Approval Of Biosimilars Research Articles

Biosimilar Drugs for Psoriasis: Principles, Present, and Near Future.

Psoriasis is a chronic, inflammatory, lifelong disease with a high prevalence (afflicting approximately 1–5% of the population worldwide) and is associated with significant morbidity. The introduction of biologic therapies has improved the management of this disease. Multiple biologic medicines that block cytokine signaling, including tumor necrosis factor (TNF) antagonists (adalimumab, etanercept, and infliximab) and inhibitors of interleukin (IL)-17 (brodalumab, ixekizumab, and secukinumab), IL-23 (guselkumab), or IL-12/23 (ustekinumab), are approved for the treatment of psoriasis. Despite the clinical benefits associated with use of biologics in psoriasis, many patients are not treated with biologic therapy, and access to treatment may be limited for various reasons, such as high treatment costs. Patents for many biologics have expired or will soon expire, and biosimilar versions of these agents are available or in development. A biosimilar is a biological product that is highly similar to an approved biologic (i.e., originator or reference) product, and has no clinically meaningful differences in safety, purity, or potency when compared with the reference product. Biosimilars may offer less expensive treatment options for patients with psoriasis; they also may increase access to and address problems with underutilization of biologic therapy. Biosimilar development and approval follows a well-regulated process in many countries, with guidelines developed by the European Medicines Agency, US Food and Drug Administration, and World Health Organization. Currently, several anti-TNF biosimilars are available for use in patients with psoriasis, and other monoclonal antibodies are in development. This review provides dermatologists and those who treat and/or manage psoriasis with a working knowledge of the scientific principles of biosimilar development and approval. It also examines real-world experience with biosimilars available for or used in dermatology that will enable physicians to make informed treatment decisions for their patients with psoriasis.Funding: Pfizer Inc.

Incorporating historical information in biosimilar trials: Challenges and a hybrid Bayesian-frequentist approach.

For the approval of biosimilars, it is, in most cases, necessary to conduct large Phase III clinical trials in patients to convince the regulatory authorities that the product is comparable in terms of efficacy and safety to the originator product. As the originator product has already been studied in several trials beforehand, it seems natural to include this historical information into the showing of equivalent efficacy. Since all studies for the regulatory approval of biosimilars are confirmatory studies, it is required that the statistical approach has reasonable frequentist properties, most importantly, that the Type I error rate is controlled-at least in all scenarios that are realistic in practice. However, it is well known that the incorporation of historical information can lead to an inflation of the Type I error rate in the case of a conflict between the distribution of the historical data and the distribution of the trial data. We illustrate this issue and confirm, using the Bayesian robustified meta-analytic-predictive (MAP) approach as an example, that simultaneously controlling the Type I error rate over the complete parameter space and gaining power in comparison to a standard frequentist approach that only considers the data in the new study, is not possible. We propose a hybrid Bayesian-frequentist approach for binary endpoints that controls the Type I error rate in the neighborhood of the center of the prior distribution, while improving the power. We study the properties of this approach in an extensive simulation study and provide a real-world example.

Conocimiento sobre biosimilares en Atención Primaria: Un estudio de la Sociedad Española de Médicos de Atención Primaria (SEMERGEN)

IntroductionThe objective of this study was to evaluate the awareness and training needs on biosimilar drugs in Primary Care (PC) physicians. Material and methodsDescriptive cross-sectional study based on an on-line questionnaire with a total of 34 multiple choice questions, published on the SEMERGEN website. The main Knowledge areas were: biosimilar definition; regulatory and legal framework; prescription, traceability, interchangeability and pharmacovigilance; availability of biosimilars in the PC setting, and the biosimilars contribution to sustainability. The software used for the analysis and data processing was the Barbwin 7.5. ResultsAn analysis was performed on the responses from 701 questionnaires completed. There was a slight majority (57%) of women participants. The majority of participant worked in urban centres (60.91%). The definition of biosimilar was not known by 58% of those that responded, and 73% were unaware that the management of biosimilars and generics was not comparable. Most (84%) of those that responded were not aware that the studies required for the approval of biosimilars is different from reference biological medicines. Around two-thirds (66%) those that responded did not know of any biosimilars available in PC setting, and the 94% were also unaware of the Spanish legal framework for the management of biosimilar medicines. ConclusionsThe current knowledge about biosimilars among PC physicians is low. The critical areas in need of further training include specific information on biosimilars currently available in PC setting, as well as key aspects regarding prescription, interchangeability and pharmacovigilance requirements. Six out of ten doctors do not know of any biosimilar used in PC in Spain.

The Role of Biosimilars in Patient Access to Therapeutic Antibodies for Immune Mediated Inflammatory Diseases.

Biosimilars have the potential to create competition, lower costs, and increase patient access to biological medications. However, biological medications are sensitive to their manufacturing processes and difficult to precisely characterize, leading to questions about substitution and interchangeability among products. This article reviews the role of biosimilars in patient access to therapeutic antibodies. Although pathways for the approval of biosimilars have been developed, important issues remain unresolved. Interchangeability, or the designation of one medicine as clinically similar to and/or substitutable for another, is specified in some countries but restricted or awaiting policy resolution in others. Non-medical switching, or the switching among biological medications to select a less expensive product, for reasons unrelated to patient health and safety, is controversial because of the potential for complications related to repeated switching (e.g., immunogenicity and loss of therapeutic effect), and transfer of prescribing responsibility for patient medications from the physician to the insurance company. Although biosimilars have different names in different countries, the World Health Organization (WHO) calls for nomenclature that incorporates the international nonproprietary name of the original biological medication followed by a distinguishing suffix qualifier. Naming consistency across countries seems sensible, and adoption of the WHO recommended suffix would greatly simplify pharmacovigilance. Support for the WHO proposal is advised by numerous stakeholders, and resolution of the remaining outstanding issues is urged so that patients and physicians can safely access biosimilars.

The Experience with Biosimilars of Infliximab in Inflammatory Bowel Disease.

biosimilars are similar versions of existing innovator biologic agents but with distinct manufacturing processes. They were approved in inflammatory bowel disease (IBD) by extrapolation of indication from rheumatic diseases. As regulatory requirements for biosimilar approval focus on pre-clinical evidence of similarity rather than clinical data on efficacy, safety and immunogenicity, it is critical to review clinical evidence supporting their use in IBD in order to overcome reluctance from patients and clinicians alike. to review clinical studies using infliximab (IFX) biosimilars in IBD. we reviewed PubMed for original articles published up to July 1st 2017, reporting data on efficacy and/or safety of IFX biosimilars in IBD. 23 observational studies were found, 12 of them assessing switch from IFX originator to biosimilar and 17 assessing induction therapy with IFX biosimilar. Efficacy, safety and immunogenicity were compared, generally yielding similar results for originator and biosimilar IFX. So far only one randomized controlled trial assessed switching from originator to biosimilar IFX and it was not powered to show similarity in IBD. Ongoing trials are comparing IFX biosimilar and originator head to head in patients in remission, as well as switch versus reverse-switch. Current IBD clinical guidelines are discussed as well as future perspectives for biosimilars in IBD. observational studies seem to confirm biosimilarity in a real-world clinical setting. Current trials are expected to elucidate the remaining doubts about clinical biosimilarity.

Abstract P3-14-05: Safety of granulocyte colony-stimulating factors and their biosimilars: A meta-analysis of randomized clinical trials in breast cancer patients receiving cytotoxic chemotherapy

Abstract Background: Neutropenia is a common adverse event reported in cancer patients undergoing cytotoxic chemotherapy. Granulocyte colony-stimulating factors (G-CSFs) such as filgrastim and pegfilgrastim are widely used to prevent neutropenia. Several biosimilars of G-CSF are now available. Biosimilar development involves a series of comparisons between the proposed biosimilar and reference performed in a step-wise fashion to eliminate any concerns regarding the similarity of the medicines. Randomized clinical trials (RCTs) are then performed to confirm that the reference product and its biosimilar provide the same clinical efficacy and safety. Patients with breast cancer (BC) are the most sensitive population in which to confirm similarity of G-CSF biosimilars, however there are some differences between clinical studies. The aim of this meta-analysis was to compare the safety profiles of approved or proposed G-CSF biosimilars (filgrastim or pegfilgrastim) with reference G-CSF in patients with BC. Methods: A Medline literature search up to March 2017 identified randomized clinical trials (RCTs) comparing biosimilar G-CSF to reference in BC patients. Safety analyses included calculation of risk ratios for bone pain events, myalgia events and serious adverse events. Random effect models were fitted to obtain the pooled estimates of the risk ratio for the outcomes and their corresponding 95% confidence intervals (CIs). Results: Eight eligible RCTs were included in this meta-analysis. Risk ratios for bone pain events (risk ratio 1.01 [95% CI -0.76, 1.34]; Table), myalgia events (risk ratio 0.94 [95% CI 0.63, 1.40]) and serious adverse events (risk ratio 1.01 [95% CI 0.76, 1.34]) showed no significant differences between reference and biosimilar G-CSF. Risk ratios for bone pain events BiosimilarsReference productsRisk RatioStudy and year of publicationReference G-CSF / Biosimilar G-CSFEventsTotalEventsTotalWeightIV, Random, 95% CIBlackwell 2015Filgrastim / Filgrastim331073810729.9%0.87 [0.59, 1.27]Blackwell 2016Pegfilgrastim / Pegfilgrastim101551715311.8%0.58 [0.27, 1.23]Harbeck 2016Pegfilgrastim / Pegfilgrastim715981577.3%0.86 [0.32, 2.33]Waller 2010Filgrastim / Filgrastim48183169521.1%1.56 [0.94, 2.59]Waller 2016Pegfilgrastim / Pegfilgrastim51127246729.7%1.12 [0.76, 1.65]Total (95% CI)731579100%1.01 [0.76, 1.34]Heterogeneity: Chi2 = 5.86, df = 4 (P = 0.21); I2 = 32% Test for overall effect: Z=0.07 (P=0.94) Conclusions: This meta-analysis showed no differences in the safety profile of biosimilar and reference G-CSF in breast cancer patients. Citation Format: Krendyukov A, Botteri E, Curigliano G. Safety of granulocyte colony-stimulating factors and their biosimilars: A meta-analysis of randomized clinical trials in breast cancer patients receiving cytotoxic chemotherapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-05.

Epoetin Biosimilars in the Treatment of Chemotherapy-Induced Anemia: 10Years' Experience Gained.

High-quality, safe, and effective biosimilars have the potential to increase access to biological therapies worldwide and to reduce cancer care costs. The European Medicines Agency (EMA) was the first regulatory authority to establish legislative procedures for the approval of biosimilars when they published their guidelines on similar biological medicinal products in 2005. Biosimilar epoetins were first approved in 2007, and a wealth of data has been collected over the last decade. Two biosimilar epoetins (under five commercial names) have been approved by the EMA so far. The availability of epoetin biosimilars generated discussion among the oncology community regarding prescribing these products, their efficacy, and their safety. These agents are approved only if they are shown in extensive analytical and clinical testing to have comparable quality, safety, and efficacy to the reference medicine, and real-world studies provide further data that biosimilar epoetins are an effective and well-tolerated option for the treatment of chemotherapy-induced anemia in patients with cancer. Other countries have adopted similar regulatory pathways to those in Europe and have approved epoetin biosimilars. The now extensive European experience with biosimilar epoetins should reassure regulators from other territories.

Physicochemical Characterization, Glycosylation Pattern and Biosimilarity Assessment of the Fusion Protein Etanercept.

Etanercept is a soluble fusion protein of the tumor necrosis factor receptor (TNFR) extracellular domain, linked to an Fc part of IgG1. It possesses three N- and 13 O-glycosylation sites. Due to its complex structure, an analytical challenge is facing the development and approval of biosimilars. In the current study, physicochemical characterization using state-of-the-art analytics was performed to analyze intact and subunit masses, post-translational modifications (PTMs), higher order structure and potency of Etanercept originator Enbrel® and its biosimilar Altebrel™ (AryoGen Pharmed) in accordance to critical quality attributes of biopharmaceuticals. Intact mass and subunit analysis revealed a size of about 126kDa for both biologicals. Similar glycoprotein species for the complete monomer and the Fc domain of originator and follow-on product were observed, however, small differences in lysine variants and oxidation were found. N-Glycopeptide analysis with UHPLC-QTOF-MSE confirmed the N-glycosylation sites (N149, N171 and N317) as well as Fc-specific glycosylation on N317, and TNFR-specific highly sialylated glycans on N149 and N171 on both investigated products. Small quantitative variations in the N-glycan profile were detected, although the N-glycans were qualitatively similar. Four different O-glycopeptides bearing core 1-type glycans were detected. For both, N- and O-glycopeptide analysis, determination was achieved without prior cleavage of the sialic acid residues for the first time. In addition, ion mobility spectrometry data confirmed close similarity of higher-order structure of both biologics. Furthermore, a neutralization assay, investigating the impact of altered PTMs on potency, indicated that the differences within all batches are still in the acceptable range for biosimilarity.

The nocebo effect challenges the non-medical infliximab switch in practice

BackgroundIn clinical practice, non-medical switching of biological medication may provoke nocebo effects due to unexplained deterioration of therapeutic benefits. Indication extrapolation, idiosyncratic reactions, and interchangeability remain challenged in clinical practice after biosimilar approval by the European Medicines Agency. The principle of “first do no harm” may be challenged in a patient when switching from originator to biosimilar biological.AimTo describe the 1-year results of a pragmatic study on infliximab biosimilar implementation in immune-mediated inflammatory disease patients on the basis of shared decision-making under effectiveness and safety monitoring.MethodsInflammatory bowel disease and rheumatology patients on infliximab originator were converted to infliximab biosimilar after providing informed consent. Nocebo response patients were monitored after switch back to originator. Linear mixed models were used to analyze continuous endpoints on effectiveness and laboratory outcomes to determine significance (P ≤ 0.05) of change over time after switching.ResultsAfter inviting 146 patients, a group of 125 patients enrolled in the project over time, respectively, 73 Crohn’s disease, 28 ulcerative colitis, nine rheumatoid arthritis, ten psoriatic arthritis, and five ankylosing spondylitis patients. No statistically significant changes in effectiveness and safety were observed in any of the indications after a median of 4 infusions in 9 months of study. An overall nocebo response of 12.8% was found among the patients during a minimal observation period of 6 months after the transition to biosimilar infliximab. The overall nocebo response rate did not differ between the studied indications.ConclusionsIn inflammatory bowel disease and rheumatological patients, similar effectiveness and safety were demonstrated on the transition into infliximab biosimilar. In our series, patient empowerment and registration of treatment outcomes delineated biosimilar transition, an approach that hypothetically could reduce nocebo response rates which are relevant to account for regarding biosimilar implementation.

ABP 980: promising trastuzumab biosimilar for HER2-positive breast cancer

ABSTRACTIntroduction: Approval of the HER2-targeted antibody trastuzumab dramatically improved outcomes for patients with HER2-positive breast cancer. Multiple trastuzumab biosimilars, including ABP 980, are in clinical development. Biosimilars are not identical to the reference biologic, but exhibit equivalence and safety in analytical and clinical studies.Areas covered: A brief introduction to trastuzumab, overview of trastuzumab biosimilars, and detailed review of ABP 980 preclinical and clinical studies are included. We searched PubMed and 2016–2017 ASCO and ESMO conference proceedings for ‘ABP 980’ or ‘trastuzumab biosimilar’. ‘ABP 980 and breast cancer’ or ‘trastuzumab biosimilar and breast cancer’ were used to search clinicaltrials.gov for phase III trials. Analytical studies of ABP 980 pharmacokinetics (PK) or pharmacodynamics (PD), phase I studies of ABP 980 safety and PK/PD, and phase III studies of clinical efficacy vs trastuzumab are included.Expert opinion: Questions remain regarding long-term impact of biosimilars on overall healthcare costs, insurance coverage of multiple approved biosimilars, and extensive clinical safety and efficacy follow-up. By producing a competitive market, trastuzumab biosimilars are anticipated to improve access to standard of care therapies, although real-world evidence remains to be obtained. Increased global access to HER2-targeted therapy may eventually alter the landscape of breast cancer and survival rates.

Sample Size for Multiple Hypothesis Testing in Biosimilar Development

ABSTRACTIn biosimilar development, often multiple endpoints within a study, multiple doses and routes of administration or multiple studies in different populations are considered. However, a regulatory requirement is that equivalence of the biosimilar and the reference drug has to be shown for all comparisons, which would typically require a large sample size for a clinical development program. One way that the sample size can be reduced, when m null hypotheses are to be considered, is to require that only k < m null hypotheses have to be rejected to get approval. In fact, this is a realistic requirement, since despite their guidelines the European Medicines Agency (EMA) has already approved applications for biosimilars where not all primary endpoints met the equivalence criteria. In this article, we investigate the properties of the test for the success of at least k out of m endpoints and discuss several multiplicity adjustments that might be useful in practice. We illustrate the impact of multiple hypotheses testing on the sample size using three real-world examples of pharmacokinetic studies that were submitted to the EMA for the approval of biosimilars. Supplementary materials for this article are available online.

Food and Drug Administration guidances on biosimilars: an update for the gastroenterologist

The management of inflammatory bowel disease (IBD), a significant cause of morbidity in the United States (US), has been revolutionized over the last two decades by the introduction of biologic therapies. These include antitumor necrosis factor α (TNF-α) agents. Since 2016, five biosimilar TNF-α inhibitors have been approved by the US Food and Drug Administration (FDA) for use in the treatment of IBD. The FDA has published a series of guidance documents related to the evaluation, licensing, and approval of biosimilars. The aim of this review is to provide an overview of these FDA guidances and the issues associated with biosimilars in the US.

The use of biosimilar medicines in oncology - position statement of the Brazilian Society of Clinical Oncology (SBOC).

A biosimilar is a biologic product that is similar to a reference biopharmaceutical product, the manufacturing process of which hinders the ability to identically replicate the structure of the original product, and therefore, it cannot be described as an absolute equivalent of the original medication. The currently available technology does not allow for an accurate copy of complex molecules, but it does allow the replication of similar molecules with the same activity. As biosimilars are about to be introduced in oncology practice, these must be evaluated through evidence-based medicine. This manuscript is a position paper, where the Brazilian Society of Clinical Oncology (SBOC) aims to describe pertinent issues regarding the approval and use of biosimilars in oncology. As a working group on behalf of SBOC, we discuss aspects related to definition, labeling/nomenclature, extrapolation, interchangeability, switching, automatic substitution, clinical standards on safety and efficacy, and the potential impact on financial burden in healthcare. We take a stand in favor of the introduction of biosimilars, as they offer a viable, safe, and cost-effective alternative to the biopharmaceutical products currently used in cancer. We hope this document can provide valuable information to support therapeutic decisions that maximize the clinical benefit for the thousands of cancer patients in Brazil and can contribute to expedite the introduction of this new drug class in clinical practice. We expect the conveyed information to serve as a basis for further discussion in Latin America, this being the first position paper issued by a Latin American Oncology Society.

Overview of Biosimilars

Biosimilar is a biologic product that is similar to the original innovator product that has been manufactured by a different company.Though, biosimilar and biologics are analogous to each other, biosimilar is the generic version of biologics. Unlike generics where the active ingredients are identical to the reference drug, biosimilar is not identical, rather similar to the reference biologics. Due to post-transcriptional changes, the manufacture of biosimilar is difficult. These complexities that occur in the manufacture of biosimilar make it hard to claim patent. The Patient Protection and Affordable Care Act vindicate the future for granting biosimilars in the U.S through its subtitle, the Biologics Price Competition Innovation Act (BPCIA). 351 (a) application is used for getting approval of new biosimilar while 351 (k) is the biologic license application. For Europe, approval of biosimilars occurs through EMA via centralised procedure. The pilot study can be conducted by the sponsor for scientific advice needed in the filing of biosimilar. The GCC (Gulf Cooperation Council) is an economic and political confederation of six Middle Eastern countries- Kuwait, Oman, Saudi Arabia, UAE (United Arab Emirates), Qatar, Bahrain.Therefore, technically, patent infringement is no big concern as there are no patents for these products in India.

First Biosimilar Approved for Breast &amp; Stomach Cancers

First Biosimilar Approved for Breast &amp; Stomach Cancers

Comparing granulocyte colony–stimulating factor filgrastim and pegfilgrastim to its biosimilars in terms of efficacy and safety: A meta-analysis of randomised clinical trials in breast cancer patients

BackgroundGranulocyte colony–stimulating factors (G-CSFs) are widely used to prevent neutropenia in cancer patients undergoing myelosuppressive chemotherapy. Several biosimilar medicines of G-CSF are now available, with their development involving a step-wise series of comparisons to demonstrate similarity to reference biologics. Randomised clinical trials (RCTs) are considered confirmatory, and for G-CSF biosimilars, patients with breast cancer (BC) undergoing myelosuppressive chemotherapy are the most sensitive population in which to confirm similarity. This meta-analysis aimed to compare the clinical efficacy and safety of approved or proposed G-CSF biosimilars (filgrastim or pegfilgrastim) with reference G-CSF in patients with BC. MethodsA Medline literature search up to March 2017 identified RCTs comparing biosimilar G-CSF to reference in BC patients. The primary efficacy end-point was mean difference in duration of severe neutropenia (DSN). Secondary efficacy end-points were differences in depth of absolute neutrophil count (ANC) nadir, time to ANC recovery and incidence of febrile neutropenia. Safety analyses included calculation of risk ratios for bone pain events, myalgia events and serious adverse events. Random effect models were fitted to obtain the pooled estimates of the mean difference for continuous outcomes and the risk ratio for dichotomous outcomes and their corresponding 95% confidence intervals (CIs). FindingsEight eligible RCTs were included in this meta-analysis. Overall difference in DSN between reference and biosimilar medicines was not statistically significant (0·06 d [95% CI −0·05, 0·17]). The analysis of secondary efficacy end-points showed no significant differences between reference biologics and biosimilar medicines, as well as the analysis of bone pain events, myalgia events and serious adverse events. InterpretationThis meta-analysis showed no significant differences in clinical efficacy and safety between biosimilar and reference G-CSF in BC patients.

A Systematic Review of U.S. Biosimilar Approvals: What Evidence Does the FDA Require and How Are Manufacturers Responding?

Biosimilars undergo an abbreviated licensure pathway called 351(k), which was created by the Biologics Price Competition and Innovation Act of 2009. This approval process is different from the 351(a) pathway for original biologic approval and, as of August 2017, has been used to approve 5 biosimilars in the United States. To identify the types and quantities of evidence required by the FDA for biosimilar approval and the corresponding evidence manufacturers have provided in their 351(k) biosimilar approval applications. To collect data for this review, we searched through drug-specific FDA approval documents and approval-related FDA webcasts for approval indications and dates; reference product names; formulations; postmarketing requirements and commitments; evidence used for extrapolation claims; advisory committee votes; and evidence on similarity in analytical and functional characteristics, pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity. All biosimilars approved in the United States provided a large evidence base to demonstrate similarity in analytical and functional characteristics-3 to 5 clinical studies showed similarity in pharmacokinetics and pharmacodynamics, and 1 to 2 clinical studies demonstrated efficacy. Safety and immunogenicity were evaluated across all clinical studies. All biosimilars were compared with either the U.S.-licensed reference product or the reference product licensed by the European Union. Extrapolation allowed biosimilars to be approved for indications in which clinical studies were not conducted. The few indications for which biosimilars did not share approval with the reference product were due to market exclusivity protection. None of the 5 biosimilars have been approved as interchangeable in the United States. The approval process for the first 5 biosimilars on the market in the United States provides a baseline understanding of what type and degree of evidence is required for biosimilar approval. There was no external funding for this study. Hung reports employment as a pharmacist for CVS Health, an AHRQ F32 grant, and meeting/accommodation/travel support from AACP, DIA, and ISPOR, all outside the submitted work. Vu and Mostovoy have nothing to disclose. Study concept and design were contributed by Hung and Mostovoy, along with Vu. Hung and Vu collected the data, and data interpretation was performed primarily by Hung, along with Mostovoy. The manuscript was written by Hung and Vu and revised by all the authors. Some of the study results were previously presented as a poster at the ISPOR 22nd Annual International Meeting; May 20-24, 2017; in Boston, Massachusetts.

Integrating Biosimilars Into Oncology Practice: Implications for the Advanced Practitioner

Biosimilar agents are biologic products that have been shown to be "highly similar" to an already approved reference biologic product. Their integration into clinical practice has the potential to significantly decrease costs for patients, health-care systems, and insurance companies. Through legislation, the US Food and Drug Administration (FDA) approved the Biologics Price Competition and Innovation (BCPI) Act in 2009. In 2010, it was signed into law, allowing for an abbreviated pathway for biosimilar approval. This law implemented a framework for development and regulation of biosimilars for manufacturers and provided guidance for the key submission components necessary to achieve final FDA approval. Many factors will influence how biosimilars are integrated into health-care systems and oncology clinics. As biosimilar utilization in the United States expands beyond supportive care, unique challenges will emerge. Patient and staff education will be at the forefront of the successful application of biosimilar agents in oncology, and advanced practitioners will be in a unique position to lead change. The goal of this article is to describe the chemical and clinical nature of biosimilars, review focus areas of interest for biosimilar development in oncology, discuss implementation strategies for biosimilars, and provide techniques for patient education on biosimilars.

Application of the FDA Biosimilar Extrapolation Framework to Make Off-Label Determinations.

The FDA's extrapolation framework allows for a biosimilar to obtain licensure for indications that were not explicitly studied in the context of a clinical trial by extending conclusions from studies in 1 population to make inferences in other populations. Within routine clinical care, drugs and biologics are routinely used for medically accepted off-label indications. The appropriateness of these products for off-label indications are typically curated by compendia and guidelines, which have established processes and criteria for reviewing and evaluating the evidence to make such determinations. The evidence paradigm for biosimilars is different from originator biologics and is one of comparability to a reference product, not to reestablish clinical benefit. Thus, this paradigm shift can be applied to the exercise of making off-label determinations for biosimilars, and the FDA's framework of extrapolation can be used by clinicians and coverage policy decision makers to determine appropriate off-label indications for biosimilars. To highlight how the FDA's biosimilar extrapolation framework can be used to make off-label policy decisions, using to 2 approved biosimilars for filgrastim and infliximab as case studies. This study describes the FDA extrapolation framework for evaluating whether there are any differences in the mechanism of action, pharmacokinetics/biosdistribution, immunogenicity, and toxicity between on-label and off-label indications. Two case studies are presented that evaluate the biosimilars filgrastim-sndz and infliximab-dyyb for the offlabel indications of treating symptomatic anemia in patients with myelodysplastic syndromes and immune-mediated colitis, respectively. The analytical, nonclinical, and clinical pharmacology, along with clinical studies demonstrating that filgrastim-sndz and infliximab-dyyb are biosimilar to their respective reference products, are reviewed and discussed in context with the extrapolation framework to ascertain whether use of the biosimilar within the off-label indications is scientifically justified. The mechanism of action of filgrastim and infliximab between their FDA-approved and off-label indications are the same. In addition, there is a high degree of similarity with the analytical and nonclinical characteristics of filgrastim-sndz and infliximab-dyyb and their respective reference products. There is no expectation of differences in safety and immunogenicity across the patient populations. Thus, some decision makers may determine that filgrastim-sndz and infliximab-dyyb be used for the off-label indications of treating symptomatic anemia in patients with myelodysplasia and immune-mediated colitis, respectively. In some cases, the use of biosimilars for off-label indications can be scientifically justified. Since coverage policy decisions are intimately tied to compendia and guideline listings, it is incumbent upon these groups to conduct formal assessments of biosimilar off-label indications using the FDA extrapolation framework. No outside funding supported this study. Li discloses that he has received honoraria and/or paid travel expenses as an advisory board and speaker's bureau participant for Pfizer; for speaking on behalf of Mylan and Apobiologix; and for participating on advisory boards for Eli Lilly and Mylan. Lobaina has nothing to disclose. Li was responsible for study design and manuscript revision. Li took the lead in data collection and interpretation and manuscript preparation, along with Lobaina.

Improving the power to establish clinical similarity in a Phase 3 efficacy trial by incorporating prior evidence of analytical and pharmacokinetic similarity

ABSTRACTTo improve patients’ access to safe and effective biological medicines, abbreviated licensure pathways for biosimilar and interchangeable biological products have been established in the US, Europe, and other countries around the world. The US Food and Drug Administration and European Medicines Agency have published various guidance documents on the development and approval of biosimilars, which recommend a “totality-of-the-evidence” approach with a stepwise process to demonstrate biosimilarity. The approach relies on comprehensive comparability studies ranging from analytical and nonclinical studies to clinical pharmacokinetic/pharmacodynamic (PK/PD) and efficacy studies. A clinical efficacy study may be necessary to address residual uncertainty about the biosimilarity of the proposed product to the reference product and support a demonstration that there are no clinically meaningful differences. In this article, we propose a statistical strategy that takes into account the similarity evidence from analytical assessments and PK studies in the design and analysis of the clinical efficacy study in order to address residual uncertainty and enhance statistical power and precision. We assume that if the proposed biosimilar product and the reference product are shown to be highly similar with respect to the analytical and PK parameters, then they should also be similar with respect to the efficacy parameters. We show that the proposed methods provide correct control of the type I error and improve the power and precision of the efficacy study upon the standard analysis that disregards the prior evidence. We confirm and illustrate the theoretical results through simulation studies based on the biosimilars development experience of many different products.