Introduction
Hyrimoz
®
, (GP2017 SDZ-ADL), is a biosimilar to Humira
®
(REF-ADL). SDZ-ADL was approved in 2018 by both the United States Food and Drug Administration (US FDA) and European Medicines ...Agency (EMA) for the indications of REF-ADL not protected by orphan exclusivity. In 2023, the US FDA and EMA also approved a citrate-free high-concentration formulation (HCF) of SDZ-ADL.
Totality of Evidence—the approach
Approval of SDZ-ADL was based on data gathered using the US FDA, EMA and World Health Organization (WHO)-recommended step-wise Totality of Evidence approach. This approach is a robust dataset confirming high confidence in analytical, functional, pharmacokinetic (PK) and clinical biosimilarity between the biosimilar and reference medicine determined through analytical and clinical investigation.
Evidence of biosimilarity
Evidence supporting the biosimilarity of SDZ-ADL and REF-ADL was reported at each stage of investigation. Comprehensive comparative analytical and functional assessments demonstrated that SDZ-ADL was analytically indistinguishable from REF-ADL in required critical quality attributes, including receptor binding. Phase I clinical data showed PK similarity of SDZ-ADL and REF-ADL in healthy volunteers, with similar safety, tolerability and immunogenicity profiles. Phase III confirmatory efficacy and safety studies, ADACCESS (included in US/EU dossiers) and ADMYRA (separate to US/EU dossiers), both confirmed that SDZ-ADL’s efficacy, safety, and immunogenicity matched REF-ADL in all patient groups with no clinically meaningful differences. More recently, this data package was the basis for a citrate-free HCF of SDZ-ADL to be developed, and its PK, safety and immunogenicity were confirmed against the initially approved formulation of SDZ-ADL.
Conclusion
Overall, the Totality of Evidence provided for biosimilar adalimumab, SDZ-ADL, confirmed the analytical, functional and clinical similarity of SDZ-ADL to REF-ADL, supporting its regulatory approval and providing a data bridge with which to evaluate and support the approval of citrate-free HCF SDZ-ADL for clinical use.
Plain Language Summary
A biosimilar is a type of medicine that is designed to match the structure and function of a ‘reference’ biologic medicine. Hyrimoz
®
(SDZ-ADL) is a biosimilar of the adalimumab reference medicine, Humira
®
(REF-ADL). SDZ-ADL was approved in the US and Europe in 2018. For SDZ-ADL to be approved, a collection of evidence needed to be created, called the ‘Totality of Evidence.’ The purpose of this collection of data is to show there is a high confidence that the new biosimilar medicine matches the reference medicine, from the structure of the medicine to the effect of the medicine on the human body. For SDZ-ADL, this investigation started with comparing the physical structure and other functional properties of SDZ-ADL versus REF-ADL and ended with clinical studies in both healthy volunteers and in patients with diseases treated with adalimumab. This Totality of Evidence gathered for biosimilar adalimumab, SDZ-ADL, confirmed the similarity of SDZ-ADL to REF-ADL and therefore supported the approval of SDZ-ADL. In 2018, a citrate-free high-concentration version (high concentration formulation HCF) of REF-ADL was launched that matched REF-ADL. HCF REF-ADL has since become the primary formulation of REF-ADL used in practice. In 2023, a HCF version of SDZ-ADL was also approved in the US and EU based on evidence confirming that HCF SDZ-ADL matched SDZ-ADL. As SDZ-ADL had been previously confirmed to match the reference medicine, this meant that HCF SDZ-ADL could be directly compared against SDZ-ADL to confirm biosimilarity and support its approval.
•Provides coherent interpretation of previous research on slope using APOS Theory.•Proposes framework to classify teaching, learning and researching slope.•Uses APOS notions of transition levels and ...new proposed Totality stage.•Adds cognitive dimension to research on conceptualizations of slope.
In this paper a framework for slope is proposed using APOS (Action-Process-Object-Schema) Theory and conceptualizations of slope previously identified in research. The proposed APOS-slope framework allows for discussion of students’ cognitive development in relation to different conceptualizations of slope. As such, it may be adopted as a means to advance future research or as a way to plan instruction. In particular, the framework uses specific examples to consider interrelations between the ways of thinking about slope that have been reported to provide additional insight on how individuals understand this concept. The proposed framework contributes to the field by bringing together a number of past studies related to slope and providing a common ground under which these works might be interpreted.
Surgical face masks have become commonplace during the COVID-19 pandemic, producing debates on mask practices. This paper explains the semiotic practices of the face mask among Koreans, who accepted ...the mask early and have simultaneously remained uneasy about it until late 2020. It aims to explain this paradox by discovering various meanings Koreans ascribe to the mask. A content analysis of reader responses to news articles finds that Koreans signify what the mask means for life in various voices (i.e., instrumental meanings) in which they concurrently reveal multiple and contradictory meanings of everyday life (i.e., existential meanings) during the pandemic. Eight themes-beneficence, futility, nuisance, routine, privacy, dominance, collective commitment, and intricacy-constitute what the mask and everyday life mean. This study also finds that contradictions among these meanings are resolved either incidentally by their being simultaneously harbored in one piece of the mask that stays and holds tight in most circumstances or semiotically by certain integrative meanings embracing multiple meanings at once. The study argues that the meanings of the mask reflect meanings of life that are often contradictory and yet held together during the pandemic. It demonstrates that mask sociology serves as a promising humanistic inquiry on how the Maussian totality of everyday life is concretely experienced in the context of the pandemic.
This study explores diversity reporting by New Zealand Stock Exchange (NZX) listed companies, arguing that diversity goes beyond gender and includes differences in age, ethnicity, sexuality, ...religious beliefs and physical disability. We argue that gender diversity and deep diversity elements (race, age, sexual orientation, disabilities, ethnicity) have a synergistic relationship and that gender diversity objectives cannot be achieved without attaining diversity objectives in these other elements and vice versa. Designing a 30-item diversity disclosures index, this study undertakes a content analysis of the diversity-related disclosures made by 152 NZX listed companies. Analysing diversity-related disclosures in annual and sustainability reports, we find that the NZX listed companies predominantly relate diversity only to board gender diversity. Deep diversity elements at all organisational levels, however, do not receive much attention, with a few exceptions. Our results highlight that female representation on organisational boards has a positive impact on overall organisational gender and other diversity aspects and vice versa. The results of an emphasis on the totality of diversity have important implications for boards of directors, corporate managers and regulators interested in improving the corporate governance and diversity practices in New Zealand organisations.
Armstrong famously argued in favour of introducing totality facts in our ontology. Contrary to fully negative (absence) facts, totality facts yield a theory of “moderate” or “partial” negativity, ...which allegedly provides an elegant solution to the truthmaking problem of negative claims and, at the same time, avoids postulating (many) first-order absences. Friends of totality facts argue that partial negativity is (i) tolerable vis-à-vis the Eleatic principle qua mark of the real, and (ii) achieves a significant advantage in terms of ontological parsimony. But are totality facts, which are partially negative, really more ontologically acceptable than fully negative facts? In this paper, we argue that, comparatively, the case for totality facts is weaker than commonly assumed and that, ultimately, the answer is negative.
Call a truth complete with respect to a subject matter if it entails every truth about that subject matter. One attractive way to formulate a complete truth is to state all the relevant positive ...truths, and then add:
and that’s it
. When the subject matters under consideration are non-contingent, a non-trivial conception of completeness must invoke a hyperintensional conception of entailment, and of the completion operation denoted by ‘that’s it’. This paper develops two complementary hyperintensional conceptions of completion using the framework of truthmaker semantics and determines the resulting logics of totality.
The first biosimilar of bevacizumab was approved by the US FDA; other potential biosimilars of bevacizumab are in late-stage clinical development. Their availability offers opportunity for increased ...patient access across a number of oncologic indications. The regulatory pathway for biosimilar approval relies on the totality of evidence that includes a comprehensive analytical assessment, and a clinical comparability study in a relevant disease patient population. Extrapolation of indications for a biosimilar to other eligible indications held by the originator, in the absence of direct clinical comparison, frequently forms part of the regulatory judgment. Herein, we consider the evidence required to demonstrate biosimilarity for bevacizumab biosimilars, with particular focus on the rationale for extrapolation across oncologic indications.
Este ensayo practica una hermenéutica a Totalidad e infinito a partir de cinco epígrafes, abocados todos a explorar los múltiples sentidos de la propuesta levinasiana en torno al fundamento ...trascendental de lo ético. El primer apartado busca analizar la relación entre lo que Lévinas designa como la faz del ser y el concepto de totalidad; en el epígrafe siguiente se explicita la diferencia existente, en el interior de la comprensión temporal de lo total, entre lo histórico y lo escatológico; en el tercer epígrafe se analizan los móviles que llevan a Lévinas a sustituir lo metafísico por lo ético, revelando a este segundo saber como filosofía primera; y, finalmente, el cuarto y el quinto epígrafe quedan dedicados a entender dos conceptos que, entrelazados, condensan la matriz conceptual desde donde Lévinas acentúa la originalidad de su propuesta: el rostro del Otro y la idea de infinito.
This paper, accompanying Baeumler’s 1922 essay on Croce, illustrates the German philosopher’s thesis that modern thought on beauty does lead to aesthetics only when, with Kant, it acquires a notion ...of taste, understood as the sensible manifestation of the concrete individuality of man.
Do causes necessitate their effects? Causal necessitarianism (CN) is the view that they do. One major objection—the “monotonicity objection”—runs roughly as follows. For many particular causal ...relations, we can easily find a possible “blocker”—an additional causal factor that, had it also been there, would have prevented the cause from producing its effect. However—the objection goes on—, if the cause really
necessitated
its effect in the first place, it would have produced it
anyway
—despite the blocker. Thus, CN must be false. Though different from Hume’s famous attacks against CN, the monotonicity objection is no less important. In one form or another, it has actually been invoked by various opponents to CN, past and present. And indeed, its intuitive appeal is quite powerful. Yet, this paper argues that, once carefully analysed, the objection can be resisted—and should be. First, I show how its success depends on three implicit assumptions concerning, respectively, the notion of cause, the composition of causal factors, and the relation of necessitation. Second, I present general motivations for rejecting at least one of those assumptions: appropriate variants of them threaten views that even opponents to CN would want to preserve—in particular, the popular thesis of
grounding
necessitarianism. Finally, I argue that the assumption we should reject is the one concerning how causes should be understood: causes, I suggest, include an element of completeness that excludes blockers. In particular, I propose a way of understanding causal completeness that avoids common difficulties.
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