The mode of delivery and content of communication strategies used in mandatory and non-mandatory biosimilar transitions: a systematic review with meta-analysis.

Effective patient-provider communication is crucial to promote shared decision-making. However, it is unclear how to explain treatment changes to ensure patient acceptance, such as when transitioning from a bio-originator to a biosimilar. This review investigates communication strategies used to educate patients on transitioning to biosimilars and explores whether the willingness to transition and treatment persistence differs for the delivery (verbal or written) and the amount of information provided. MEDLINE, Embase, Scopus, and relevant conference databases were systematically searched. Communication strategies from 33 studies (88% observational cohort studies) published from 2012 to 2020 were synthesized and willingness to transition, persistence, and subjective adverse events explored. Patients only received information verbally in 11 studies. The remaining 22 studies also provided written information. Cost-saving was the main reason provided for the transition. Patients were most willing to transition when receiving written and verbal information (χ2 = 5.83, p = .02) or written information that only addressed a few (3-5) concerns (χ2 = 16.08, p < .001). There was no significant difference for persistence or subjective adverse events (p's > .05). Few randomized controlled trials have been conducted. Available data shows more willingness to transition when patients received written and verbal information. Initial documents should contain basic information and consultations or telephone calls used to address concerns.

A bio-what? Medical companions' perceptions towards biosimilars and information needs in rheumatology.

Patient perceptions influence biosimilar uptake in non-mandatory transitions. Companions (support people) are often actively involved in the patient's medical journey and are likely to have unique perceptions of biosimilars, which may shape patient attitudes. This study explores the congruence between patient and companion perceptions towards biosimilars and their information needs. Patients taking bio-originators for rheumatic diseases (59% for rheumatoid arthritis) and their companions received an explanation about biosimilars. Participants (N = 78) completed questionnaires assessing their familiarity with biosimilars, perceptions, concerns, and benefits of being accompanied. Contingency tables and paired sample t-tests were used to explore differences in familiarity, confidence in knowledge, and perceptions. Intra-class correlation coefficients were calculated to assess the degree of congruence for perceptions towards biosimilars. Companions were significantly less familiar with biosimilars (p = 0.014, Cramer's V = 0.28) and reported lower confidence in their knowledge (p = 0.006, Cohen's d = 0.47) than patients. Companions and patients had moderate to good congruency for perceptions toward confidence in biosimilar use and safety, efficacy, and side-effect expectations (intra-class correlation coefficients ranging from 0.75 to 0.81). Companions and patients were most concerned about safety and effectiveness. Companions also reported concerns about cost savings driving the transition, while patients had concerns about uncertainty and testing. Patients reported the ability for discussion, improved understanding, and validation as benefits of being accompanied. Companions and patients have similar levels of perceptions and expectations towards biosimilars but report some unique information needs. Future educational interventions should involve companions and address their concerns to help improve biosimilar acceptance.

Is Three a Crowd? The Influence of Companions on a Patient's Decision to Transition to a Biosimilar.

BACKGROUND: Involving patients in treatment decisions is commonplace in healthcare, and patients are frequently accompanied by a companion (support person). Companions are often actively involved in medical consultations, yet their impact on decisions to change medications is unknown. PURPOSE: This study examines the influence of companions on a patient's decision to transition from their bio-originator therapy to a biosimilar. METHODS: A parallel, two-arm randomized controlled trial was conducted with 79 patients taking a bio-originator for rheumatic diseases who regularly attend clinic with a companion. Patients were randomized to receive an explanation about a hypothetical transition to a biosimilar alone or with their companion. Patients reported willingness to transition, risk perceptions, difficulty understanding, social support, and completed the Decisional Conflict Scale and Satisfaction with Decision Scale. RESULTS: Companions did not influence decisions to transition to biosimilars or cognitive and affective risk perceptions. Accompanied patients reported more difficulty understanding the explanation (p = .006, Cohen's d = .64) but thought it was more important to receive information with companions (p = .023, Cohen's d = -.52). Companions did not impact decision satisfaction or decisional conflict. Receiving emotional, but not practical support, was associated with less decisional conflict in accompanied patients (p = .038, r2 = 0.20). CONCLUSIONS: The presence of companions does not seem to influence risk perceptions or decisions about transitioning to biosimilars. Companions, however, impact the patient's reporting of their ability to understand treatment explanations. Providers should check understanding in all patients but may need to provide additional time or educational resources to accompanied patients and companions. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry: ACTRN12619001435178.

Patients' beliefs and behaviours are associated with perceptions of safety and concerns in a hypothetical biosimilar switch.

Although patient acceptance is important for biosimilar adoption and reducing healthcare costs, many patients perceive biosimilars to be unsafe and have concerns about switching. Studies show that patients' characteristics influence negative perceptions toward generic drugs, but little research has explored biosimilar acceptance. This study examines which demographic and psychological characteristics are associated with patients' safety perceptions and concerns about switching to biosimilars. Ninety-six patients taking bio-originators for rheumatic conditions (65% for rheumatoid arthritis) completed the Brief Illness Perceptions Questionnaire, Beliefs about Medicines Questionnaire and Perceived Sensitivity to Medicines Scale. Demographic factors, information seeking, concerns about switching and safety perceptions were also assessed. Pearson's correlations and hierarchical linear regressions were conducted to explore whether patient characteristics are associated with perceptions of biosimilars. Negative safety perceptions were associated with being female, short-term bio-originator use, illness beliefs, seeking health information online, high perceived sensitivity to medicines and negative beliefs about medicines. Only being female (ß = 0.24, P = 0.02) was independently associated. More concerns about switching were associated with being female, illness beliefs, high perceived sensitivity to medicines, information-seeking behaviours and preferring innovator drugs. Seeking health information online (ß = 0.20, P = 0.04), preferring innovator drugs (ß = 0.29, P = 0.004) and stronger emotional responses (ß = 0.26, P = 0.01) were independently associated. Perceived bio-originator effectiveness was inversely associated with preferring biosimilars (rs= - 0.33, P < 0.001). Patients who have stronger emotional responses to their condition, are females, seek health information online and prefer innovator drugs that have more negative perceptions about biosimilars. Experiences with bio-originators influence attitudes towards switching.

The non-medical switching of prescription medications.

Non-medical switching of medication, whereby a patient's treatment regimen is changed for reasons other than efficacy, side effects, or adherence, is often related to drug formulary changes aimed at reducing drug costs. In the era of health care reform, while cost-cutting measures are important, there is considerable evidence that non-medical switching, particularly when applied to medication used to treat chronic conditions such as diabetes, may impact patient outcomes, medication-taking behavior, and use of health care services. Ultimately, overall costs may be increased, as savings by insurers are cancelled out by higher costs to the health care system as a whole, such as extra administration, treatment failure from new medicines, and increased adverse events. The emergence of biosimilar and follow-on biologic treatments raises further questions among patients receiving biologic treatments, with patient advocacy groups calling for clear legislation to ensure that patients with complex or chronic conditions continue to receive effective, evidence-based medications for their disease. This article will discuss non-medical switching in the US, taking into account the different parties involved, such as patients, health care providers, pharmacists, payers, and pharmacy benefit managers, with the aim of providing a detailed overview of this complex and evolving topic.

Midyear Commentary on Trends in Drug Delivery and Clinical Translational Medicine: Growth in Biosimilar (Complex Injectable Drug Formulation) Products Within Evolving Collaborative Regulatory Interagency (FDA, FTC, and DOJ) Practices and Enforcement.

Before the 2009 Biologics Price Competition and Innovation Act that enabled the U.S. Federal Drug Administration (FDA) to create the 351(k) Biologic License Application-an abbreviated biosimilar approval process, FDA approved follow-on biomolecule products such as beta-interferon, glucagon, hyaluronidase, and somatropin (human growth hormone) under varying and evolving rules. With the 351(k) Biologic License Application biosimilar approval process in place, currently, there are 4 (licensed in 2015-2016) biosimilars available, namely Neupogen (filgrastim; $1 B/y), Humira (adalumumab; $14.2 B/y), Enbrel (etanercept; $8.7 B/y), and Remicade (infliximab; $6.5 B/y). With well-established product market capitalization of these and other top income producers-such as Rituxan (rituximab; $6.8 B/y), Herceptin (trastuzumab; $6.5 B/y), and Avastin (bevacizumab; $5.8 B/y), and a price differential of 15%-30% compared to branded products, there is an intense interest in development of biosimilars by established pharmaceutical companies. Currently, there are 160 biosimilar candidates in clinical studies, many of which are sponsored by large pharmaceutical companies known for product innovation. This trend will likely continue. Additional information on a biomolecule platform is presented in the Journal of Pharmaceutical Sciences Drug Delivery Clinical Trials Database (jpharmscidatabase.org). There are 44,789, 18,456, and 12,897 clinical trials registered to evaluate (1) drug delivery technology, (2) biomolecule platform, and (3) drug metabolism and pharmacokinetic-pharmacodynamic interactions; representing 19%-60% increase over the last 3 years.

Production, Characterization, and Biological Evaluation of Well-Defined IgG1 Fc Glycoforms as a Model System for Biosimilarity Analysis.

Four different well-defined IgG1 Fc glycoforms are proposed as a model system to examine important biological and physicochemical features for protein drug biosimilar analyses. The IgG1 Fc glycoforms were produced by yeast expression combined with in vitro enzymatic synthesis as a series of sequentially truncated high-mannose IgG1 Fc glycoforms with an anticipated range of biological activity and structural stability. Initial characterization with mass spectrometry, SDS-PAGE, size exclusion HPLC, and capillary isoelectric focusing confirmed that the glycoproteins are overall highly similar with the only major difference being glycosylation state. Binding to the activating Fc receptor, FcγRIIIa was used to evaluate the potential biological activity of the IgG1 Fc glycoproteins. Two complementary methods using biolayer interferometry, 1 with protein G-immobilized IgG1 Fc and the other with streptavidin-immobilized FcγRIIIa, were developed to assess FcγRIIIa affinity in kinetic binding studies. The high-mannose IgG1 Fc and Man5-IgG1 Fc glycoforms were highly similar to one another with high affinity for FcγRIIIa, whereas GlcNAc-Fc had weak affinity, and the nonglycosylated N297Q-Fc had no measurable affinity for FcγRIIIa. These 4 IgG1 Fc glycoforms were also evaluated in terms of physical and chemical stability profiles and then used as a model system to mathematically assess overall biosimilarity, as described in a series of companion articles.

Traceability of biologicals: present challenges in pharmacovigilance.

INTRODUCTION: Traceability is important in the postmarketing surveillance of biologicals, since changes in the manufacturing process may give rise to product- or batch-specific risks. With the expected expansion of the biosimilar market, there have been concerns about the ability to trace individual products within pharmacovigilance databases. AREAS COVERED: The authors discuss the present challenges in the traceability of biologicals in relation to pharmacovigilance, by exploring the processes involved in ensuring traceability. They explore both the existing systems that are in place for the recording of exposure information in clinical practice, as well as the critical steps involved in the transfer of exposure data to various pharmacovigilance databases. EXPERT OPINION: The existing systems ensure the traceability of biologicals down to the manufacturer within pharmacy records, but do not support the routine recording of batch information. Expected changes in supply chain standards provide opportunities to systematically record detailed exposure information. Spontaneous reporting systems are the most vulnerable link in ensuring traceability, due to the manual nature of data transfer. Efforts to improve the traceability should, in the short term, be focused toward encouraging health professionals and patients to systematically record and report detailed exposure information. Long-term solutions lie in expanding the accessibility to, and increasing the electronic exchange of exposure data.

Sample size calculations for the development of biosimilar products.

The most widely used design for a Phase III comparative study for demonstrating the biosimilarity between a biosimilar product and a renovator biological product is the equivalence trial, whose aim is to show that the difference between two population means of a primary endpoint is less than a prespecified equivalence margin. A well-known sample size formula for the equivalence trial is given by [Formula: see text] Since this formula is obtained based on the approximate power rather than the exact power, we investigate in this article the accuracy of the sample size formula. We conclude that the sample size formula is very conservative. Specifically, we show that the exact power based on the sample size calculated from the formula to have power [Formula: see text] is actually [Formula: see text] under some conditions. Therefore, the use of the sample size formula may cause a huge extra cost to biotechnology companies. We propose that the sample size should be calculated based on the exact power precisely and numerically. The R code to calculate the sample size numerically is provided in this article.

Nonparametric tests for evaluation of biosimilarity in variability of follow-on biologics.

As more biologic products are going off patent protection, the development of follow-on biologic products (also known as biosimilars) has gained much attention from both the biotechnology industry and regulatory agencies. Unlike small molecules, the development of biologic products is not only more complicated but also sensitive to a small change in procedure/environment during the manufacturing process. In practice, biologics are expected to have much larger variation, which will potentially impact the product quality and potency. Thus, it is suggested that the assessment of biosimilarity between biologic products should take variability into consideration, in addition to average biosimilarity of endpoints of interest. In this article, we propose the use of nonparametric tests for evaluation of biosimilarity in variability between the follow-on biologic product and the reference product. Extensive simulations are conducted to compare the relative performance of the proposed methods with the adapted parametric F-test in terms of correctly concluding biosimilarity in variability. Under normality assumption, the proposed nonparametric tests are found to be comparably well with the adapted F-test. However, the proposed methods are more robust when the assumption is violated.

Nanomedicines: addressing the scientific and regulatory gap.

Nanomedicine is the application of nanotechnology to the discipline of medicine: the use of nanoscale materials for the diagnosis, monitoring, control, prevention, and treatment of disease. Nanomedicine holds tremendous promise to revolutionize medicine across disciplines and specialties, but this promise has yet to be fully realized. Beyond the typical complications associated with drug development, the fundamentally different and novel physical and chemical properties of some nanomaterials compared to materials on a larger scale (i.e., their bulk counterparts) can create a unique set of opportunities as well as safety concerns, which have only begun to be explored. As the research community continues to investigate nanomedicines, their efficacy, and the associated safety issues, it is critical to work to close the scientific and regulatory gaps to assure that nanomedicine drives the next generation of biomedical innovation.

Bioequivalencia, biosimilares, biológicos subsecuentes, medicamentos intercambiables o sustituibles, ¿son lo mismo? / Bioequivalence, biosimilars, biological subsequent, interchangeable or replaceable drugs, are the same?

Biologic drugs are medicinal substances derived from living cells and generally they are a mix of clinically active and inactive molecules. The final products are the result of proprietary processes and highly sensitive to the specific manufacturing technology and handling. Stability and reproducibility of the processes are crucial to guarantee the safety and efficacy of the end products. National regulatory agencies need to establish a set of standards and mechanisms to certify the similarity between follow on biologics and the reference ones; they also might authorize substantially different manufacturing processes to obtain a biosimilar drug; nevertheless, the producer must demonstrate they own sophisticated biotechnologic facilities, stable manufacturing processes, quality control mechanisms, appropriate storage and transportation, a pharmacovigilance program, and also an end-product with similar efficacy and safety to the reference one, for at least one of the approved clinical indications. Besides of complex analytical assays needed to attest the molecular identities, immunogenicity and purity of the biosimilar drug —among other aspects— the final evidence supporting the similarity on efficacy and safety must be accrued from appropriate randomized controlled trials. Full interchangeability between a reference drug and a biosimilar is not a regulatory requisite yet; on the other hand, some biosimilars have demonstrated that they can fully comply with a scientifically defined standard of safety and efficacy. It should be assumed that two proprietary closely similar manufacturing processes, produce different end-products, similar but not identical between each other...

Las drogas biológicas son generalmente moléculas medicinales grandes, derivadas de células vivas. Están constituidas por principios clínicamente activos e inactivos. El producto final es el resultado de procesos propietarios complejos, al punto que suele sostenerse que la droga es el proceso; su reproducibilidad y estabilidad en el tiempo son cruciales para asegurar su eficacia y seguridad. Las agencias regulatorias autorizan que el proceso productivo de un biosimilar pueda ser substancialmente diferente del original; sin embargo, quien lo produce debe demostrar que dispone de instalaciones tecnológicamente sofisticadas, procesos productivos estables, adecuados controles de calidad, almacenamiento y transporte, programa de fármaco vigilancia, así como un producto terminado eficaz, seguro, estable en el tiempo y comparable con el producto innovador para al menos una de las indicaciones terapéuticas del original. Las pruebas de eficacia, seguridad y similitud con un producto de referencia deben obtenerse insoslayablemente mediante ensayos clínicos apropiados, sin perjuicio de los ensayos analíticos para tipificar las moléculas contenidas en el medicamento y determinar su pureza e inmunogenicidad, entre otros aspectos. Las pruebas de intercambios absolutos, obtenidas en ensayos clínicos, no se han establecido aún como una exigencia regulatoria. Dos procesos productivos similares, pero algo diferentes, no pueden conducir a productos biológicos molecularmente idénticos; no obstante, el producto terminado puede satisfacer suficientemente los criterios de eficacia y seguridad similar a uno de referencia con el cual se compara...

Follow-on biologics in oncology - the need for global and local regulations.

The patent expiration for first-generation biological drugs has prompted the development of a new group of biopharmaceuticals - follow-on biologics. The extent of studies needed in the process of follow-on biologics approval is incomparably greater than in the case of generics but reduced in comparison to innovative biologics. The basis for the approval is to show the similarity sufficient to ensure the same quality, safety and efficacy as the reference medicine. In oncology, the most widely used among so far registered follow-on biologics are biosimilar granulocyte colony-stimulating factors, and in the hitherto clinical practice, there have been no concerns about their effectiveness and safety. It is expected that along with the patent expiry of next biologics, the number of follow-on biologics will increasingly grow, that implies the need to develop and implement specific regulations for this new class of medicine.

Emerging patient safety issues under health care reform: follow-on biologics and immunogenicity.

US health care reform includes an abbreviated pathway for follow-on biologics, also known as biosimilars, in an effort to speed up access to these complex therapeutics. However, a key patient safety challenge emerges from such an abbreviated pathway: immunogenicity reactions. Yet immunogenicity is notoriously difficult to predict, and even cooperative approaches in licensing between companies have resulted in patient safety concerns, injury, and death. Because approval pathways for follow-on forms do not involve cooperative disclosure of methods and manufacturing processes by innovator companies and follow-on manufacturers, the potential for expanded immunogenicity must be taken into account from a risk management and patient safety perspective. The US Institute of Safe Medication Practices (ISMP) has principles of medication safety that have been applied in the past to high-risk drugs. We propose adapting ISMP principles to follow-on biologic forms and creating systems approaches to warn, rapidly identify, and alert providers regarding this emerging patient safety risk. This type of system can be built upon and provide lessons learned as these new drug forms are developed and marketed more broadly.