Biosimilars in rheumatic diseases: structural and functional variability that may impact clinical and regulatory decisions

Abstract

Biologics as therapeutic interventions for human disease represent both a distinctly modern novelty and an echo of ancient, or at least old, medical practice. The similarity lies in the sense that in both the synthetic effort occurs in living organisms (an extract of a plant, animal tissue, or a cell culture) while the difference is apparent in the bioengineering required in modern methods and the corresponding flexibility to customize the therapeutic product. Although the concept of looking to living systems as a source of medically useful compounds either for research or for actual patient care has never vanished, the development of biochemistry and advances in medicinal chemistry made production by total synthesis the standard for a safe, reliable, and commercial drug production at sufficient scale. In this interval was where much of the modern apparatus for approving medical therapies came to be developed, and as such, the most proper extension of the regulatory regime to modern biologics is not entirely obvious. In particular, the notion of generics for off-patent conventional pharmaceuticals and their role in the marketplace with respect to increasing the accessibility of treatment is not congruent with the relationship between what are known as biosimilars and off-patent originating biologics. In this article, we review elements of the scientific basis for challenges in the production, use, and regulation of biosimilars. In light of these advances, we propose suggestions to modify constraints on biosimilar regulations in the interest of patient care and access to therapies.

Clinical Trial Design in Juvenile Idiopathic Arthritis

“…Whereas new biologic drugs require extensive efficacy testing in specific populations emphasizing clinical trials, biosimilar evaluation requires proof of similarity, including extensive preclinical testing of physiochemical and biological characteristics [30, 31]. Various techniques may be used to prove product similarity, such as mass spectrometry, chromatography, and assays to show binding to selected targets [32]. Despite extensive physiochemical similarities, there may be significant post-translational differences between biologic products that impact clinically significant drug behavior, such as immunogenicity [32].…”

“…Various techniques may be used to prove product similarity, such as mass spectrometry, chromatography, and assays to show binding to selected targets [32]. Despite extensive physiochemical similarities, there may be significant post-translational differences between biologic products that impact clinically significant drug behavior, such as immunogenicity [32]. Additional testing for immunogenicity is therefore essential.…”

“…The EMA approved Celltrion’s Remsima/CT-P13 biosimilar for infliximab in 2013 based on 1) comparable major physical and chemical characteristics and biological activity, and 2) clinical trials evaluating PK and efficacy/safety [34–36]. The FDA approved Celltrion’s Inflectra/CT-P13 in 2016, but required an additional single PK study [32]. …”

“…For example, the EMA and FDA accepted extrapolation of the results from the CT-P13 trial in RA to all reference indications, including psoriatic arthritis, plaque psoriasis, adult/pediatric Crohn’s disease (CD), and adult/pediatric ulcerative colitis (UC) [33]. However, Canadian regulators have not approved CT-P13 use in CD and UC due to preclinical differences between CT-P13 and the reference product in antibody-dependent cell mediated cytotoxicity [32, 36]. which has been thought to be a plausible yet unfounded mechanism of action in IBD.…”

“…Applications for biosimilars to adalimumab (ABP 501/Amjevita from Amgen) and etanercept (GP2015/Erelzi from Sandoz) were accepted by the FDA [32, 37, 38]. In July 2016, the FDA’s Arthritis Advisory Committee unanimously voted to extrapolate the efficacy of ABP 501 to JIA for patients 4 years and older, based on 1) similar biologic exposure between pediatrics and adults receiving US-licensed adalimumab, 2) similar immunogenicity between ABP 501 and EU/US licensed adalimumab, and 3) similar TNF binding and neutralizing potency between ABP 501 and EU/US licensed adalimumab [37].…”