Determinants of Use of Biotherapeutics in sub-Saharan Africa.

Biologic drugs are reshaping clinical practice in various disciplines, even while access to them is imbalanced across global settings. In sub-Saharan Africa, biotherapeutics have potential roles to play in the treatment of a range of conditions that include infectious and noncommunicable diseases (NCDs). However, the literature is scarce on guidance for addressing local access challenges, including technical, regulatory, affordability, and other healthcare delivery aspects. This article aims to assess fundamental determinants of use of biologic medicines in sub-Saharan Africa. The purpose is to inform strategic actions of scientists, physicians, policymakers, and other stakeholders that are working to improve access to innovative therapies in low resource parts of the world.

The Path Towards a Tailored Clinical Biosimilar Development.

Since the first approval of a biosimilar medicinal product in 2006, scientific understanding of the features and development of biosimilar medicines has accumulated. This review scrutinizes public information on development programs and the contribution of the clinical studies for biosimilar approval in the European Union (EU) and/or the United States (US) until November 2019. The retrospective evaluation of the programs that eventually obtained marketing authorization and/or licensure revealed that in 95% (36 out of 38) of all programs, the comparative clinical efficacy studies confirmed similarity. In the remaining 5% (2 out of 38), despite meeting efficacy outcomes, the biosimilar candidates exhibited clinical differences in immunogenicity that required changes to the manufacturing process and additional clinical studies to enable biosimilar approval. Both instances of clinical differences in immunogenicity occurred prior to 2010, and the recurrence of these cases is unlikely today due to state-of-the-art assays and improved control of process-related impurities. Biosimilar candidates that were neither approved in the EU nor in the US were not approved due to reasons other than clinical confirmation of efficacy. This review of the development history of biosimilars allows the proposal of a more efficient and expedited biosimilar development without the routine need for comparative clinical efficacy and/or pharmacodynamic studies and without any compromise in quality, safety, or efficacy. This proposal is scientifically valid, consistent with regulation of all biologics, and maintains robust regulatory standards in the assessment of biosimilar candidates. Note: The findings and conclusion of this paper are limited to biosimilar products developed against the regulatory standards in the EU and the US.

Biosimilars in oncology: A decade of experience with granulocyte colony-stimulating factor and its implications for monoclonal antibodies.

Biosimilars offer the potential for improved sustainability of cancer care. In oncology, granulocyte colony-stimulating factor and erythropoiesis-stimulating agent biosimilars have been available for almost a decade, with biosimilars of monoclonal antibodies a more recent development. Sandoz biosimilar filgrastim was approved based on Phase III confirmatory studies conducted in patients with breast cancer experiencing chemotherapy-induced neutropenia, with other indications granted based on extrapolation. Despite the fact that extrapolation is a well-established scientific principle in regulation of biological medicines, it is a commonly misunderstood part of the biosimilar concept. Broad experience from almost a decade of use of Sandoz biosimilar filgrastim includes >21 million patient-days exposure and >9 years of real-world clinical evidence, indicates extrapolation successfully at work. Together, this can help reassure oncologists that extrapolation is based on sound scientific principles. Efforts to improve understanding of extrapolation are critical to ensure the acceptance of future oncology biosimilar monoclonal antibodies.

The in-use stability of the rituximab biosimilar Rixathon®/Riximyo® upon preparation for intravenous infusion.

PURPOSE: The purpose of this study was to evaluate the in-use physicochemical and biological stability of the Sandoz rituximab biosimilar, marketed under the trade names Rixathon® and Riximyo® in the European Union, upon preparation for intravenous infusion. METHODS: Three batches of Rixathon®/Riximyo® in the final month of their 36 month shelf life were exposed to room temperature and light for 14 days to recapitulate a major temperature excursion. Samples were diluted to the lowest allowable concentration of 1 mg/mL in 0.9% NaCl solution in either polypropylene or polyethylene infusion bags and stored for 14 or 30 days at 5 ± 3℃ followed by an additional 24 h at room temperature to simulate product handling. Samples stored in infusion bags were analyzed using SEC, CEX, non-reducing CE-SDS, peptide mapping and CDC to assess physicochemical and biological stability. RESULTS: Analysis of Rixathon®/Riximyo® diluted to the lowest allowable concentration in 0.9% sodium chloride in either polypropylene or polyethylene infusion bags revealed no change in molecular weight variants, charge variants, deamidation, oxidation, overall composition or potency over a 31-day period. CONCLUSION: Physicochemical and biological analyses demonstrate that Rixathon®/Riximyo® stability is not impacted by dilution and formulation conditions required for intravenous infusion, even under worst case conditions with regard to product shelf life, temperature excursion, light exposure, dilution factor and infusion bag storage time over a 31-day period.

The Assessment of Quality Attributes for Biosimilars: a Statistical Perspective on Current Practice and a Proposal.

Establishing comparability of the originator and its biosimilar at the structural and functional level, by analyzing so-called quality attributes, is an important step in biosimilar development. The statistical assessment of quality attributes is currently in the focus of attention because both the FDA and the EMA are working on regulatory documents for advising companies on the use of statistical approaches for strengthening their comparability claim. In this paper, we first discuss "comparable" and "not comparable" settings and propose a shift away from the usual comparison of the mean values: we argue that two products can be considered comparable if the range of the originator fully covers the range of the biosimilar. We then introduce a novel statistical testing procedure (the "tail-test") and compare the operating characteristics of the proposed approach with approaches currently used in practice. In contrast to the currently used approaches, we note that our proposed methodology is compatible with the proposed understanding of comparability and has, compared to other frequently applied range-based approaches, the advantage of being a formal statistical testing procedure which controls the patient's risk and has reasonable large-sample properties.

Correction to: Epoetin Biosimilars in the Treatment of Chemotherapy-Induced Anemia: 10 Years' Experience Gained.

Figure 1, HX575 column, 5th box down, which previously read "SC HX575 vs. Eprex®/Erypo® 417 patients with CKD-related anemia" as shown here.

Epoetin Biosimilars in the Treatment of Renal Anemia: What Have We Learned from a Decade of European Experience?

Biosimilars are biological medicines that are approved via stringently defined regulatory pathways on the basis that comparable safety, efficacy, and quality have been demonstrated to their reference medicine. The advantage of biosimilar drugs is that they may be less expensive than the reference medicine, allowing for greater patient access and cost savings in already stretched healthcare budgets. Biosimilar epoetins have been available in Europe for a decade. Complementing in vitro and preclinical characterization, and pharmacokinetic/pharmacodynamic studies, clinical trials provided the additional data needed to reassure European authorities that biosimilar epoetins were sufficiently similar to the reference epoetin to warrant approval. Post-approval, real-world studies have provided further evidence that biosimilar epoetins are an effective and well-tolerated option for the treatment of renal anemia, with ongoing pharmacovigilance and observational studies monitoring for any unexpected long-term signals that have not been identified in clinical development studies. As the evidence and experience with these products increase, many of the initial concerns are being alleviated. Nephrologists can be increasingly confident that European Medicines Agency-approved biosimilars offer high-quality, affordable, effective alternatives to existing reference medicines used to treat renal anemia, and may help yield cost savings and improve patient access.

Epoetin Biosimilars in the Treatment of Chemotherapy-Induced Anemia: 10 Years' Experience Gained.

High-quality, safe, and effective biosimilars have the potential to increase access to biological therapies worldwide and to reduce cancer care costs. The European Medicines Agency (EMA) was the first regulatory authority to establish legislative procedures for the approval of biosimilars when they published their guidelines on similar biological medicinal products in 2005. Biosimilar epoetins were first approved in 2007, and a wealth of data has been collected over the last decade. Two biosimilar epoetins (under five commercial names) have been approved by the EMA so far. The availability of epoetin biosimilars generated discussion among the oncology community regarding prescribing these products, their efficacy, and their safety. These agents are approved only if they are shown in extensive analytical and clinical testing to have comparable quality, safety, and efficacy to the reference medicine, and real-world studies provide further data that biosimilar epoetins are an effective and well-tolerated option for the treatment of chemotherapy-induced anemia in patients with cancer. Other countries have adopted similar regulatory pathways to those in Europe and have approved epoetin biosimilars. The now extensive European experience with biosimilar epoetins should reassure regulators from other territories.

Maintaining consistent quality and clinical performance of biopharmaceuticals.

INTRODUCTION: Biopharmaceuticals are large protein based drugs which are heterogeneous by nature due to post translational modifications resulting from cellular production, processing and storage. Changes in the abundance of different variants over time are inherent to biopharmaceuticals due to their sensitivity to subtle process differences and the necessity for regular manufacturing changes. Product variability must thus be carefully controlled to ensure that it does not result in changes in safety or efficacy. AREAS COVERED: The focus of this manuscript is to provide improved understanding of the science and strategies used to maintain the quality and clinical performance of biopharmaceuticals, including biosimilars, throughout their lifecycle. This review summarizes rare historical instances where clinically relevant changes have occurred, defined here as clinical drift, and discusses modern tools used to prevent such changes, including improved analytics, quality systems and regulatory frameworks. EXPERT OPINION: Despite their size complexity and heterogeneity, modern analytics, manufacturing quality systems and comparability requirements for the evaluation of manufacturing changes cumulatively help to ensure the consistent quality and clinical performance of biopharmaceuticals throughout their product lifecycle. Physicians and patients can expect the same safety and efficacy from biopharmaceuticals and their respective biosimilars irrespective of batch or production history.

The structure-function relationship of disulfide bonds in etanercept.

Etanercept is a TNFα receptor Fc fusion protein used for the treatment of rheumatic disease and psoriasis. Physicochemical and functional investigation of process fractions during development of the etanercept biosimilar GP2015 (Erelzi®) revealed a correlation between reduced potency and incorrect disulfide bridging between specific cysteines in the receptor domain. This novel structure-function relationship was found to be the molecular basis for reduced potency in recent Enbrel® batches, which exhibit higher levels of incorrect disulfide bridging. Interestingly, incorrect disulfide bridging was found to be reversible under serum-like redox conditions, restoring potency to normal levels. This redox dependent reversibility suggests that these variants are likely not relevant for clinical efficacy once the drug enters the bloodstream. Nonetheless, incorrect disulfide bridging in etanercept represents a new quality attribute that is critical for biopharmaceutical functionality and should thus be carefully monitored and controlled to guarantee patient safety.

Ten years of biosimilars in Europe: development and evolution of the regulatory pathways.

A biosimilar is defined by the European Medicines Agency as a biological medicine that is similar to another biological medicine that has already been authorized for use. A science-based regulatory framework to ensure high-quality biosimilars has been established in Europe since 2005 and is monitored and updated on an ongoing basis. The guiding principle of a biosimilar development program is to establish similarity between the biosimilar and the reference medicine by the best possible means, ensuring that the previously proven safety and efficacy of the reference medicinal product also applies to the biosimilar. Development of a biosimilar is underpinned by state-of-the-art analytical techniques to characterize both reference medicines and biosimilars. The extent and nature of the nonclinical in vivo studies and clinical studies to be performed depend on the level of evidence obtained in the previous step(s), including the robustness of the physicochemical, biological, and nonclinical in vitro data. Extrapolation is an important element of the biosimilarity concept. When biosimilar comparability has been demonstrated in one indication, extrapolation of the data package to other indications of the reference medicine could be acceptable, but needs to be scientifically justified and considered in light of the demonstrated level of sameness by all analytical, nonclinical, and clinical data. The credibility of the scientific basis behind the biosimilar concept, and quality of regulatory decision-making, is demonstrated by the successful approval and clinical use of 20 biosimilar medicines since 2006 when Omnitrope® was the first biosimilar to be approved. The regulatory environment for biosimilars continues to evolve, both in recognition of advances in technology/analytical methods and the availability of new targets for biosimilar development.

The totality-of-the-evidence approach to the development and assessment of GP2015, a proposed etanercept biosimilar.

OBJECTIVE: The aim of this review is to describe the inherent variability that is natural to biologics and, using the proposed etanercept biosimilar (GP2015) as an example, provide details on the "totality-of-the-evidence" concept, whereby all physicochemical, biologic, preclinical, and clinical data for a biosimilar and reference medicine are evaluated in an iterative, stepwise manner and shown to be highly similar. METHODS: This review was carried out by a search of published articles, reviews, abstracts and patents in PubMed/Medline and Google Scholar up to November 2016. RESULTS: Analytical, functional, preclinical, and clinical data provide a comprehensive understanding of both GP2015 and reference etanercept, and demonstrate a high level of similarity between the two products in accordance with regulatory requirements. The totality of the evidence from all analyses and performed trials provides a robust scientific bridge between the biosimilar and clinical experience with the reference medicine, and is used to justify the use of the biosimilar in all indications for which the reference medicine is approved. CONCLUSION: Biologic therapies have revolutionized the treatment of immune-mediated inflammatory diseases. The availability of biosimilars has the potential to improve patient access to biologic medicines and stimulate innovation. Physicians may be unfamiliar with the totality-of-the-evidence concept; therefore education and information on this unique approach to developing biosimilars is required to facilitate the use of biosimilars in clinical practice and allow physicians to make informed treatment decisions.

The role of the quality assessment in the determination of overall biosimilarity: a simulated case study exercise.

A determination of biosimilarity is based on a thorough characterization and comparison of the quality profiles of a similar biotherapeutic product and its reference biotherapeutic product. Although the general principles on the role of the quality assessment in a biosimilar evaluation are widely understood and agreed, detailed discussions have not been published yet. We try to bridge this gap by presenting a case study exercise based on fictional but realistic data to highlight key principles of an evaluation to determine the degree of similarity at the quality level. The case study comprises three examples for biosimilar monoclonal antibody candidates. The first describes a highly similar quality profile whereas the second and third show greater differences to the reference biotherapeutic product. The aim is to discuss whether the presented examples can be qualified as similar and which additional studies may be helpful in enabling a final assessment. The case study exercise was performed at the WHO implementation workshop for the WHO guidelines on quality assessment of similar biotherapeutic products held in Xiamen, China, in May 2012. The goal was to illustrate the interpretation of the comparative results at the quality level, the role of the quality assessment in the entire biosimilarity exercise and its influence on the clinical evaluation. This paper reflects the outcome of the exercise and discussion from Xiamen.

Physicochemical and functional comparability between the proposed biosimilar rituximab GP2013 and originator rituximab.

BACKGROUND: Regulatory approval for a biosimilar product is provided on the basis of its comparability to an originator product. A thorough physicochemical and functional comparability exercise is a key element in demonstrating biosimilarity. Here we report the characterization of a proposed biosimilar rituximab (GP2013) and originator rituximab. OBJECTIVE: To compare GP2013 with originator rituximab using an extensive array of routine analytical and extended characterization methods. METHODS: Primary and higher order protein structures were analyzed using a variety of methods that included high-performance liquid chromatography electrospray ionization mass spectrometry (HPLC-ESI-MS), peptide mapping with UV and MS detection, circular dichroism (CD), Fourier transform infrared (FTIR) spectroscopy, hydrogen deuterium exchange (HDX) MS, 1D (1)H nuclear magnetic resonance (NMR) spectroscopy, X-ray crystallography and differential scanning calorimetry (DSC). Charge and amino acid modifications were assessed using cation exchange chromatography (CEX) and peptide mapping using reversed-phase (RP) HPLC. Boronate affinity chromatography was used to determine the relative amount of glycation. Glycans were identified and quantified after 2-aminobenzamide (2-AB) labeling and separation using normal phase HPLC with fluorescence and MS detection, respectively. Glycan site occupancy was determined using reducing capillary electrophoresis with sodium dodecyl sulfate (CE-SDS). Size heterogeneity was determined using reducing and non-reducing CE-SDS, size exclusion chromatography (SEC) and asymmetric flow field flow fractionation (AF4). Biological characterization included a series of bioassays (in vitro target binding, antibody-dependent cell-mediated cytotoxicity [ADCC], complement-dependent cytotoxicity [CDC] and apoptosis) and surface plasmon resonance (SPR) Fc receptor binding assays. RESULTS: Intact mass analysis of GP2013 and the heavy and light chains using RP HPLC-ESI-MS revealed the expected molecular mass of rituximab. The amino acid sequence was shown to be identical between GP2013 and the originator rituximab. Further sequence confirmation using RP-HPLC-UV/MS peptide mapping showed non-distinguishable chromatograms for Lys-C digested GP2013 and originator rituximab. The higher order structure of GP2013 was shown to be indistinguishable from originator rituximab using a large panel of redundant and orthogonal methods. GP2013 and originator rituximab were comparable with regard to charge variants, specific amino acid modifications and the glycan pattern. GP2013 was also shown to have similar purity, aggregate and particle levels when compared with the originator. Functionally, and by using a comprehensive set of bioassays and binding assays covering a broad range of rituximab's functional activities, GP2013 could not be distinguished from originator rituximab. CONCLUSION: GP2013 was shown to be physicochemically highly similar to originator rituximab at the level of primary and higher order structure, post-translational modifications and size variants. An extensive functional characterization package indicated that GP2013 has the same biological properties as originator rituximab.

A biosimilar industry view on the implementation of the WHO guidelines on evaluating similar biotherapeutic products.

The WHO guidelines on evaluating biosimilar products represent an important step forward in the global harmonization of biosimilar(1) products regulation, and provide clear guidance for regulatory bodies and industry. They confirm the key principles of biosimilarity, namely stand alone manufacturing process development and demonstrated comparability, which are described in many existing regional guidelines for biosimilars. Based on the premise that companies which have developed capabilities for the production of safe and efficacious recombinant biopharmaceuticals also have the foundation and tools available to make safe and efficacious biosimilars, the guidelines provide industry with clear direction on how to actually do so. Finally, when applying the WHO guidelines, it should be considered that the experience gained by industry and regulators when evaluating manufacturing process changes of originator products can be leveraged and directly applied to the development and approval of biosimilar products.