Biosimilar Drug Development Research Articles

Higher Order Structure Differences Among Insulin Crystalline Drugs Revealed by 2D heteronuclear NMR.

During therapeutic protein development, two-dimensional (2D) heteronuclear NMR spectra can be a powerful analytical method for measuring protein higher order structure (HOS) in solution since the spectra exhibit much higher resolution than homonuclear 1H spectra. However, 2D NMR capabilities for characterizing protein HOS in crystalline states remain to be assessed, given the low 13C natural abundance and intrinsically broader lines in solid-state NMR (SSNMR). Herein, high-resolution heteronuclear correlation (HETCOR) SSNMR was utilized to directly measure intact crystal drug products of insulin human, insulin analogs of insulin lispro and insulin aspart. The fingerprint regions in 2D 1H-13C HETCOR spectra were identified, which distinguished the insulin crystals in their primary structure, HOS heterogeneity and dynamics, as well as the manufacturing processes. The HOS heterogeneity in insulin analogs is consistent with their therapeutic effect of rapid action; while insulin human crystals showed more structural homogeneity, consistent with their slower pharmacokinetics (PK)peak time than insulin analogs. Therefore, heteronuclear NMR could be broadly applicable to study protein drug dosage forms from liquid to solid, yielding improved molecular level structure data for assessing drug HOS in biosimilar drug development.

Benefits of Biosimilars in the Management of Patients with Inflammatory Bowel Disease: An International Survey.

Background/Objectives: The development of biosimilar drugs has revolutionized the management of patients with inflammatory bowel diseases (IBD), significantly reducing healthcare costs. However, the impact of biosimilar availability on patient care is unknown. We conducted a survey to investigate the benefits of using biosimilars in patients with IBD. Methods: Physicians involved in the IBD care were invited to participate in an anonymous online survey. The questionnaire consisted of 42 questions addressing availability, cost, recommendations, and positioning regarding the use of biosimilars. Results: A total of 233 physicians (88.4% gastroenterologists) from 63 countries worldwide participated in the survey. Most respondents had >10 years of practice (202/233, 85.9%). Biosimilars were available in almost all cases (221, 94.8%), and over two-thirds of respondents had more than one biosimilar of adalimumab or infliximab on hospital formulary. In most cases, adalimumab and infliximab biosimilars had a reduced cost of at least 30% compared to the originators. The savings resulting from the use of biosimilars allowed physicians to improve patient care (3/233, 1.3%) or to improve research (2/233, 0.8%) in only a few cases. Interestingly, for about 50% of respondents, the cost of biologics was a limitation for patient access to therapy. For the majority of participants, the availability of biosimilars did not influence treatment decisions in Crohn's disease (70/165, 42.4%) and ulcerative colitis (83/165, 50.3%). Conclusions: The reduced cost of biosimilars compared to reference products is the main driver of choice in IBD. The impact of biosimilars of ustekinumab and vedolizumab in improving access to therapies and changing the treatment algorithm remains to be defined.

Biosimilar Drug Development and Safety: Issues with Autoimmune Rheumatic Diseases (ARDs)

Biosimilar Drug Development and Safety: Issues with Autoimmune Rheumatic Diseases (ARDs)

New science, drug regulation, and emergent public health issues: The work of FDA's division of applied regulatory science.

The U.S. Food and Drug Administration (FDA) Division of Applied Regulatory Science (DARS) moves new science into the drug review process and addresses emergent regulatory and public health questions for the Agency. By forming interdisciplinary teams, DARS conducts mission-critical research to provide answers to scientific questions and solutions to regulatory challenges. Staffed by experts across the translational research spectrum, DARS forms synergies by pulling together scientists and experts from diverse backgrounds to collaborate in tackling some of the most complex challenges facing FDA. This includes (but is not limited to) assessing the systemic absorption of sunscreens, evaluating whether certain drugs can convert to carcinogens in people, studying drug interactions with opioids, optimizing opioid antagonist dosing in community settings, removing barriers to biosimilar and generic drug development, and advancing therapeutic development for rare diseases. FDA tasks DARS with wide ranging issues that encompass regulatory science; DARS, in turn, helps the Agency solve these challenges. The impact of DARS research is felt by patients, the pharmaceutical industry, and fellow regulators. This article reviews applied research projects and initiatives led by DARS and conducts a deeper dive into select examples illustrating the impactful work of the Division.

Global Biosimilar Drug Development: Any Chance for Consolidation after 15 Years of Positive Regulatory Experience?

Global Biosimilar Drug Development: Any Chance for Consolidation after 15 Years of Positive Regulatory Experience?

Clinical applications of bevacizumab in the treatment of colorectal and ovarian cancer.

The development of biological drugs, which began in the 1980s, has revolutionized the treatment of numerous oncological diseases and severely disabling autoimmune diseases, with widely demonstrated evidence of benefit. Today, biological drugs represent an important and continuously developing category and are used both as a support therapy in onco-hematology and as molecules with their own therapeutic activity, such as monoclonal antibodies. Among these, bevacizumab represents a drug of relevant clinical value, used as antiangiogenic therapy in numerous cancers, in particular colorectal and ovarian cancers. The expiry of the patent period of monoclonal antibodies, including bevacizumab, has opened up to the development of biosimilar drugs, represented by structurally similar molecules with pharmacokinetic, pharmacodynamic and clinical characteristics equivalent to a biological drug already present in clinical use (originator biologic). The development process of these drugs is contained in the guidelines of the major regulatory bodies (FDA/EMA) and is faster than that provided for the originator biologic. Since biosimilars have a lower cost than reference drugs, their use represents a possibility of containing health care costs and of satifying the growing demand in terms of efficacy and personalization of pharmacological therapies. Considering the particular severity of the diseases treated, including colorectal and ovarian cancers, biosimilar drugs must be used with full awareness, in terms of efficacy and safety, since their approval is based on a rigorous analytical process, as well as preclinical and clinical evaluation.

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.

Development Predicament and Countermeasures of Anti-tumor Bio-similar Industry in China

&lt;p&gt;&lt;span lang="EN-US"&gt;Biosimilar has the advantages of precise efficacy, high safety and stable quality, and occupy an important position in the field of anti-tumor therapy. In order to reduce the expenditure of drugs, the research and development of biosimilar drugs has attracted much attention. Compared with European and American countries in the development of the anti-tumor biosimilar industry, there are still some shortcomings and parts that need improvement in China. According to the current development status of China, analyzed the reasons for the development dilemma of my country’s anti-tumor biosimilar industry, and put forward suggestions for the development of this industry.&lt;/span&gt;&lt;/p&gt;

Type I Error Inflation of Blinded Sample Size Re-Estimation in Equivalence Testing

Biosimilar products are a relative newcomer in the pharmaceutical industry. It was only in 2006 that the first biosimilar product, Omnitrope[textregistered] (somatropin), a human growth hormone produced by Sandoz was approved by the European Medicine Agency, followed later the same year by the US Food & Drug Administration, and in 2009 by Pharmaceuticals and Medical Devices Agency in Japan. The clinical component of a biosimilar development borrows extensively from traditional drug development. However, when it comes to clinical study designs, this may not always be applicable. This article investigates Type I error violations that occur when blinded sample size reviews are applied in equivalence testing as used in biosimilar drug development. We give a derivation which explains why such violations are more pronounced in equivalence testing than in the case of superiority testing. In addition, the amount of Type I error inflation is quantified by simulation as well as by some theoretical considerations. Nonnegligible Type I error violations arise when blinded interim reassessments of sample sizes are performed particularly if sample sizes are small, but within the range of what is practically relevant.

Role of Patents in Biosimilar Drug Development and Public Interest

Role of Patents in Biosimilar Drug Development and Public Interest

Barriers to accessibility of targeted therapy for breast cancer: A qualitative study in Yerevan, Armenia.

e13013 Background: The treatment prospects for Human Epidermal Growth Factor Receptor 2 positive (HER2p) breast cancer (BC) patients are continuously evolving, however, BC remains a major public health problem. Multiple therapeutic and biological strategies are already in function, and specifically the anti-HER2 therapy (trastuzumab, pertuzumab, lapatinib, and ado-trastuzumab emtansine) remains a mainstream clinically approved treatment method. Implementation of the anti-HER2 therapy has substantially strengthened the prognosis for HER2p patients. This has remarkably improved the 5-year survival rates upto 80% in high-income countries, 60% in middle-income countries and 40% in low-income countries by establishing anti-HER2 therapy. Barriers to anti-HER2p therapies in low- and middle-income countries (LMICs) can be minimized by further instigation and licensing of the bio-similar drugs as a low-cost alternative treatment. Bio-similar drugs will also potentially result in a considerable savings for patients and eventually lessen the burden on the health care systems of LMICs as the usual cancer treatment regimen includes multiple systemic therapies for an extended time period, which are highly expensive. The aim of the study is to identify the barriers to accessibility of targeted therapy for BC, among patients seeking BC treatment in Yerevan, Armenia. Methods: The qualitative study assessed the out-of-pocket (OOP) payment burden among patients and their opinions about the quality of treatment using an interview guide with probe questions, adapted to the Armenian context. The study participants were patients seeking BC treatment at Hematology Center and Mikhaelyan Medical Center. Results: All the study participants were satisfied with the quality of health care and health care providers, however, majority of the study participants paid OOP for the examination, analysis and therapeutic drugs. Most participants were sponsored by family members and stated being financially vulnerable. Conclusions: The study provides evidence for the development and implementation of biosimilar drugs, implementation of mandatory health insurance to increase the access to targeted therapy, enhance collaboration with international funding agencies and strengthen diaspora support.

Testing Procedures for Claiming Success on at Least k Out of m Hypotheses with an Application to Biosimilar Development

Multiplicity is a common issue in clinical drug development and there exists many proposals for the handling of multiple testing in clinical trials. However, the literature on testing procedures for claiming success on at least k out of m tests and the operating characteristics of these procedures is still sparse. Such testing is very relevant in biosimilar drug development, for example, where products have gained regulatory approval in the past, even though not all hypotheses could be rejected. Obviously, simple adjustments for multiplicity like the Bonferroni-adjustment or the Holm-procedure are valid as well for this testing problem, but can be conservative. In this article, we propose simple testing procedures for claiming success on at least k out of m tests which are more powerful than standard procedures while still providing strong control of the family-wise error rate. We illustrate their applicability in practice using an example from biosimilar drug development. In the supplementary materials, we provide proofs of the properties of our testing procedures and demonstrate the superiority of the proposed methodologies using simulations.

Recommendations for the Development and Validation of Immunogenicity Assays in Support of Biosimilar Programs.

For biosimilar drug development programs, it is essential to demonstrate that there are no clinically significant differences between the proposed biosimilar therapeutic (biosimilar) and its reference product (originator). Based on a stepwise comprehensive comparability exercise, the biosimilar must demonstrate similarity to the originator in physicochemical characteristics, biological activity, pharmacokinetics, efficacy, and safety, including immunogenicity. The goal of the immunogenicity assessment is to evaluate potential differences between the proposed biosimilar product and the originator product in the incidence and severity of human immune responses. Establishing that there are no clinically meaningful differences in the immune response between the products is a key element in the demonstration of biosimilarity. An issue of practical, regulatory, and financial importance is to establish whether a two-assay (based on the biosimilar and originator respectively) or a one-assay approach (based on the biosimilar) is optimal for the comparative immunogenicity assessment. This paper recommends the use of a single, biosimilar-based assay for assessing immunogenic similarity in support of biosimilar drug development. The development and validation of an ADA assay used for a biosimilar program should include all the assessments recommended for an innovator program (10-16, 29). In addition, specific parameters also need to be evaluated, to gain confidence that the assay can detect antibodies against both the biosimilar and the originator. Specifically, the biosimilar and the originator should be compared in antigenic equivalence, to assess the ability of the biosimilar and the originator to bind in a similar manner to the positive control(s), as well as in the confirmatory assay and drug tolerance experiments. Practical guidance for the development and validation of anti-drug antibody (ADA) assays to assess immunogenicity of a biosimilar in comparison to the originator, using the one-assay approach, are described herein.

PB2281 BIOSIMILAR TRIALS IN DEVELOPING COUNTRIES: FINAL RESULTS OF AN ACTION PLAN TO DETECT AND ERADICATE BARRIERS TO PATIENT RECRUITMENT

Background:The development of biosimilar drugs requires a strong comparability exercise and also a phase 3 head‐to‐head trial to show no differences between reference and biosimilar drugs. Discussion about study design issues and biosimilarity evaluation has been done, but little has been discussed about its impact on clinical trial conduction, in special related to recruitment issues.Aims:To identify barriers in an international biosimilar trial with rituximab in patients with diffuse large B cell lymphoma, propose actions to overcome those issues and analyze the results.Methods:In order to understand the barriers in a biosimilar trial, Libbs Farmacêutica organized a meeting with investigators and clinical research coordinators involved in a biosimilar trial where the recruitment was a gap and proposed an action plan to solve the identified issues.Results:The main barriers to recruitment related to the biosimilar drug were the negative attitude towards biosimilar drugs caused due to misconception or lack of knowledge related to biosimilar drug or its development process among patients and physicians. Some issues not related to the biosimilar were lack of clinical research network, lack of knowledge from patients related to clinical trials, complexity of onco‐hematologic diseases, study complexity and eligibility criteria and low motivation among investigators due to lack of knowledge about biosimilar. The action plan included to reinforce and spread the concept of biosimilar and clinical research included a Brazilian site on biosimilars (www.biossimilaresbrasil.com.br); scientific publications in medical and patient congresses; advertisements in medical and patient journals; visits to the research centers in 15 Brazilian states to report on the study and on biosimilars, as well as visits to pathologists and treatment centers in these states that did not participate in the study to refer patients to the research centers; video to explain clinical research for patients; involvement of the local state health secretary; strategies for early diagnosis of cancer to allow the patient to enter the clinical study; pay PET‐CT that is not available in the public health system in Brazil. Considering one year prior to this action plan, 11 patients were recruited and 4 randomized; after one year (end of the inclusion period) 51 patients were recruited (an increase of 3.6 in the number of patients) and 28 randomized (an increase of 7), allowing Brazil to reach its goal in relation to the patients’ inclusion (Figure).Summary/Conclusion:Modification of physician and patient's attitude toward participation in clinical trials with biosimiliar is the main challenge and can be overcome through continuing education. The development of a national network reference to investigational sites among physicians can act as facilitators through promotion of communication and enhancing integration. The diminished resources in the public health care system has impact on accrual to cancer clinical trials. Multidimensional approaches such as publication plan, screening and enrollment strategies, and awareness activities are the best strategy to raise recruitment in multicenter trials. The development of biosimilar trials is needed in order to the delivery of high quality biosimilar products and to increase drug access.image

Abstract 831: Reproducible, mechanism of action-reflecting reporter based bioassays to enable drug development of biosimilars and biobetters

Abstract The demand for biosimilars and bioassays for biosimilars are increasing as the patent cliff approaches for many blockbuster biologics. Recently, the expanded approval of Actemra (Tocilizumab) to treat CAR T-cell-induced cytokine release syndrome (CRS) demonstrated the role of anti-IL-6 blocking drugs as critical for the treatment of serious diseases such as cancer and autoimmune diseases. Here we describe a portfolio of luciferase reporter-based bioassays to support the development and potency determination of biosimilar drugs targeting cytokines such as IL-2, IL-6, IL-12, IL-15, IL-12/23, IL-17, VEGF, RANK, Epo, IFNs, etc. The availability of quantitative, functional bioassays in Thaw-and-Use format provides the benefit of convenience, reproducibility, and transferability. We demonstrate these assays are able to measure relative potency for antibody biologics and detect potency changes for stressed antibody samples. In summary, the reporter-based bioassay portfolio for biosimilars provides a valuable tool for the development, stability testing, and potency determination in manufacture of biosimilars and biobetters. Citation Format: Richard L. Somberg, Rich Moravec, Dun Li, Aileen Paguio, Mei Cong. Reproducible, mechanism of action-reflecting reporter based bioassays to enable drug development of biosimilars and biobetters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 831.

BIOSIMILARS, PRODUCED USING THE RECOMBINANT DNA TECHNOLOGY

The review presents materials on the scientific principles underlying the development, preclinical and clinical research, registration and control of the safety of biosimilar medicines produced using genetic engineering techniques. The number of biosimilars used in the clinic, defined as «biosimilars», is steadily increasing. The features of biotechnological preparations are presented, that requires a special approach to assessing the newly developed preparation evidence of similarity with the original (reference) preparation. To ensure the effectiveness and safety of their use, the procedure for registration of such medicines is determined by the regulatory framework governing the requirements for proof of similarity with previously approved biological medicinal products. The data concerning the differences in the nature and scope of studies at the stages of quality assessment, preclinical and clinical development of biosimilar and original drugs are performed. The issues related to extrapolation of clinical trial results and the issues of medicines interchangeability are reported. The modern information on international experience of biosimilar medicines registration, scientific achievements and regulatory requirements concerning evidence of similarity in assessing the quality, effectiveness and safety of biosimilar biotechnological medicines («biosimilars») has been reported.

Recommendations for the Development and Validation of Neutralizing Antibody Assays in Support of Biosimilar Assessment

The American Association of Pharmaceutical Scientists (AAPS) biosimilar focus group on nonclinical and clinical assays has developed this manuscript to guide the industry on best practices and testing strategies when developing neutralizing antibody (NAb) assays for biosimilar programs. The immunogenicity assessment to biosimilar and originator drug products is one of the key aspects of clinical programs for biosimilars to demonstrate biosimilarity. Establishing that there are no clinically meaningful differences in immune response between a proposed product and the originator product is a key element in the demonstration of biosimilarity. It is critical to collect, evaluate, and compare the safety and immunogenicity data from the clinical pharmacology, safety, and/or efficacy studies especially when the originator drug product is known to have potential for immune-mediated toxicity. This manuscript aims to provide a comprehensive review and recommendations on assay formats, critical reagents, approaches to method development, and validation of the neutralizing antibody assays in extrapolation within the scope of biosimilar drug development programs. Even if there are multiple options on the development and validation of NAb assays for biosimilar programs, the type of drug and its MoA will help determine the assay format and technical platform for NAb assessment (e.g., cell-based or non-cell-based assay). We recommend to always perform a one-assay approach as it is better to confirm the biosimilarity using one-assay for NAb. If a one-assay approach is not feasible, then a two-assay format may be used. This manuscript will provide all the details necessary to develop NAb assays for biosimilars.

Demonstrating biosimilar and originator antidrug antibody binding comparability in antidrug antibody assays: a practical approach.

Biosimilar drug development has brought new challenges to bioanalytical ligand-binding assays used to determine drug concentration, antidrug antibodies and neutralizing antibodies. One particular challenge is how to demonstrate that the antidrug antibody assay can adequately detect antibodies against both biosimilar and originator. In this paper, we review the current guidelines and literature for practical recommendations and present a gap analysis. Case examples of antibody binding comparability testing are presented, and the challenges and implications are discussed. Based on the lessons learned from our biosimilar assay applications, we recommend a bioanalytical comparability testing approach that is outlined and discussed.

Multiplexing N-glycan analysis by DNA analyzer.

Analysis of N-glycan structures has been gaining attentions over the years due to their critical importance to biopharma-based applications and growing roles in biological research. Glycan profiling is also critical to the development of biosimilar drugs. The detailed characterization of N-glycosylation is mandatory because it is a nontemplate driven process and that significantly influences critical properties such as bio-safety and bio-activity. The ability to comprehensively characterize highly complex mixtures of N-glycans has been analytically challenging and stimulating because of the difficulties in both the structure complexity and time-consuming sample pretreatment procedures. CE-LIF is one of the typical techniques for N-glycan analysis due to its high separation efficiency. In this paper, a 16-capillary DNA analyzer was coupled with a magnetic bead glycan purification method to accelerate the sample preparation procedure and therefore increase N-glycan assay throughput. Routinely, the labeling dye used for CE-LIF is 8-aminopyrene-1,3,6-trisulfonic acid, while the typical identification method involves matching migration times with database entries. Two new fluorescent dyes were used to either cross-validate and increase the glycan identification precision or simplify sample preparation steps. Exoglycosidase studies were carried out using neuramididase, galactosidase, and fucosidase to confirm the results of three dye cross-validation. The optimized method combines the parallel separation capacity of multiple-capillary separation with three labeling dyes, magnetic bead assisted preparation, and exoglycosidase treatment to allow rapid and accurate analysis of N-glycans. These new methods provided enough useful structural information to permit N-glycan structure elucidation with only one sample injection.

CMC considerations for biosimilar drug development

CMC considerations for biosimilar drug development