Approval Of Biosimilars Research Articles

Real-world trends in biosimilar prescribing among oncology providers, 2019-2021.

e18701 Background: The number of approved biosimilars in the United States has increased exponentially in recent years. Within the oncology market, there are currently 14 approved biosimilars, with 11 launched since the start of 2019. The emergence of new oncology biosimilars provides a tool for success in value-based care, and has the potential to lower costs to patients and providers and expand access to care. Methods: Analysis of biosimilar prescribing behavior was performed using 2020 prescription data (Wolters Kluwer, n = 130,836), sales data (IQVIA), and dosage data for patients taking bevacizumab, trastuzumab, rituximab, or an FDA-approved biosimilar for these products (FDA Purple Book), between 2019-2021 (ION Solutions, n = 69,884). Drugs not directly interchangeable with the bevacizumab, trastuzumab or rituximab reference products according to NCCN guidelines were excluded. Results: Biosimilar products are currently available for bevacizumab (2 biosimilars), rituximab (3 biosimilars), and trastuzumab (5 biosimilars). We found that in 2020, 8.2% of new prescriptions for any of these three reference products were for a biosimilar. An analysis of real-world drug administration data revealed that in the 3 months following the 2019 launch of trastuzumab’s first biosimilar (trastuzumab-anns), 7.3% of initiating line 1 patients were prescribed the biosimilar over the reference product. During the same period in 2020, when a total of 5 trastuzumab biosimilars were available, 80.5% of initiating line 1 trastuzumab patients began treatment on a biosimilar, suggesting rapid uptake by providers. However, this differed by product, with the initial uptake for the first rituximab biosimilar (rituximab-pvvr), at only 2.3%. Uptake also occurred within treatment lines, with 11.1% of all patients (bevacizumab: 11.3%, trastuzumab: 14.1%, rituximab: 7.9%) switching from a reference product to a biosimilar during treatment. Uptake was particularly rapid for trastuzumab biosimilars: among patients on trastuzumab at the time of its first biosimilar launch, 18.2% switched to trastuzumab-anns in the first 90 days post-launch. Biosimilars launched at significantly lower prices than their reference products, with cost per prescription at -42.0%, -29.9% and -89.5% relative to the reference product for trastuzumab, rituximab and bevacizumab, respectively. However, biosimilar launches had little impact on reference product pricing, with 2019-2020 year-over-year (YOY) differences in price per prescription close to the YOY averages in previous years (2015-2019) for all three reference products. Conclusions: We conclude that uptake of biosimilars among oncology providers between 2019-2020 was rapid, although the extent of biosimilar prescribing varied among products. Biosimilars offered greatly reduced costs to providers, although reference product prices remained stable despite increased biosimilar competition.

On- and off-label use of rituximab in rheumatic diseases

Steadily growing knowledge about pathogenetic mechanisms in autoimmune rheumatic diseases (RDs) has paved the way to different therapeutic approaches. In particular, the availability of biologics on the market has dramatically modified the natural history of rheumatic chronic inflammatory diseases with a meaningful impact on patients’ quality of life. Among the wide spectrum of available biological treatments, rituximab (RTX), initially used in the treatment of non- Hodgkin’s lymphoma, was later approved for rheumatoid arthritis and anti-neutrophil cytoplasmic antibodies-associated vasculitis. Currently, in rheumatology, RTX is also used with off-label indications in patients with systemic sclerosis, Sjögren’s syndrome and systemic lupus erythematosus. RTX is a monoclonal antibody targeted to CD20 molecules expressed on the surface of pre-B and mature B lymphocytes. It acts by causing apoptosis of these cells with antibody- and complement-dependent cytotoxicity. As inflammatory responses to cell-associated immune complexes are key elements in the pathogenesis of several autoimmune RDs, such an approach might be effective in these patients. In fact, RTX promotes a rapid and long-term depletion of circulating and lymphoid tissue-associated B cells, thus leading to a lower recruitment of these effector cells at sites of immune complex deposition, therefore reducing inflammation and tissue damage. RTX is extremely interesting for rheumatologists, as it represents an important additional therapeutic approach. Therefore, the advent in clinical practice of approved RTX biosimilars, such as CT-P10, may help in improving treatment access as well as reducing costs.

The Great Debate With IBD Biosimilars: Pro: Biosimilars Should Be Routinely Used as a First Line Biologic and May Be Switched From Reference Biologics.

The relatively high cost of anti-TNF agents and looming or actual expiry of patents for several biologics have led to the development of "highly similar" versions of the "originator" drugs called "biosimilars." The approval of biosimilars has been based on "extrapolation," whereby approval is granted in licensed indications for the reference product without the need for clinical trials. We discuss efficacy and safety data in support of biosimilar use from prospective studies, switching from originator biologic, impact on immunogenicity, pharmaco-economic, and practical considerations for clinicians.

Evolving Biosimilar Clinical Requirements: A Qualitative Interview Study with Industry Experts and European National Medicines Agency Regulators.

A biosimilar is a biological medicine highly similar to another already approved biological medicine (reference product). The availability of biosimilars promotes competition and subsequently lower prices. Changing the current biosimilar clinical comparability trial requirements may lead to lower biosimilar development costs that potentially could increase patients' access to biologics. The aim was to determine the perceptions of industry and medicines agency regulators regarding the value, necessity, and future developments of the European biosimilar clinical comparability trial requirements for establishing biosimilarity. Semi-structured interviews were conducted with eight European national medicines agency regulators and 17 pharmaceutical company employees or consultants with experience in biologics between September 2018 and August 2019. Data were subjected to content analysis. In general, the participants expected that clinical comparability trial requirements will continue to be reduced, in particular based on advancements in analytical testing and knowledge generated from prior biosimilar approvals. However, there are also competing issues at play, such as competition, physician's trust, and ethical considerations. Participants also reported that any new initiative to reduce or waive biosimilar clinical requirements needs to be scientifically sound and could potentially lower biosimilar development costs. The main findings are that biosimilar clinical comparability trial requirements are likely to change in the near future. Clarity is needed on how to ensure adequate correlation between physicochemical data, pharmacokinetic/pharmacodynamic studies, and the drugs' performance in the clinic, as well as how to continue sufficient immunogenicity assessment. Obtaining this clarity can facilitate regulatory assessment of the next biosimilars.

Analysis of the Regulatory Science Applied to a Single Portfolio of Eight Biosimilar Product Approvals by Four Key Regulatory Authorities.

Slow uptake of biosimilars in some regions is often attributed to a lack of knowledge combined with concerns about safety and efficacy. To alleviate physician and patient apprehensions, regulatory reviews from four major regulatory authorities (RAs) (European Medicines Agency, US Food and Drug Administration, Health Canada, and Japan Pharmaceuticals and Medical Devices Authority) across a portfolio of eight biosimilars were analyzed to provide insight into RA review focus and approach. RA queries were evaluated in an unbiased and systematic manner by major classification (Chemistry, Manufacturing and Controls [CMC], nonclinical, clinical or regulatory) and then via detailed sub-classification. There was a consistent, predominant focus on CMC from all RAs. The review focus based on sub-classification of clinical and regulatory queries was influenced by molecular complexity, with significant differences between categories (monoclonal antibody or protein) in the distribution of query topics; specifically, bioanalytical (p = 0.023), comparative safety and efficacy (p = 0.023), and statutory (including the justification of extrapolation) (p = 0.00033). Each biosimilar had a distinct distribution of clinical query topics, tailored to product-specific data. This analysis elucidated areas of heightened RA interest, and validated their application of regulatory science in the evaluation of biosimilar safety and efficacy.

Biosimilars – status in July 2020 in 16 countries

The World Health Organization has provided specific guidance for biosimilar products to assist regulators, manufacturers and other professionals involved in the development and evaluation of these products. The development and approval of biosimilars are important for health care, as they allow the marketing of safe, efficacious and affordable biological products. Since the first biosimilars were approved in the EU in 2006, a series of biosimilars have been approved in many countries/geographical regions. This manuscript provides the figures on the status of approved biosimilars in 16 countries based on the information from regulatory experts and from publicly available data. It is clear that increasing numbers of biosimilars are now available in many countries and provide more options for treatments. It is expected that adoption of biosimilars will allow affordable health care and greater patient access to important medicinal products. It will also contribute to the overall WHO goal recognized by the World Health Assembly in 2014 by adopting a resolution on access to biotherapeutic products including biosimilars and on ensuring their quality, safety and efficacy.

First 2021 GaBI Journal issue highlights

The articles in this first issue contain a large volume of useful information on the global development, approval, manufacturing, marketing, and uptake of biosimilars. The first Original Research by Dr Hye-Na Kang et al. from the World Health Organization (WHO) presents an extensive listing of data on the status of

Type and Extent of Information on (Potentially Critical) Quality Attributes Described in European Public Assessment Reports for Adalimumab Biosimilars.

Regulatory approval of biosimilars predominantly relies on biosimilarity assessments of quality attributes (QAs), particularly the potentially critical QAs (pCQAs) that may affect the clinical profile. However, a limited understanding exists concerning how EU regulators reflect the biosimilarity assessments of (pC)QAs in European public assessment reports (EPARs) by different stakeholders. The type and extent of information on QAs and pCQAs in EPARs were evaluated for seven adalimumab biosimilars. Seventy-seven QAs, including 31 pCQAs, were classified and assessed for type (structural and functional attributes) and extent (biosimilarity interpretation and/or test results) of information in EPARs. Reporting on the QAs (35–75%) varied between EPARs, where the most emphasis was placed on pCQAs (65–87%). Functional attributes (54% QAs and 92% pCQAs) were reported more frequently than structural attributes (8% QAs and 22% pCQAs). About 50% (4 structural and 12 functional attributes) of pCQAs were consistently reported in all EPARs. Regulators often provided biosimilarity interpretation (QAs: 83% structural and 80% functional; pCQAs: 81% structural and 78% functional) but rarely include test results (QAs: 1% structural and 9% functional and pCQAs: 3% structural and 9% functional). Minor differences in structural attributes, commonly in glycoforms and charge variants, were often observed in adalimumab biosimilars but did not affect the functions and clinical profile. Despite the variability in reporting QAs in EPARs, the minor observed differences were largely quantitative and not essentially meaningful for the overall conclusion of biosimilarity of the seven adalimumab biosimilars.

Regulatory Approval Scenario of Biosimilars in Pediatric Patients in the United States and European Union.

Regulatory agencies of the USA and European Union (EU) have introduced multiple guidelines in the last decade to standardize and accelerate biosimilar development. As a result, a large number of biosimilars are being approved in the USA and EU. In the present review, we identified the biosimilars and their corresponding reference biologics approved for pediatrics in the USA and EU, and then assessed their approval details. In the USA, a biosimilar applicant needs to submit an initial pediatric study plan under the Pediatric Research Equity Act (PREA). We found that the PREA requirements of a pediatric assessment for biosimilars were waived where the reference biologics were not approved for one or more pediatric age groups for an indication. The PREA requirements of a pediatric assessment were deferred if the indication was under orphan drug exclusivity or a pediatric formulation was not available. Excluding the waiver and deferral scenarios, biosimilars were approved for the same pediatric indications as those of the reference biologics based on scientific justification extrapolation from the pediatric information of the reference biologics to biosimilars. The applicants were asked to submit a pediatric assessment in the deferred indication and/or develop a dedicated formulation that can ensure accurate dose delivery in pediatric population, as applicable. In the EU, pediatric assessments were not required for biosimilars; hence, all biosimilars (except rituximab) have been approved for the same indications as those of the reference biologics. Biosimilar developers need to be aware of the possible requirement of a pediatric study plan, development of pediatric drug delivery devices, and requirement of human factor studies for a device, to avoid delay in approval of biosimilars in the USA.

The global landscape of drug development of trastuzumab biosimilars

BackgroundLimited access to prevention, screening, timely diagnosis, affordable and effective treatment is the main driver of disparities in cancer care. The high costs represent a common barrier for the affordable access to biological agents. The only biological agent included in the World Health Organization list of essential medicines for the management of breast cancer is trastuzumab, and its biosimilars. MethodsWe reviewed the pivotal trials for approved trastuzumab biosimilars and searched the proposed biosimilars under investigation in clinical trials, then mapped them against metrics of national epidemiology and health system capacity. ResultsThirteen clinical trials were extracted. Across 40 countries and 825 research facilities, more than three- fourth enrolling centers were located in low- and middle- income countries (n = 633) Correlation analysis suggested that the research and drug development of biosimilars was prioritized in settings where weaker health systems can result in poorer cancer- related outcomes and higher out of pocket expenses (range of r: -0,37; + 0.53; all p-values <0.05). Eleven countries had no biosimilars approved at the time of the analysis: in these countries, the drug development of biosimilars was more represented. ConclusionThe drug development of biosimilars occurs significantly in low- and middle- income countries. Our correlative findings must be interpreted cautiously, to understand if the biosimilar drug development is congruent with the national health priorities of cancer control. Health, societal and economic impacts on populations should be accounted, as relevant metrics for clinical trial implementations. Policy SummaryThe implementation of cancer research should be developed under the national cancer control priorities, to ensure consistency across the evidence- informed relevant national policies, thus result in a population health impact. Biosimilars drug development can drive tangible population health benefits by accelerating the uptake of more sustainable health interventions and shaping more efficient regulatory environments.

Knowledge and Perception Assessment of Pharmacy Technicians on Biosimilars at the University Hospital Center -Tlemcen

Biosimilars are similar products, but not identical, to a reference biological drug already approved by the authorities, whose protection certificate has expired. Biosimilars have recently been introduced at Tlemcen University Hospital Center (TUHC). Pharmacy technicians are essential health actors for good distribution and use of biodrugs in particular biosimilars within the TUHC. For this, we have done a study to assess the knowledge of pharmacy technicians on biosimilars as well as their opinion on their efficacy-safety profiles. The data collection was carried out by the distribution of a questionnaire with 12 questions (Figure 1). We have analyzed the questionnaires of the 10 pharmacy technicians who agreed to join our study. More than half of pharmacy technicians could not correctly define a biosimilar. In addition, according to the answers provided, the stages of development and approval of biosimilars are not well known. Continuous training on the topic of biosimilars is necessary in order to raise awareness in this category of the importance of rigorous monitoring of these treatments within the TUHC. Regarding the accessory goal of the questionnaire attributed to pharmacy technicians, to provide their opinions on the efficacy and safety of biosimilars according to their daily professional experience, a large part of pharmacy technicians has expressed a satisfaction with the efficiency and safety of these drugs. However, since a certain category of pharmacy technicians affirms to witness suspicion of side effects of biosimilar treatment without informing the Central Pharmacy, it is imperative to raise awareness of the need to declare them to regional and national pharmacovigilance centers.

Knowledge and Perception Assessment of Pharmacy Technicians on Biosimilars at the University Hospital Center-Tlemcen

Biosimilars are similar products, but not identical, to a reference biological drug already approved by the authorities, whose protection certificate has expired. Biosimilars have recently been introduced at Tlemcen University Hospital Center (TUHC). Pharmacy technicians are essential health actors for good distribution and use of bio-drugs in particular biosimilars within the TUHC. For this, we have done a study to assess the knowledge of pharmacy technicians on biosimilars as well as their opinion on their efficacy-safety profiles. The data collection was carried out by the distribution of a questionnaire with 12 questions. We have analyzed the questionnaires of the 10 pharmacy technicians who agreed to join our study. More than half of pharmacy technicians could not correctly define a biosimilar. In addition, according to the answers provided, the stages of develo in order to raise aw pment and approval of biosimilars are not well known. Continuous training on the topic of biosimilars is necessary areness in this category of the importance of rigorous monitoring of these treatments within the TUHC. Regarding the accessory goal of the questionnaire attributed to pharmacy technicians, to provide their opinions on the efficacy and safety of biosimilars according to their daily professional experience, a large part of pharmacy technicians has expressed a satisfaction with the efficiency and safety of these drugs. However, since a certain category of pharmacy technicians affirms to witness suspicion of side effects of biosimilar treatment without informing the Central Pharmacy, it is imperative to raise awareness of the need to declare them to regional and national pharmacovigilance centers.

Comparison of consistency and complementarity of reporting biosimilar quality attributes between regulatory and scientific communities: An adalimumab case study

Biosimilar approval relies on the comparability of quality attributes (QAs), for which information can be derived from regulatory or scientific communities. Limited information is known about whether these sources are consistent with or complementary to each other. The consistency and complementarity of QA reporting in biosimilarity assessments for adalimumab biosimilars approved by the European Medicines Agency in European public assessment reports (EPARs) and scientific publications was assessed. A classification of 77 different QAs (53 structural and 24 functional attributes) was used to assess the types of and information on QAs reported. Six adalimumab biosimilars were analyzed, for which the number of QAs reported in EPARs and publications varied (range = 47 [61%]–60 [78%]). The proportion of QAs consistently reported in both sources varied (range = 28%–75%) among biosimilars; functional QAs (mean = 21 QAs [88%]; range = 19–23) were more consistently reported than structural QAs (mean = 33 QAs [62%]; range = 27–34). The EPARs frequently reported biosimilarity interpretation without providing test results (9–57 QAs in EPARs versus 0–8 QAs in publications), whereas publications frequently reported both test results and interpretations (13–40 QAs in publications versus 0–3 QAs in EPARs). Both sources provided information on the biosimilarity of QAs in a complementary manner and the same biosimilarity interpretation of test results for reported QAs (mean = 90%; range = 78%–100%), with a small discrepancy in biosimilarity interpretations of a few clinically relevant QAs related to post-translation modifications and biological activity. Comprehensive reporting of QAs can contribute to an improved understanding of the role of structural and functional attributes in establishing biosimilarity and the mechanism of action of biological substances in general.

Biosimilar knowledge and viewpoints among Brazilian inflammatory bowel disease patients.

Background:In this analysis we aimed to describe Brazilian inflammatory bowel disease (IBD) patients’ knowledge and perceptions regarding biosimilars and compare with viewpoints from non-Brazilian patients.Methods:An online survey consisting of 19 questions was made available by the European Federation of Crohn’s and Ulcerative Colitis Associations between July 2018 and December 2018. Only respondents who had heard of biosimilars were asked to respond to all of the questions.Results:A total of 102 Brazilian IBD patients responded to the survey. The majority (78.4%) of patients had been exposed to anti-tumor-necrosis-factor drugs and 63.4% of them had heard of biosimilars. Brazilian respondents worried significantly more about biosimilars being less effective than the originator (62.5% versus 47.9%, p value 0.03) and molecular differences between biosimilars and originators (53.1% versus 31.8, p value 0.001) as compared with non-Brazilian IBD patients. The majority of Brazilian (75%) and non-Brazilian (64.1%) respondents thought that the lower cost of biosimilars should not come before their safety and efficacy (p value 0.09). In addition, 79.1% of Brazilian respondents believed that the arrival of biosimilars will have an impact on the management of IBD.Conclusions:Brazilian patients reported higher rates of misconceptions regarding biosimilars than non-Brazilian IBD patients. Although patients still worry about different aspects regarding biosimilars, they also tend to be confident that biosimilars will have an impact on the management of their disease. With the recent approval of many biosimilars in Brazil and the imminent widespread use of these drugs, our data raise awareness for the need of providing patient education to prevent negative expectations toward switching to biosimilars.

The Biosimilar Landscape: An Overview of Regulatory Approvals by the EMA and FDA

Biosimilar medicines expand the biotherapeutic market and improve patient access. This work looked into the landscape of the European and US biosimilar products, their regulatory authorization, market availability, and clinical evaluation undergone prior to the regulatory approval. European Medicines Agency (EMEA, currently EMA) and Food and Drug Administration (FDA) repositories were searched to identify all biosimilar medicines approved before December 2019. Adalimumab biosimilars, and particularly their clinical evaluations, were used as a case study. In the past 13 years, the EMA has received 65 marketing authorization applications for biosimilar medicines with 55 approved biosimilars available in the EU market. Since the first biosimilar approval in 2015, the FDA has granted 26 approvals for biosimilars with only 11 being currently on the US market. Five adalimumab biosimilars have been approved in the EU and commercialized as eight different medicines through duplicate marketing authorizations. Whilst three of these are FDA-approved, the first adalimumab biosimilar will not be marketed in the US until 2023 due to Humira’s exclusivity period. The EU biosimilar market has developed faster than its US counterpart, as the latter is probably challenged by a series of patents and exclusivity periods protecting the bio-originator medicines, an issue addressed by the US’s latest ‘Biosimilar Action Plan’.

A white paper: US biosimilars market on pace with Europe

In the US, 28 biosimilars have been approved, with 10 in the last two years. The US is keeping pace with the EU who pioneered biosimilars approvals a decade earlier. Herein, current FDA regulations and hurdles encountered for US biosimilar approval and uptake are discussed.

Adalimumab Biosimilars in the Treatment of Rheumatoid Arthritis: A Systematic Review of the Evidence for Biosimilarity.

Although treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) has significantly improved clinical outcomes in patients with rheumatoid arthritis (RA), many patients do not have access to these treatments. As cost-effective alternatives to their reference products (RPs), biosimilars provide an opportunity to increase access to bDMARDs. The European Medicines Agency and the US Food and Drug Administration have detailed pathways for the approval of biosimilars based on establishing the similarity of the biosimilar to the RP in terms of structure and function, pharmacokinetics (PK), efficacy, safety, and immunogenicity. A number of biosimilars of adalimumab, infliximab, etanercept, and rituximab RPs have been approved in the United States and/or European Union. This article is focused on the seven adalimumab biosimilars. A review of the data for the biosimilars FKB327, ABP 501, BI 695501, GP2017, MSB11022, PF-06410293, and SB5 confirm that these products are highly similar to the adalimumab RP with regard to structure, physicochemical and biological properties, PK, safety, immunogenicity, and efficacy in the treatment of RA and other chronic immune-mediated, inflammatory conditions. Data from several switching studies showed no changes in efficacy, safety, trough serum drug concentration, or immunogenicity between the biosimilars and their RP.Trial registration: ClinicalTrials.gov identifiers: NCT02260791, NCT02405780, NCT01970475, NCT02137226, NCT02045979, NCT02744755, NCT02144714, NCT02167139, NCT03014947, NCT02114931, NCT02640612, NCT02167139, NCT03052322, NCT02480153. EudraCT numbers: 2012-005140-23, 2012-000785-37, 2013-003722-84, 2015-000579-28, 2014-002879-29, 2014-000662-21, 2013-004654-13, 2015-002634-41, 2014-005229-11, 2016-002852-26, 2014-000352-29

Improving oncology biosimilar launches in the EU, the USA, and Japan: an updated Policy Review from the Southern Network on Adverse Reactions

The EU, the USA, and Japan account for the majority of biological pharmacotherapy use worldwide. Biosimilar regulatory approval pathways were authorised in the EU (2006), in Japan (2009), and in the USA (2015), to facilitate approval of biological drugs that are highly similar to reference products and to encourage market competition. Between 2007 and 2020, 33 biosimilars for oncology were approved by the European Medicines Agency (EMA), 16 by the US Food and Drug Administration (FDA), and ten by the Japan Pharmaceuticals and Medical Devices Agency (PMDA). Some of these approved applications were initially rejected because of manufacturing concerns (four of 36 [11%] with the EMA, seven of 16 [44%] with the FDA, none of ten for the PMDA). Median times from initial regulatory submission before approval of oncology biosimilars were 1·5 years (EMA), 1·3 years (FDA), and 0·9 years (PMDA). Pharmacists can substitute biosimilars for reference biologics in some EU countries, but not in the USA or Japan. US regulation prohibits substitution, unless the biosimilar has been approved as interchangeable, a designation not yet achieved for any biosimilar in the USA. Japan does not permit biosimilar substitution, as prescribers must include the product name on each prescription and that specific product must be given to the patient. Policy Reviews published in 2014 and 2016 in The Lancet Oncology focused on premarket and postmarket policies for oncology biosimilars before most of these drugs received regulatory approval. In this Policy Review from the Southern Network on Adverse Reactions, we identify factors preventing the effective launch of oncology biosimilars. Introduction to the market has been more challenging with therapeutic than for supportive care oncology biosimilars. Addressing region-specific competition barriers and educational needs would improve the regulatory approval process and market launches for these biologics, therefore expanding patient access to these products in the EU, the USA, and Japan.

Biosimilars in Malaysia: Regulatory Framework, Approved Products, and Adverse Effects.

Biosimilars are a cost-effective alternative to original biologic medicines that allow patients access to biologic therapies for various chronic diseases. Our paper aims to provide an overview of biosimilars in Malaysia with emphasis on the comparison of Malaysian guidelines with guidelines from well-established regulatory agencies, a review of biosimilars' market approval and their reported adverse effects (AEs) as well as clinical trials conducted in Malaysia. We searched the official websites of the National Pharmaceutical Regulatory Agency (NPRA) Malaysia and three other well-established agencies, online databases of Medline® and EMBASE for guidelines on legislation and regulations of biosimilars. Meanwhile, we extracted the reports of AEs involving biosimilars in Malaysia from the NPRA database and for global AEs from the World Health Organisation VigyLize database. The ClinicalTrials.gov Website by the U.S. National Library of Medicines was the source for data on clinical trials. Malaysia followed the principles of the European Medicines Agency biosimilar regulations and issued their guideline in 2008. Since then, NPRA has approved 24 biosimilar products and recorded 499 AE reports, of which 43 (8.6%) were serious. NPRA has also approved ten Phase III clinical trials in Malaysia with four trials still ongoing. Malaysia follows a stringent regulatory pathway for the approval of biosimilars enacted by well-established regulatory agencies to maintain the quality, efficacy and safety of biosimilars. Introducing biosimilars to the Malaysian market would improve patients' accessibility to biologic therapies.

Regulatory challenges with biosimilars: an update from 20 countries.

The World Health Organization (WHO) issued guidelines for the regulatory evaluation of biosimilars in 2009 and has provided considerable effort toward helping member states implement the evaluation principles in the guidelines into their regulatory practices. Despite this effort, a recent WHO survey (conducted in 2019–2020) has revealed four main remaining challenges: unavailable/insufficient reference products in the country; lack of resources; problems with the quality of some biosimilars (and even more with noninnovator products); and difficulties with the practice of interchangeability and naming of biosimilars. The following have been identified as opportunities/solutions for regulatory authorities to deal with the existing challenges: (1) exchange of information on products with other regulatory authorities and accepting foreign licensed and sourced reference products, hence avoiding conducting unnecessary (duplicate) bridging studies; (2) use of a “reliance” concept and/or joint review for the assessment and approval of biosimilars; (3) review and reassessment of the products already approved before the establishment of a regulatory framework for biosimilar approval; and (4) setting appropriate regulatory oversight for good pharmacovigilance, which is essential for the identification of problems with products and establishing the safety and efficacy of interchangeability of biosimilars.