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16 BioPharm International eBook October 2021 www.biopharminternational.com ger requires certain in-vivo testing and comparative clinical trials, which should accelerate not only the review process at MHR A, but a lso mean biosimilar companies to make appli- cations at an earlier stage in their timeline to market. MHRA has also encouraged the use of invented brand names for biosimilar products." For M HR A , a biosimi la r must demonst rate h igh si m i l a r it y to a reference product in terms of phys- icochemica l proper t ies, biolog ica l activity/potency, and clinical profiles, continues Lancaster. "The biosimilar product must also undergo impurity profiling and the nature of excipients should not give rise to safet y con- cerns," he says. "Although changes in the excipient formulation of the biosimilar are not encouraged, they can be considered in the interest of the patient, but must be carefully evaluated from a safety point of view and in relation to the route of administration, if this is the first time that the new excipients are used by this route," asserts Lanucara. A d d it i o n a l l y, t h e a m i n o a c i d sequence is expected to be the same for t he biosim i la r produc t a s for the reference product in the eyes of MHRA, points out Lancaster. "Only small differences in post-translational modif ications are expected, such as small modifications in sugars that are added to the protein after it has been made," he adds. " To d e m on s t r at e a bio s i m i l a r meets t he M H R A requ i rements , the agency recommends a stepwise approach sta r ting w ith a compre- hensive physicochemical and biolog- ical characterization, followed by a pivotal pharmacokinetic study," says Lancaster. "But, critically, without the need for a confirmatory clinical effi- cacy study if a scientific rationale sup- ports this approach." MHRA does not consider in-vivo anima l st ud ies as necessa r y when demonstrating comparability between a reference produc t a nd t he pro- posed biosimilar. "In-vivo studies in animals are not expected to resolve ambiguities on biosimilarity arising from the analytical comparability and should not be performed with this intent," explains Lanucara. "However, if toxicity studies performed to good manufacturing practice (GMP) stan- dards are available, the results should be submitted." Via the MHR A guidance, appli- ca nts a re encou raged to leverage in-depth knowledge of the reference product and the data generated from analytical and in-vitro functional test- ing, which has the potential to reduce the need for head-to-head clinical testing, emphasizes Lanucara. "The absence of an eff icacy clinical trial must, however, be thoroughly justified, and scientific advice should be sought as soon as the analytical and functional data is available to support such a strat- egy," he states. "Where the mechanism of action is not known or fully char- acterized, a clinical trial to demon- strate efficacy and safety will still be required. Additionally, if differences between the reference product and the proposed biosimilar are disclosed at the analytical level, a confirmation clinical trial will be required if the impact of these differences on safety and efficacy cannot be predicted." In c a se s where h igh si m i l a r it y between the biosimilar and reference product is ascertained at the analyt- ica l and f unctiona l levels, MHR A g u idance states that the proposed bio s i m i l a r w i l l b e a p p r o v e d fo r the same ind ications as the refer- ence product, Lanucara continues. Approv a l s of t h is nat u re w i l l be applicable for indications that are not protected by ma rket exclusiv it y or patents, and the products will be con- sidered interchangeable. Ot her key d i f ferences bet ween the guidance documents of the UK and EU include the use of reference products that are approved in Great Britain—although products from out- side the UK are acceptable if they are licensed in a location with similar sci- entif ic and regulatory standards and are representative of a British refer- ence product. Changes that may ben- efit the patient, such as reduction of injection pain, should also be consid- ered in the application, Manley adds. Furthermore, MHRA has introduced a new 150 day 'accelerated assess- ment' procedure to streamline bio- similar licensing, which could lead to UK developers obtaining a marketing authorization more easily, she adds. " Fol lo w i n g Br e x it , t he U K i s increasingly looking to future-proof its regulator y framework and align with international bodies and over- seas regulators, to ensure it remains a competitive market, which provides patients with cost-effective access to treatments," Manley says. "Therefore, it is no surprise that the UK partic- ipates in a number of international, cross-border consortia to speed up evaluation of treatments." While increasing regulatory efforts, the UK is also revamping the early access framework, Manley notes. The MHR A offers t wo new accelerated assessment procedu res, wh ich a re available to biosimilars; the 150-Day Assessment for high-quality applica- tions and the Rolling Review route. Both shou ld give rise to a greater number of biosimilars being able to progress via accelerated assessment procedures in the UK, she explains. "It is unlikely that there will be a signif icant amount of short-term divergence in the UK approach given the widely accepted expertise of the EU process in this matter. However, the UK has overall committed to a less stringent regulatory approach, which may increasingly lead to more diver- gence in the future, especially regard- ing the conducting of comparative clinical studies," Manley says. "This [change] links to the UK's desire to become a market leader in scientif ic Regulatory Sourcebook Biosimilars