the PFS permits better control over the speed and duration of injection. Smaller (29-gauge) needle outer diameter is associated with less ISP; reference ADL and seven ADL biosimilars offer a device with a 29-gauge needle. In the USA, an approved biosimilar can be designated "interchangeable," allowing pharmacy-level substitution, where state law permits. In the USA, two ADL biosimilars have received interchangeability designation; others are seeking interchangeability designation from the Food and Drug Administration (n = 2), are being evaluated in clinical studies to support interchangeability (n = 2), or do not have/are not seeking interchangeability designation (n = 3). Product-related attributes influence patient experience of ISP caused by subcutaneous ADL injection. Reference ADL and ADL biosimilar products differ in their attributes, so discussion with patients about treatment options is essential to optimize adherence and outcomes.

Leveraging the holistic benefits of biosimilars in Europe - part 2: how payers can safeguard the future of a healthy biosimilar market environment.

INTRODUCTION: Biosimilars have improved access to biologic medicines; however, historical thinking may jeopardize the viability of future markets. AREAS COVERED: An expert panel of eight diverse European stakeholders provided insights about rethinking biosimilars and cost-savings, reducing patient access inequalities, increasing inter-market equity, and improving education. The insights reported here (Part 2) follow a study that provides perspectives on leveraging the holistic benefits of biosimilars for market sustainability based on independent survey results and telephone interviews of stakeholders from diverse biosimilar markets (Part 1). Directional recommendations are provided for payers. EXPERT OPINION: The panel's market maturity framework for biosimilars has three stages: 'Invest,' 'Expand' and 'Harvest.' Across market stages, re-thinking the benefits of biosimilars beyond cost-savings, considering earlier or expanded access/new indications, product innovations, and re-investment of biosimilar-generated cost-savings should be communicated to stakeholders to promote further engagement. During 'Expand' and 'Harvest' stages, development of efficient, forward-looking procurement systems and mechanisms that drive uptake and stabilize competition between manufacturers are key. Future biosimilars will target various therapy areas beyond those targeted by existing biosimilars. To ensure a healthy, accessible future market, stakeholders must align their objectives, communicate, collaborate, and coordinate via education, incentivization, and procurement, to maximize the totality of benefits.

Capturing the holistic value of biosimilars in Europe - part 1: a historical perspective.

INTRODUCTION: Approved biosimilars exhibit comparable efficacy, safety, and immunogenicity to reference products. This report provides perspectives on the societal value of biosimilars within Europe and potential factors that have influenced market dynamics. METHODS: An independent, self-administered survey or one-on-one in-depth interview was used to collect viewpoints about the impact of biosimilar medicines within European markets. Key insights were also sought from an expert panel of European stakeholders. RESULTS: Survey respondents were clinicians, pharmacists, and payers from Europe (N = 103). Perceived benefits of biosimilars included increased access to innovative medicines (73% of respondents) or biologic treatments (66%). Biosimilar competition was thought to expand access to biologics (~50% of respondents) or drug combinations (~36%) and reduce biologic access time (34%). Key drivers of biologic access after biosimilar competition included increased biologic awareness (51%) and changes to prescribing guidelines (37%) and/or treatment paradigms (28%). The expert panel developed a market maturity framework of biosimilar adoption/opportunities comprising three stages: 'Invest,' 'Expand,' and 'Harvest.' Findings were supported by published literature. CONCLUSIONS: In Europe, the perceptions of well-informed survey/interview respondents are that biosimilars have improved patient outcomes via increased access to biologics and innovative biologic products, contributing to earlier and longer treatment of a broader population.

The Adherence and Outcomes Benefits of Using a Connected, Reusable Auto-Injector for Self-Injecting Biologics: A Narrative Review.

Many biologics are now self-administered by patients at home. A variety of self-injection devices are available, including vials and syringes, prefilled syringes, and spring-driven prefilled pens or auto-injectors. Each has advantages and drawbacks, and different devices suit different patients. For example, some patients have difficulty achieving consistent and successful self-injection due to poor manual dexterity, or experience anxiety at the prospect of self-injection or injection-site pain. These factors can reduce patients' medication adherence and overall experience. Furthermore, while self-injection brings patients many benefits, the proliferation of single-use injection devices has implications for environmental sustainability, including the reliance on single-use plastics, repeated freighting requirements, and need for incineration as hazardous waste. Recently developed, innovative electromechanical auto-injector devices offer technological enhancements over existing devices to overcome some of these issues. Features include customisable injection speeds or durations, consistent rate of injection, electronic injection logs and reminders, and step-by-step, real-time instructions. Indeed, a growing body of evidence points to higher adherence rates among patients using electromechanical devices compared with other devices. Further, with time, the reusability of electromechanical devices may prove to lighten the environmental impact compared with disposable devices, especially as research continues to optimise their sustainability, driven by increased consumer demands for environmental responsibility. This narrative review discusses the differences between prefilled syringes, spring-driven prefilled pens, and electromechanical devices. It also explores how these features may help reduce injection-associated pain and anxiety, improve patient experience, connectivity and adherence, and drive sustainability of biologic drugs in future.

Biologics are a type of medicine becoming widespread in the treatment of many diverse diseases. Biologics are injected under the skin and can sometimes be injected by patients themselves at home. Many injection devices are available to help patients with this self-injection, and fall into three broad categories: prefilled syringes, prefilled pens, and electromechanical devices. Each has its own advantages and disadvantages, and different devices suit different patients. For example, some patients have difficulty achieving consistent and successful self-injection because of limited hand movement or become anxious at the prospect of self-injection or injection-site pain. These factors can reduce patients' ability and willingness to take medication as prescribed and may worsen their overall experience. Further, many disposable devices involve single-use plastics and may pose an environmental toll. Reusable electromechanical devices are the newest of the available devices and offer enhanced features over some earlier devices. These include customisable injection speeds or durations, consistent rates of injection, electronic injection logs, reminders, and real-time instructions. Evidence suggests that patients using electromechanical devices may have higher rates of adherence (i.e. more patients take their medication as prescribed) than those using other devices. Additionally, with time and further research, the reusability of electromechanical devices may prove to lighten the environmental impact compared with disposable devices. Here we discuss the differences between prefilled pens, prefilled syringes, and electromechanical devices, and explore the features that may help reduce injection-associated pain and anxiety, improve patient experience, connectivity, and adherence, and drive greater sustainability.

Design Development of the SMARTCLIC®/CLICWISE® Injection Device for Self-Administered Subcutaneous Therapies: Findings from Usability and Human Factor Studies.

INTRODUCTION: An easy-to-use, multiuse, single-patient, electromechanical autoinjector, the SMARTCLIC®/CLICWISE® injection device, was recently developed to improve the self-administration options available to patients with chronic inflammatory disease treated with biologic agents. An extensive series of studies were conducted to guide the design and development of this device and to ensure its safety and effectiveness. METHODS: Participants in two user preference studies and three formative human factor (HF) studies evaluated evolving iterations of the autoinjector device, dose dispenser cartridge, graphical user interface, and informational materials; participants in a summative HF test subsequently assessed the final proposed commercially representative product. In the user preference studies, rheumatologists and patients with chronic inflammatory disease, interviewed online and in-person, provided feedback on the design and functionality of four prototypes. In the HF studies, the safety, effectiveness, and usability of adapted prototypes were assessed under simulated-use conditions by patients with chronic inflammatory disease, caregivers, and healthcare professionals (HCPs). The safety and effectiveness of the final refined device and system were confirmed in a summative HF test by patients and HCPs in simulated-use scenarios. RESULTS: Rheumatologists (n = 204) and patients (n = 39) interviewed in the two user preference studies provided feedback on the device size, feature ergonomics, and usability that guided prototype development in the subsequent formative HF studies. Observations from patients, caregivers, and HCPs (n = 55) participating in the latter studies yielded additional critical design revisions that culminated in development of the final device and system. Of 106 injection simulations conducted in the summative HF test, all resulted in successful medication delivery, and no potential harms were associated with injection-related use events. CONCLUSION: Findings from this research facilitated development of the SmartClic/ClicWise autoinjector device and demonstrated that it could be used safely and effectively by participants representative of the intended-use population of patients, lay caregivers, and HCPs.

High Usability and Applicability Ratings for the New SmartClic®/ClicWise® Injection Device: Evidence from a Health Care Professional Opinion Study.

INTRODUCTION: The SmartClic®/ClicWise® autoinjector is a new reusable, multi-use, single-patient device for the administration of subcutaneously administered biologics in the treatment of chronic conditions, including rheumatoid arthritis. The device will be used in conjunction with a mobile application (app). The aim of this study was to collect feedback on the usability, functionality, and applicability of the device and the companion app from health care professionals (HCPs) who perform injections as part of their role and care for patients with rheumatic conditions. METHODS: The study was conducted from September to October 2020 in Germany. HCPs participated in a training session for the device and gained experience by performing simulated injections with water. Following the simulations, HCPs answered questions on the ease of use, feature design, effectiveness, and injection speed of the SmartClic/ClicWise device and estimate the patient training time required. They also answered questions on the functionality of the proposed app after attending a storyboard presentation. Responses were recorded as multiple-choice answers, Likert scale ratings (seven-point scale), or open-ended comments. The mean, median, and mode scores were recorded. RESULTS: Twenty-five HCPs (mean age, 38.2 years; females, n = 22 [88%]; registered nurses, n = 19 [76%]) participated in the study. HCP feedback on questions related to the SmartClic/ClicWise device was positive overall, with mean scores > 4.50 across questions; mean scores < 5.00 were reported on 2/40 questions. Twenty-four of 25 participants (96%) estimated that a training time of ≤ 20 min would suffice for patients learning to use the device. Positive feedback was also reported on questions related to the companion app, with mean scores > 5.70. CONCLUSIONS: Initial feedback from HCPs on the SmartClic/ClicWise device and proposed app was generally favorable, suggesting they will provide an acceptable alternative for self-administration of biologics for patients with rheumatoid arthritis and other chronic conditions.

Burden of comorbid anxiety and depression in patients with inflammatory bowel disease: a systematic literature review.

INTRODUCTION: Patients with inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, often have comorbid anxiety and depression that affects their quality of life (QoL) and management of their IBD. AREAS COVERED: A systematic literature review (SLR) was conducted to identify articles and conference abstracts on comorbid anxiety and depression in IBD patients using MEDLINE® and Embase® (January 2003 - June 2018). The impact of these psychological comorbidities on QoL and economic burden was examined. Non-pharmacologic interventions and disease-specific unmet clinical needs associated with these comorbidities were also evaluated. EXPERT OPINION: There is evidence that individual and group-based cognitive behavioral therapy can reduce rates of anxiety and depression in adults and adolescents with IBD. Patients with IBD and anxiety or depression had an increased risk of hospitalization, emergency department visits, readmission, and used outpatient services more often than people without these conditions. Several disease-specific unmet clinical needs for IBD patients were identified. These included lack of reimbursement for mental-health care, inconsistent screening for psychological comorbidities and patients not consulting mental-health professionals when needed. IBD patients may benefit from integrated medical and psychological treatment, and should be considered for behavioral treatment.Plain Language Summary. BACKGROUND: People with IBD may have mental-health conditions, such as anxiety and depression. These conditions can affect people's quality of life and how they manage their IBD. WHAT DID THIS REVIEW LOOK AT?: We found 79 publications on anxiety or depression in people with IBD, published between January 2003 and June 2018. In people with IBD and anxiety or depression, researchers looked at: the impact on health-related quality of life and healthcare utilization, including access to and reimbursement for mental-health services how effective interventions that do not involve the use of medicines were (known as non-pharmacologic therapy). WHAT WERE THE MAIN FINDINGS FROM THIS REVIEW?: People with IBD and anxiety or depression were more likely to be admitted to hospital and visit emergency departments than people without these conditions. Access to mental-health care varied and some people with IBD were not screened for depression.Individual and group-based talking therapy (known as cognitive behavioral therapy) reduced rates of anxiety and depression in some people with IBD. WHAT WERE THE MAIN CONCLUSIONS FROM THIS REVIEW?: We found evidence that people with IBD and anxiety or depression may benefit from certain non-pharmacologic interventions. However, many people with IBD and anxiety or depression did not have access to mental-health services. Healthcare professionals should address gaps in patient care to improve outcomes in people with IBD and anxiety or depression.See Additional file 1 for an infographic plain language summary.

Understanding the Role of Comparative Clinical Studies in the Development of Oncology Biosimilars.

Biosimilars have the potential to broaden patient access to biologics and provide cost savings for health care systems. During the development of a biosimilar, data that directly compare the proposed biosimilar with the reference product are required. Such comparative data are generated in a stepwise hierarchical process that begins with extensive laboratory-based structural analyses and functional assays. This initial analytical phase serves as the foundation for the demonstration of biosimilarity and is followed by nonclinical in vivo testing (if required) and then clinical evaluation, including a comparative pharmacokinetics/pharmacodynamics study that is usually conducted in healthy volunteers. The development program typically culminates with a comparative clinical efficacy study. The aim of this study is to confirm clinical equivalence of the potential biosimilar and reference product on the basis of prespecified margins, using a study population and efficacy end point that are sufficiently sensitive for detecting potential product-related differences. Such studies also include detailed analyses of safety as well as evaluation of immunogenicity. As biosimilars become more widely available in oncology, especially with recent regulatory approvals of rituximab, trastuzumab, and bevacizumab biosimilars, it is critically important that clinicians understand how the comparative clinical study differs from a traditional phase III efficacy and safety study in the development of a novel biologic originator product. Here, we review the role of comparative clinical studies in biosimilar development, with a focus on trials conducted to support approved trastuzumab biosimilars. We discuss the study populations and end points used, extrapolation of indications, and the confirmatory nature of these studies within the totality of evidence supporting biosimilarity.

Systematic Review and Meta-analysis of Short- versus Long-Acting Granulocyte Colony-Stimulating Factors for Reduction of Chemotherapy-Induced Febrile Neutropenia.

INTRODUCTION: Short- and long-acting granulocyte-colony stimulating factors (G-CSFs) are approved for the reduction of febrile neutropenia. A systematic literature review was performed to identify randomized controlled trials (RCTs) and non-RCTs reporting the use of G-CSFs following chemotherapy treatment. METHODS: Medline®/Medline in-process, Embase®, and the Cochrane Library were searched for studies published between January 2003 and June 2016. A hand-search of relevant conference proceedings was conducted for meetings held between 2012 and 2016. Eligible studies were restricted to those reporting a direct, head-to-head comparison of short- versus long-acting G-CSFs for reduction of chemotherapy-induced febrile neutropenia. Risk-of-bias assessments were performed for full publications only. RESULTS: The search strategy yielded 4044 articles for electronic screening. Thirty-six publications were evaluated for the meta-analysis: 11 of 12 RCTs and 2 of 24 non-RCTs administered doses of the short-acting G-CSF filgrastim for ≥ 7 days. In RCT studies, there was no statistically significant difference in outcomes of interest between short- and long-acting G-CSFs. In non-RCTs, the overall risk was lower with long-acting G-CSF than with short-acting G-CSF for incidence of febrile neutropenia [overall relative risk (RR) = 0.67, P  = 0.023], hospitalizations (overall RR = 0.68, P  < 0.05), and chemotherapy dose delays (overall RR = 0.68, P  = 0.020). CONCLUSIONS: Overall, the weight of evidence from RCTs indicates little difference in efficacy between the short- and long-acting G-CSFs if dosed according to recommended guidelines. There is some evidence for greater efficacy for long-acting G-CSFs in non-RCTs, which may be a result of under-dosing of short-acting G-CSFs in general practice in real-world usage. FUNDING: Hospira Inc, which was acquired by Pfizer Inc in September 2015, and Pfizer Inc.

Correction to: Systematic Review and Meta-analysis of Short-versus Long-Acting Granulocyte Colony-Stimulating Factors for Reduction of Chemotherapy-Induced Febrile Neutropenia.

The article "Systematic Review and Meta-analysis of Short-versus Long-Acting Granulocyte Colony-Stimulating Factors for Reduction of Chemotherapy-Induced Febrile Neutropenia", written by Paul Cornes, Pere Gascon, Stephen Chan, Khalid Hameed, Catherine R. Mitchell, Polly Field, Mark Latymer, Luiz H. Arantes Jr was originally published electronically on the publisher's internet portal (currently SpringerLink) on October 8, 2018 without open access.

A quick scoping review of efficacy, safety, economic, and health-related quality-of-life outcomes of short- and long-acting erythropoiesis-stimulating agents in the treatment of chemotherapy-induced anemia and chronic kidney disease anemia.

Erythropoiesis-stimulating agents (ESAs) are man-made forms of erythropoietin used in the treatment of anemia. This quick-scoping review of systematic literature reviews (SLRs) was conducted to define the clinical, economic, and health-related quality of life (HRQoL) outcomes for short-acting and long-acting ESAs in patients with chronic kidney disease-induced anemia (CKD-IA) and patients with chemotherapy-induced anemia (CIA). Embase, Medline, and the Cochrane Database of Systematic Reviews were searched from their establishment until October 2017. SLRs related to the use of short-acting and long-acting ESAs in the treatment of CIA and CKD-IA were included. Forty-eight studies met the inclusion criteria. The evidence suggests little difference in efficacy, HRQoL, and safety outcomes among ESA types. Cost-effectiveness and market price are likely to become determining factors driving the choice of agent. Comparative studies and costing models accounting for the utilization of biosimilars are needed to establish which ESAs are more cost-effective.

Talking to patients about biosimilars.

Biologic therapies target aberrant pathways in diseases including diabetes, cancer and autoimmune disorders. Despite recent scientific advances, patient access to these agents can be limited. Biosimilars are designed to be highly similar to the originator biologic, targeting the same biological pathways, with comparable efficacy and safety. Biosimilars have the advantage of lower treatment costs, offering the potential for increased clinical use and patient access. Several biosimilars are approved for clinical use in the USA and Europe; however, there is a lack of awareness about biosimilars among healthcare providers and patients. This overview of the scientific basis of biosimilars and current indications aim to enhance discussions with patients and increase understanding of the role of biosimilars in individual treatment plans.

Neuropathic pain responds better to increased doses of pregabalin: an in-depth analysis of flexible-dose clinical trials.

BACKGROUND: Pregabalin is an effective treatment option for many patients with neuropathic pain. Higher doses of pregabalin have been shown to be more effective in improving pain outcomes but, in practice, failing to appropriately increase the dose can leave patients under-treated. METHODS: This was a pooled analysis of 6 flexible-dose clinical trials of pregabalin in patients with neuropathic pain (diabetic peripheral neuropathy, peripheral herpetic neuralgia, posttraumatic pain, or postsurgical pain). Patients were divided into "dose pathway" groups based on their weekly pregabalin dose from the start of their trial to the first week of their maintenance phase. These were: 150 mg/day only; 150 to 300 mg/day; 150 to 300 to 450 mg/day; 150 to 300 to 450 to 600 mg/day; 150 to 300 to 600 mg/day; 300 to 600 mg/day. Pain outcomes assessed for each group at each new dose were proportion of 30% and 50% responders (≥30% or ≥50% reduction in mean pain score from baseline) and mean change in pain score. Percent change in mean pain score from baseline was assessed using a marginal structural model. RESULTS: Seven hundred and sixty-one patients treated with flexible-dose pregabalin were included in the analysis. For each dose pathway group, there was a notably greater proportion of 30% and 50% responders and change in pain score, at each escalating dose. As assessed by the marginal structural model, higher doses of pregabalin were estimated to result in a significantly greater change in mean pain score at each week. This dose response with flexible-dose pregabalin was consistent with that previously observed with fixed-dose pregabalin. CONCLUSION: Many patients who do not respond to lower doses of pregabalin will respond with notable improvements in pain outcomes when the dose is escalated. These data should encourage physicians treating patients with neuropathic pain to escalate pregabalin to the dose that delivers optimal analgesia and tolerable side effects.

Does Duration of Neuropathic Pain Impact the Effectiveness of Pregabalin?

BACKGROUND: Patients with chronic pain conditions such as neuropathic pain frequently experience delays in diagnosis and treatment. Ideally, all patients should be treated in a timely manner, but in those patients with more established disease it is important to know that approved treatments remain effective. METHODS: This was a pooled analysis of 19 randomized placebo-controlled trials of pregabalin for peripheral neuropathic pain conditions, including diabetic peripheral neuropathy, postherpetic neuralgia, and post-traumatic/postsurgical pain. Patients were divided into 5 pain duration categories based on time since onset of pain (< 6 months, 6 months to < 1 year, 1 year to < 2 years, 2 years to < 5 years, and ≥ 5 years). Mean change in pain score at endpoint, vs. placebo, was assessed for each category, together with changes in Patient Global Impression of Change (PGIC) responders ("very much" or "much" improved at endpoint). RESULTS: The analysis included 5,783 patients (n = 3,619 pregabalin; n = 2,164 placebo). Mean baseline pain scores were similar across the pain duration categories (range 6.3 to 6.5). Pregabalin significantly improved pain score at endpoint, vs. placebo, in all patients together (treatment difference [95% confidence interval], -0.59 [-0.67, -0.52], P < 0.0001) and similarly in each pain duration category (P < 0.0001 for each). There were significantly more PGIC responders with pregabalin, vs. placebo, for all patients (45.0% vs. 30.9%, P < 0.0001) and each category separately (P < 0.001 for each). There were no consistent, significant differences in treatment response between the different pain duration categories. CONCLUSIONS: Pregabalin significantly improves pain irrespective of the length of time since onset of neuropathic pain.

A comprehensive drug safety evaluation of pregabalin in peripheral neuropathic pain.

Pregabalin is a commonly used therapy currently recommended as first-line treatment for a number of neuropathic pain (NeP) conditions. Since licensure, a number of clinical trials of pregabalin in different NeP conditions have been completed from which additional data on safety and tolerability can be drawn. In this analysis, patient-level data from 31 randomized clinical trials of pregabalin in peripheral NeP sponsored by Pfizer were pooled and assessed for incidence of adverse events (AEs). Incidence by age, disease condition, and race, together with risk differences and time to onset and resolution of AEs, was assessed. In total, 7,510 patients were included: 4,884 on pregabalin (representing 805 patient-years treatment) and 2,626 on placebo. Pregabalin vs. placebo risk analysis identified 9 AEs with a risk difference, for which the lower limit of the 95% confidence interval (CI) was > 1%: dizziness (risk difference [95% CI]: (17.0 [15.4 to 18.6]), somnolence (10.8 [9.5 to 12.1]), peripheral edema (5.4 [4.3 to 6.4]), weight increase (4.7 [3.9 to 5.5]), dry mouth (2.9 [2.1 to 3.8]), constipation (2.3 [1.5 to 3.2]), blurred vision (2.2 [1.6 to 2.9]), balance disorder (2.0 [1.5 to 2.5]), and euphoric mood (1.6 [1.2 to 2.0]). The most common AEs, dizziness and somnolence, typically emerged within the first 1 to 2 weeks of treatment and resolved 1 to 2 weeks later, without resulting in cessation of treatment. The data from this review provide information, indicating which AEs may be expected in patients treated with pregabalin, and suggest that careful dose titration to the highest tolerable dose is the most appropriate approach in clinical practice.