Approval Of Biosimilars Research Articles

Biosimilar Biologic Drugs: A Systematic Approach to Development, Manufacturing and Clinical Applications

This publication addresses biosimilar biologic drugs development and future innovations. Emphasis is placed on quality system approaches to the development and availability of new biosimilar drug products presented in premarket applications. For approvals of new biosimilars, the sponsors of premarket applications must present analytical and biological characterization to demonstrate that a proposed biosimilar drug is highly similar to the licensed reference product. The premarket application protocol requires a sponsor to describe the biosimilar product’s PK/PD clinical data comparing its safety, efficacy, and immunogenicity to that of the licensed reference product. Emphasis is placed on Quality by Design (QbD), Validation, Verification, and c-GMP risk-based monitoring criteria. A brief discussion is presented on risk-benefit assessment that guides the clinical use of the new biosimilar drug product by providing patients organized data and appropriate labeling information in conformance with the new biosimilar drug’s intended clinical use.
 Keywords: biosimilar biologic drugs, safety, efficacy and immunogenicity, Quality by Design (QbD)

Totality of Scientific Evidence in the Development of ABP 798, a Biosimilar to Rituximab

Background: ABP 798 is a proposed biosimilar to rituximab reference product (RP). Regulatory approval of biosimilars is based on a totality of evidence (TOE) approach which includes similarity in analytical characteristics (structural and functional), in mechanism of action (MoA) -clinical pharmacology, pharmacokinetics (PK), pharmacodynamics (PD), and in comparative clinical studies. Evidence from analytical, functional, clinical PK/PD, and efficacy and safety evaluations indicate that ABP 798 is similar to rituximab RP. Similarity of efficacy and safety in patients with non-Hodgkin lymphoma (NHL) was demonstrated in a randomized, double-blind, comparative clinical study in which the primary analysis was based on data from central, independent, and blinded assessments of disease and the sensitivity analysis was based on data using investigator assessments of disease. Here we present in vitro chemo synergy, preclinical in-vivo tumor efficacy data and show how the results of the sensitivity analysis using investigator assessments of the response rate from the NHL clinical study further add to the TOE supporting similarity of ABP 798 with the RP. Methods: In vitro synergy with chemotherapeutic agents was investigated by assessing the effect of docetaxel, gemcitabine, or doxorubicin with ABP 798 and rituximab RP in SU-DHL-6 cell lines and measured using the ATP-based cell viability endpoint (ATPLite). In vivo efficacy was assessed by evaluating the anti-tumor activity of ABP 798 and rituximab RP in NHL xenograft models in NOD/SCID mice using CD20-expressing RL and Raji cell lines. A sensitivity analysis was conducted to assess the robustness of the results of the primary efficacy endpoint of the proportion of patients with the best overall response of complete response, partial response, or unconfirmed complete response (ORR) in the NHL comparative clinical study using the investigator's assessment of disease on the full analysis set. Waterfall plots of the maximum percent reduction in the sum of the products of the greatest diameters (SPD) for index nodal lesions based on both the central, independent, blinded assessment of disease and the investigator's assessment of disease were used. Results: In vitro study results demonstrated synergistic activity of the combination of docetaxel and ABP 798 or the RP (synergy score = 6.35±0.69 [with ABP 798]; 6.79±0.12 [with RP]). In contrast, combinations with gemcitabine (synergy score = 2.68±0.20 [with ABP 798] and 2.54±0.29 [with RP]) or doxorubicin (synergy score = 1.95±0.56 [with ABP 79]) and 3.23±0.53 [with RP]) were additive. In RL cell lines, ABP 798 inhibited tumor growth similarly to rituximab RP, with no statistical difference between dose groups at 3 and 30 mg/kg (p = 0.951 and p = 0.996, respectively). In Raji cells, ABP 798 and rituximab RP significantly and similarly inhibited tumor growth when compared to an IgG1 isotype control (p < 0.001 for 3 and 30 µg/kg doses). ABP 798, at both dose levels, inhibited tumor growth similarly to rituximab RP by 27-41%, with no statistical difference. In the NHL comparative clinical study, risk difference (RD) of ORR with 1-sided 95% lower and upper confidence limits from the adjusted linear model was 7.7% (-3.2%, 18.6%) using central, blinded, independent assessments of the modified full analysis set based on randomized treatment assignment. The sensitivity analysis using investigator assessments of disease of the full analysis set of all randomized subjects based on the randomized treatment assignment received was RD = 0.5% (-7.8%, 8.8%). Waterfall plots of the maximum percent reduction in the SPD for index nodal lesions further demonstrate similarity of efficacy with central or local assessments of disease. Conclusions: In vitro and in vivo preclinical studies demonstrated chemo synergy and in vivo tumor efficacy. The sensitivity analysis of ORR using local assessments in the NHL comparative clinical study was consistent with results from the primary efficacy analysis; the maximum percent reduction in index nodal lesions was similar for central and local assessments of disease. These results further support that ABP 798 is similar to the RP across a range of efficacy evaluations as well as primary and secondary mechanisms of action and add additional supporting data to the TOE. Disclosures Niederwieser: Novartis: Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees; Daiichi: Research Funding; Amgen: Speakers Bureau. Hamm:Amgen: Consultancy. Cobb:Amgen: Consultancy. Thway:Amgen: Current Employment, Current equity holder in publicly-traded company. Forsyth:Amgen: Consultancy; Janssen Pharmaceuticals Australia: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tucci:Amgen: Consultancy. Delwail:Amgen: Consultancy. Hajek:Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; Oncopeptides: Consultancy. Hanes:Amgen: Current Employment, Current equity holder in publicly-traded company.

Barriers to biosimilar utilization in the United States.

Biologic agents are large-molecule drugs developed from living sources. Biologic agents include vaccines, monoclonal antibodies, blood components and a variety of other therapies. Widely used for a variety of disease states, biologic agents are generally more expensive than small-molecule drugs, accounting for 69% of Medicare Part B drug expenditures in 2014.1 Spending on biologic agents in the United States rose at least 10% per year from 2011 to 2016. In 2016, 5 of the top 10 drugs in terms of US market spend were biologic agents.2 The Biologic Price Competition and Innovation Act (BPCIA) defined biosimilars as drugs that are highly similar to an existing biologic agent (often call the reference biologic) and have no clinically meaningful differences in efficacy or safety.3 In 2010, the BPCIA created an expedited pathway for approval of biosimilars. Several of the requirements for biosimilar approval established in the BPCIA are similar to those established for the approval of generic small-molecule drugs under the Hatch-Waxman Act. However, there are substantial differences that have resulted in decreased market permeation of biosimilars relative to small-molecule generic drugs.3 The biosimilar market environment that resulted has changed the impact on health-system pharmacy from that initially predicted.4,5

Biosimilar usage in practices within the ASCO PracticeNET learning network.

77 Background: In recent years, several antineoplastic biosimilar products have been approved and marketed for use. We analyzed data from the ASCO PracticeNET learning network to gain insights on the adoption of biosimilar products for bevacizumab, rituximab, and trastuzumab. Methods: Our analysis included the following products: bevacizumab, bevacizumab-awwb, bevacizumab-bvzr, rituximab (excluding rituximab and hyaluronidase), rituximab-abbs, trastuzumab, trastuzumab-anns, and trastuzumab-dkst, administered from July 2019 to March 2020. 19 practices submitted their billing data; practices ranged in size from 2 to 29 hematologists/oncologists. Products were identified through use of healthcare common procedure coding system codes. The proportion of biosimilar product doses administered, as a percent of total doses for all related products, was calculated per participating practice. Results: Use of biosimilar products for bevacizumab (first biosimilar approval in September 2017) was first detected in August 2019, averaging 1.4% of administered doses (confidence intervals included in Table) with a range from 0% to 27% among participating practices; by March 2020, average use increased to 31% with a range from 0% to 100%. Use of biosimilar products for rituximab (first biosimilar approval in November 2018), was first detected in January 2020, averaging 2.6% of administered doses, with range of 0% to 30%; by March 2020, average use increased to 18%, with a range of 0% to 61%. Use of biosimilar products for trastuzumab (first biosimilar approval in December 2017) was first detected in September 2019, averaging 0.9% of administered doses with a range of 0% to 17%; by March 2020, average use increased to 35%, with a range of 0% to 98%. Conclusions: The release of biosimilar products has been identified as a potential opportunity to lower the cost of drug therapy for cancer patients. Our analysis identified an approximate 2-year lag from product approval to initial utilization followed by a steady increase in the use of biosimilar products, along with a wide range of use among practices. [Table: see text]

Assessment of Availability, Clinical Testing, and US Food and Drug Administration Review of Biosimilar Biologic Products

Biosimilar biologic products were authorized in 2010, after the US Congress established an expedited pathway for approval of clinically similar versions of approved biologic products. Unlike for most small-molecule generic drugs, approval requirements for a biosimilar included animal studies and a comparative efficacy clinical trial. To analyze the evidence required to support a biosimilarity license application, examine the US Food and Drug Administration (FDA) evaluation process, and estimate the costs of the key clinical trial evidence. This study evaluated all biosimilar biologic products approved from January 2010 through October 2019, using the publicly available FDA review documents, disclosures from ClinicalTrials.gov, and the published peer-reviewed literature. The costs of efficacy clinical trials were estimated using licensed proprietary software. The following elements of each approved biosimilar were evaluated: the extent of human clinical testing to establish that the biosimilar had no clinically meaningful differences with the reference product, results of comparative animal studies, and FDA-cited application deficiencies. The cited deficiencies included the following categories: (1) facility inspection, (2) manufacturing or product quality, (3) animal studies, (4) laboratory analytical studies, (5) phase 1 and/or immunogenicity studies, and (6) phase 3 comparative efficacy trials. As of October 2019, the FDA had approved 23 biosimilar biologics for 9 reference products. The 29 clinical trials that established that the efficacy of the biosimilar products was comparable to that of the reference products enrolled a median (interquartile range [IQR]) of 504 (258-612) patients, had a median (IQR) estimated cost of $20.8 ($13.8-$35.3) million, and had a median (IQR) treatment duration of 52 (28-68) weeks. Substantial deficiencies temporarily halted the review of 9 applications, and the most frequent deficits were failed facilities inspections (n = 5) and manufacturing process quality problems (n = 6). The approved biosimilar submissions included 51 animal studies on species that included mice, rats, rabbits, dogs, and cynomolgus monkeys. Negative outcomes in 2 animal studies were attributed to differences between human and test species. The FDA generally met the standard 12-month review deadlines or stopped the review clock when serious deficiencies were identified. This study found that most comparative efficacy trials supporting the FDA approval of biosimilars appeared to be as rigorous as and often larger, longer, and more costly than pivotal trials for new molecular entities. Further research is needed into whether less costly comparative efficacy trials could provide adequate evidence of biosimilarity and whether animal studies contribute useful scientific evidence.

Streamlined approval of biosimilars: moving on from the confirmatory efficacy trial

Licensing of biosimilars is essential to promote patient access to 21st-century biological medicines. Regulatory approval of biosimilars is based on the totality of evidence from a head-to-head comparison with reference products (RPs). A clinical efficacy trial is usually required, but this is increasingly questioned. Based on a thorough review of biosimilar applications in the European Union (EU), we conclude that in-depth knowledge of the reference product, allied with high-performing analytical tools, largely predicts clinical comparability, subject to confirmation by a comparative pharmacokinetic (PK) trial. We provide a blueprint for a biosimilar pathway that reduces the need for clinical efficacy trials in exceptional cases, together with qualifying criteria and requirements for streamlined assessment to expedite wider access to affordable biological medicines.

Commentary - A comprehensive safety understanding of granulocyte-colony stimulating factor biosimilars and Intended Copy Biologics in treating chemotherapy associated febrile neutropenia

Filgrastim, human white cell growth factor, Granulocyte colony-stimulating factor (G-CSF), is a core medicine in the WHO list of Essential Medicines. For this reason, recent reporting of statistically significant safety and efficacy differences between reference and Biosimilar brands of filgrastim by Rastogi and the Indian Pharmacopoeia Commission in Toxicology and Applied Pharmacology in 2020 is of great concern [Shruti Rastogi et al. Towards a comprehensive safety understanding of granulocyte-colony stimulating factor biosimilars in treating chemotherapy associated febrile neutropenia: Trends from decades of data. Toxicology and Applied Pharmacology Volume 395, 15 May 2020, 114,976. https://doi.org/10.1016/j.taap.2020.114976]. This commentary shows that the alarming report is a result of incorrect statistical tests misapplied to inappropriate data sets compounded by a further problem relating to the strict regulatory definition of a Biosimilar Medicine as opposed that of an Intended Copy Biologic. In contrast, the body of evidence from more than seven and a half thousand participants in Confirmatory Clinical Studies and Post Approval Clinical Studies as well as the Periodic Safety Update Reports confirms that European approved filgrastim Biosimilars show no meaningful difference in quality, safety or efficacy compared to the reference brand.

A Clinical Review of Biosimilars Approved in Oncology.

To summarize and review the clinical data of Food and Drug Administration (FDA)-approved biosimilars for use in treatment of cancer and the current challenges health care institutions face when implementing a newly approved biosimilar. A literature search of the following databases was performed between January 1, 2012, and December 31, 2019: PubMed, Google, and ClinicalTrials.gov. Search terms included the words biosimilar, bevacizumab, rituximab, and/or trastuzumab. Only primary literature on biosimilars with an ongoing or completed phase 3 trial and/or FDA approval were included in the final analysis. Primary literature consisted of peer-reviewed publications, published abstracts, and any results posted on the ClinicalTrials.gov database. Clinical trials of FDA-approved biosimilars for bevacizumab, rituximab, and trastuzumab showed no significant differences with respect to efficacy, safety, and pharmacokinetics when compared with their reference products. The anticipated growth of biologics in oncology and the recent introduction of biosimilars over the past few years have placed a lot of emphasis on biosimilars as a significant source of cost savings for the health care system. Our article compiles and analyzes existing data on biosimilar efficacy, safety, and financial impact. The major concerns of biosimilars revolve around their long-term efficacy and safety. Even with many questions to be answered, biosimilars have the potential for significant cost savings in the US health care system.

Current Status of Biosimilar Regulations in the MENA Region

This review article explores the regulatory situation of biosimilar registration pathways in the Middle East and North Africa (MENA). With most countries in the world have either adopted official regulatory guidelines for biosimilar approval or are in the process of developing such guidelines, countries in the MENA region are advised to accelerate the process of adopting pathways for biosimilar approval primarily for preventing the entry of intended copies into such markets and risking patients’ safety in addition to jeopardizing clinical outcomes of the different disease modalities that are treated by biologics. Additionally, biosimilars are playing a significant role in reducing the significant public expenditure on biological therapy and thus increasing the accessibility of these medications to a larger population of patients. The article details the countries in the MENA region that have adopted official and scientific guidelines for biosimilar approval pathways. The article also draws a comparison between different countries on issues such as comparability studies, extrapolation of indications, interchangeability and non-clinical quality requirements. In conclusion, only four countries out of the 15 countries they comprise the MENA region have adopted clear regulatory pathways for biosimilar registration and approval. This situation should be of urgent importance to policymakers responsible for public health bodies in countries that lack such guidelines due to the negative consequences that could result due to the absence of clear biosimilar regulations.

Biosimilars markets: US and EU compared

Differences between the US and European regulatory processes can lead to differences in the time taken for biosimilar approval. The European Medicines Agency is in some cases quicker to approve biosimilar drugs and Europe has overall more approved biosimilars, whilst the US approved the first biosimilar in 2015. Whatever the market, there are a number of strategies that can be employed to help address patient and healthcare provider concerns, such as educational programmes. This paper provides some insights on these aspects.

Extrapolation of indications and drug interchangeability as barriers to use trastuzumab-dkst biosimilar in Brazil.

e13010 Background: Brazil has a complex health-care system which comprises 76% of population in the public unified health system (SUS) and only 24% in private system. Even with most of the population in the public system low resources has been allocated SUS by the government compared with that in private system. Breast cancer (BC) is the more frequent malignant neoplasm in Brazilian women, including HER2 overexpression, and the most are treated in SUS. Although, the HER2 blockage benefits in overall survival have been demonstrated since 2005, the adjuvant and neoadjuvant HER2 blockage was included in SUS protocols only 2013 while the metastatic only 2018. Brazil and development countries have limited accesses to biological drugs and target therapies due to the high cost. The biosimilar technology would improve the patient access to these drugs, health-care savings with efficacy and safety. In 2017, Brazil has approved the first biosimilar in oncology, the anti-HER2 monoclonal antibody trastuzumab-dkst. Our aim is understanding the reasons that hampered the Brazilian oncologists changing practice about biosimilars. Methods: We submitted an on-line survey with 12 questions to 144 Brazilian oncologists which are registered in Brazilian Clinical Oncology Society from North, Northeast, Center east, Center west and Southeast regions in Brazil. The questions were about the anti-HER2 biosimilars knowledge, the manufacturing process, the costs, the biosimilars-based clinical trial, the drug efficacy and safety. Results: We observed that all responders have 9 years experienced oncologist with mean of care 15 patient with HER2 BC per month. In total, 95% of oncologist knows biosimilar definition and 96% assume prescribe biosimilars without doubts. However, 81% oncologists would prescribe biosimilars to all patients, 82% would interchanges and 63% would extrapolate the indication. Conclusions: This survey was conducted to understand the Brazilian oncologist knowledge about biosimilar. We demonstrated a high knowledge of biosimilar definition, however with high percentage indicated adherence barriers. The pharmacovigilance, clinical trials that support biosimilar approval and extrapolation concepts are the main aspects to be addressed. The opportunity of patient access with biosimilars is real and it is the oncologist’s duty to engage in medical education programs. This study could highlight a crucial need for greater strategies to educate physicians, to disseminate biosimilars and provide more informed decision making.

The Path Towards a Tailored Clinical Biosimilar Development.

Since the first approval of a biosimilar medicinal product in 2006, scientific understanding of the features and development of biosimilar medicines has accumulated. This review scrutinizes public information on development programs and the contribution of the clinical studies for biosimilar approval in the European Union (EU) and/or the United States (US) until November 2019. The retrospective evaluation of the programs that eventually obtained marketing authorization and/or licensure revealed that in 95% (36 out of 38) of all programs, the comparative clinical efficacy studies confirmed similarity. In the remaining 5% (2 out of 38), despite meeting efficacy outcomes, the biosimilar candidates exhibited clinical differences in immunogenicity that required changes to the manufacturing process and additional clinical studies to enable biosimilar approval. Both instances of clinical differences in immunogenicity occurred prior to 2010, and the recurrence of these cases is unlikely today due to state-of-the-art assays and improved control of process-related impurities. Biosimilar candidates that were neither approved in the EU nor in the US were not approved due to reasons other than clinical confirmation of efficacy. This review of the development history of biosimilars allows the proposal of a more efficient and expedited biosimilar development without the routine need for comparative clinical efficacy and/or pharmacodynamic studies and without any compromise in quality, safety, or efficacy. This proposal is scientifically valid, consistent with regulation of all biologics, and maintains robust regulatory standards in the assessment of biosimilar candidates. Note: The findings and conclusion of this paper are limited to biosimilar products developed against the regulatory standards in the EU and the US.Electronic supplementary materialThe online version of this article (10.1007/s40259-020-00422-1) contains supplementary material, which is available to authorized users.

Biosimilars.

Biological therapies have widened the therapeutic armamentarium for immune-mediated inflammatory diseases, providing in many cases a broad range of treatment options with different mechanisms of action. The widespread use of biological agents in systemic lupus erythematosus is currently limited to belimumab and rituximab, although results of promising larger Phase III clinical trials are awaited or have been recently circulated, especially for anti-cytokine therapies. The loss of exclusivity over the last years for several originator biologics has started the successful introduction of biosimilar products into clinical practice. There is an abbreviated pathway to biosimilar approval, but this is underpinned by the same standards of pharmaceutical quality, safety and efficacy that apply to all biological medicines. Nevertheless, there are unique reasons why development of biosimilars may be particularly challenging in lupus.

Biosimilars Regulation in the United States and FDA Approved Biosimilars from 2015-2018

Background: Biological products are the chemicals in the form of medicines that are prepared from the living cells through highly intricate manufacturing techniques that should be handled and managed under favorable conditions. The regulation of the biosimilar products consists of significant challenges, since they are part of the growing sector of the pharmaceutical industry and normally used by human beings. The regulatory framework and the technical requirements of the US biosimilars program involve a stepwise approach that relies heavily on analytical methods to demonstrate through a “totality of the evidence” that a proposed product is biosimilar to its reference product. By integrating analytical, pharmacological, and clinical data, each of which has limitations, a high level of confidence can be reached regarding clinical performance. The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the health reform (Affordable Care Act). Objective: The current manuscript will provide the information regarding the regulation of Biosimilars products with the detail of biosimilar USER fees structure and the list of approved biosimilar by FDA from 2015- 2018. Conclusion: Research is continually developing more biological products that will help treat medical conditions or add some innovation to the existing treatment options. Biosimilars and reference products are generated in the living cells and require trained expertise as well as technology for biologics being usually highly effective compared to small molecule drugs. These are usually specific against the respective target, which generally produces lesser side effects and low toxicity. FDA’s regulatory authority for the approval of biologics is under PHS (Public Health Service Act) which are also suggested to regulate under the Federal Food, Drug and Cosmetics Act (FD&C). Biosimilars can help expand access to high-quality treatment options for doctors and patients, as well as reduce costs for the healthcare system.

Recognizing and addressing challenges to the adoption of trastuzumab biosimilars and HER2-targeted therapies.

Oncology biologics are one of the fastest-growing segments of pharmaceutical development, bringing more options to patients, including those with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The advent of multiple oncology biosimilars is affecting this patient population, as 5 trastuzumab biosimilars had been FDA approved as of the end of 2019; only 2, however, have been commercially marketed. Trastuzumab serves as the foundation for treatment for patients with HER2-positive breast cancer. HER2-targeted antibody-drug conjugates have been developed to enhance efficacy, improve safety, and/or create more convenient administration. Three biologic drug entities have been approved using trastuzumab, including 2 antibody-drug conjugates and a subcutaneous trastuzumab formulation that includes hyaluronidase. More products are being developed, so biosimilars and other HER2-targeted therapies may further disrupt the biologic market. Many challenging questions surround the adoption of oncology biosimilars, including regulatory pathways, efficacy, safety, cost-benefit, and comparability. The Biologics Price Competition and Innovation Act established an abbreviated regulatory approval pathway for biosimilars to create a catalyst for innovation and competition in the biologics market and to lower the costs of biologics. Challenges to adoption of therapeutic oncology biosimilars continue in the United States and include a lack of directed education to providers and patients, residual concerns regarding efficacy and safety, and practices including "pay-for-delay." The uptake of oncology biosimilars is also affected by multiple issues stemming mainly from cost of care, including drug cost, patient access, formulary inclusion, and treatment management algorithms. Managed care organizations and payers need to be familiar with the biosimilar approval process, the concerns of stakeholders (eg, providers and patients), and factors influencing HER2-directed therapies, including the use of biosimilars and antibody-drug conjugates in today's market.

Real-World Budget Impact of Listing a Biosimilar of Rituximab

The approval of new biosimilars by national health agencies is expected to generate significant cost savings for health care systems. This is particularly the case with the biosimilar of rituximab approved for the Canadian market in 2019. However, several uncertainties remain regarding utilization of this agent. To determine the proportion of total annual drug expenses for each indication for rituximab in the hospital setting and to determine potential savings related to introduction of a biosimilar. A budget impact analysis was performed through 3 real-world scenarios, based on data obtained from a large university teaching hospital for a 12-month period. This study involved data for 420 patients. Annual expenses for rituximab for all indications represented 7.7% of total annual drug spending for the hospital, of which 5.0% was related specifically to indications approved by Health Canada. More than 6% of the annual drug expenses was attributable to the use of rituximab for oncologic indications, including 1.8% for uses not approved by Health Canada. Overall, each 10% reduction in the price of a biosimilar of rituximab (relative to the reference rituximab) would result in annual savings of about 0.8% of total drug expenses in the hospital if a biosimilar was used for all real-world indications, whether approved by Health Canada or not. The introduction of a biosimilar of rituximab to the Canadian market would generate significant savings. To properly assess the potential savings that this agent could generate in the limited budget environment of a hospital, it seems important to consider all of the indications for which it could be used.

Abstract OT2-01-05: A prospective real-world national study to evaluate the efficacy and safety of adjuvant biosimilar trastuzumab in the treatment of HER2-positive breast cancer

Abstract Background: Treatment with anti-HER2 therapy significantly improved survival outcomes in patients with HER2-positive Breast Cancer (BC). In Brazil, Trastuzumab was the first biosimilar approved in the treatment of patients with breast (any disease setting) and advanced gastric cancer with overexpression of HER2. Increase access to this important treatment may be enhanced with biosimilar approval. The aim of this Real-World study is to assess the efficacy and safety of adjuvant biosimilar trastuzumab in Brazilian patients with early HER2+ BC. Methods: This is a national, multicenter, observational prospective, real-world study in a variety of Brazilian institutions. A hundred and seventy adult patients, with diagnosis of early stage HER2-positive breast cancer, who received at least one dose of biosimilar trastuzumab (Zedora) as adjuvant therapy will be included. Patients will be followed for 5 years after the use of biosimilar trastuzumab (Zedora), unless recurrence or death. Safety outcomes will be recorded. Efficacy outcomes include invasive relapse-free survival (IRFS) rate at 18, 24, 30 and 36 months treatment initiation. Given the inexistence of a specific hypothesis to be tested, sample size was based on the accuracy of the two-sided 95% confidence interval (95% CI) for the invasive disease relapse-free survival rate. Results: In development countries such as as Brazil, oncology treatments with biological drugs have high costs and represent an import ibarrier to patients access to anti HER2 therapy. The use of biosimilars may result in significant health care savings. Conclusions: Considering the HERITAGE study, in which biosimilarity was clearly demonstrated between the reference monoclonal antibody and the biosimilar, we do expect to find the same safety and efficacy profile. Citation Format: Leandro Alves, Débora Gagliato, Mayara de Paula, Ana Carolina Cardoso, Alexandre Alcantara, Maristela Precivale, Vivienne Castilho. A prospective real-world national study to evaluate the efficacy and safety of adjuvant biosimilar trastuzumab in the treatment of HER2-positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-01-05.

Understanding the Role of Comparative Clinical Studies in the Development of Oncology Biosimilars.

Biosimilars have the potential to broaden patient access to biologics and provide cost savings for health care systems. During the development of a biosimilar, data that directly compare the proposed biosimilar with the reference product are required. Such comparative data are generated in a stepwise hierarchical process that begins with extensive laboratory-based structural analyses and functional assays. This initial analytical phase serves as the foundation for the demonstration of biosimilarity and is followed by nonclinical in vivo testing (if required) and then clinical evaluation, including a comparative pharmacokinetics/pharmacodynamics study that is usually conducted in healthy volunteers. The development program typically culminates with a comparative clinical efficacy study. The aim of this study is to confirm clinical equivalence of the potential biosimilar and reference product on the basis of prespecified margins, using a study population and efficacy end point that are sufficiently sensitive for detecting potential product-related differences. Such studies also include detailed analyses of safety as well as evaluation of immunogenicity. As biosimilars become more widely available in oncology, especially with recent regulatory approvals of rituximab, trastuzumab, and bevacizumab biosimilars, it is critically important that clinicians understand how the comparative clinical study differs from a traditional phase III efficacy and safety study in the development of a novel biologic originator product. Here, we review the role of comparative clinical studies in biosimilar development, with a focus on trials conducted to support approved trastuzumab biosimilars. We discuss the study populations and end points used, extrapolation of indications, and the confirmatory nature of these studies within the totality of evidence supporting biosimilarity.

Biosimilars: The Process & Quality System Approach to Clinical Applications

Biosimilar medicines are highly similar to FDA approved reference biologics. The sponsor’s intended use claim plays an important role in the use of biosimilar medicines in specialty therapy categories such as immunology, endocrinology, oncology. The new biosimilar products approved by the FDA, play a pivotal role in the clinical treatments of patients suffering from life-threatening diseases such as cardiac myopathies, carcinoma, sarcoma, lymphoma. The US biosimilar approval process requires a thorough characterization of the new biosimilars with a clinically meaningful outcome. Sponsors of new biosimilars follow the appropriate ICH guidelines in regard to clinical PK/PD, safety and efficacy studies. The FDA guidances for extrapolation and interchangeability state that data derived from clinical studies should be adequate to demonstrate purity, potency, safety and the intended clinical use of the new biosimilar in comparison to previously approved licensed biologics. This article emphasizes the FDA’s quality system approach to the design of studies for clinical applications for designated specialty therapy categories.

Complex Generic Products: Insight of Current Regulatory Frameworks in US, EU and Canada and the Need of Harmonisation.

The regulatory agencies all over the world have defined the pathway and regulations for the approval of simple small-molecule generics. In addition, the agencies are striving to form perspicuous regulatory frameworks for the approval of biosimilars. In this view, there are no defined regulations for the approval of complex generics, also known as non-biological complex drugs (NBCDs). Complex drugs are large, highly complex and synthetic moieties and are made of complex active substances but are different from biologics product. Regulatory frameworks being adopted for complex generics today are questionable and ambiguous. The market for complex generics is huge and there are fewer generic competitors in this area. In addition, the cost of bringing such generics into the market is high. Since the complex generics are largely used for chronic and life-threatening diseases and the competition is less, generic players show high interest in this segment. Thus, there is a need for a well-defined pathway and guidance documents for the authorization of generic versions of complex drug products. The article focuses on the regulatory frameworks currently adopted by US, EU and Canada for bringing complex generics into the market. It also describes on the regulatory disparities existing among the three agencies in the light of complex generics.