Rheum360: Focus on Biosimilars

Focus on Biosimilars: 2018 Update

Grace C. Wright, MD, PhD, FACR

The expiration of patent protection for the first biologic therapies was followed by the development of biosimilars.1 The first biosimilar to reach the marketplace was a recombinant human growth hormone, which was approved by the European Medicines Agency (EMA) in 2006.1 Since then, more than 50 biosimilar products, spanning several therapeutic areas, for products that have molecular weights ranging from 5,800 to 150,000 Daltons have been approved.1

Biosimilars represent an opportunity for patients to have additional treatment options.2-4 Demonstrating biosimilarity is undertaken by following an abbreviated but rigorous development program that results in a product that may provide cost savings, without compromising safety and effectiveness.5,6 Competition may increase access to biologic products at a lesser cost to both the patient and the health care system.6

Biosimilars

A biosimilar product is not an improved version of the originator biologic.7

Biosimilars are not copies of licensed biologic medicines that have not been subjected to the biosimilar regulatory pathway.4

Generics are small-molecule, chemically synthesized drugs that contain the identical active ingredient as the reference drug.8,9 Their approval is also based on an abbreviated drug application process, the focus of which is demonstrating bioequivalence between the generic and the innovator product.10

It is impossible to precisely duplicate another manufacturer’s biologically derived product.11 Development of a biosimilar begins with knowledge of the DNA sequence and structure of the reference product, as well as the clinical data that are available11 (Table 1). The unknown proprietary manufacturing conditions for the reference product must be developed through reverse engineering.2 Cell lines, growth media, methods of cell expansion, bioreactor conditions, protein recovery conditions, purification conditions, formulation methods, reagents, and reference standards are unknown factors that the biosimilar sponsor must successfully develop de novo to produce a product that can meet the stringent regulatory requirements for biosimilarity.5

Table 1. Factors Associated With Biosimilar Development

UNKNOWN FACTORS

KNOWN FACTORS

Cell line

DNA sequence

Growth media

Clinical Data

Method of cell expansion

 

Bioreactor conditions

 

Protein recovery conditions

 

Purification conditions

 

Formulation methods

 

Reagents

 

Reference standards

 

Source: US Food and Drug Administration.5

The US Food and Drug Administration (FDA) definition of biosimilarity admits the impossibility of exactly reproducing the reference product5 (Figure 1). Differences in components must be minor and clinically inactive, and there must be no clinically meaningful differences between the biosimilar and the reference product in safety, purity, and potency.5 

Figure 1. Public Health Service Act Definition of Biosimilarity

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Source: US Food and Drug Administration.5

Global Regulatory Pathways

The European Union (EU) EMA implemented the first biosimilar regulatory approval pathway in 2005.12 Since then, countries worldwide have followed (Figure 2), with the US statute for an abbreviated licensure pathway for biosimilars adopted in 2010.13 These guidelines are continuously evaluated as new scientific and technological advancements are made and experience with application review and marketing of biosimilar products is accumulated.1 For example, the EMA released an update to their biosimilars guidelines that went into effect in 2015.14 Three separate overarching guidelines are available, which are supplemented by 8 product-specific guidelines, including 1 for products containing monoclonal antibodies.15 The complexity of regulating biosimilar development is exemplified by the EMA Quality Issues guideline, which provides 7 additional guidelines that should be consulted as well.16

Figure 2. Countries With Biosimilar Regulatory Pathways

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World map showing countries (red) that biosimilar guidelines.
Source: Adapted from Kumar R, et al.13 Open access.

The FDA provides specific topical guidance documents, primarily as Guidance for Industry and Information Sheets, spanning the scope of its regulatory mandate.17 There are now 8 guidance documents related to biosimilar development, ranging in topic diversity from general scientific considerations to reference product exclusivity17 (Table 2).

Table 2. US Food and Drug Administration Biosimilars Guidances

TITLE

DATE

Considerations in Demonstrating Interchangeability With a Reference Producta

January 2017

Labeling for Biosimilar Products

March 2016

Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009a

May 2015

Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

April 2015

Quality Considerations in Demonstrating Biosimilarity to a Reference Product

April 2015

Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

April 2015

Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act

August 2014

Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product*

May 2014

aDraft guidance.
Source: US Food and Drug Administration.17

General Principles for Demonstrating Biosimilarity: FDA Perspective

A biosimilar must demonstrate that it has no significant differences from its reference product.5 This must be supported by robust analytical, toxicologic, pharmacokinetic (PK), pharmacodynamic, and immunogenicity studies compared with the reference product.5 Compared with clinical trial requirements for the originator product, smaller comparative effectiveness clinical trial(s) must be performed in patients with a disease for which the reference product is licensed. Demonstrating efficacy in all indications is not required.5 The similarities required extend to having the same mechanism of action, route of administration, dosage form, and strength as the reference product.5 Among these requirements, establishing toxicology similarity of the biosimilar with the reference product and demonstrating that there are no clinically meaningful differences in safety, efficacy, and immunogenicity are 2 major differences between the regulatory requirements for approval of biosimilars compared with generic drugs (Figure 3).5,6,18-21

Figure 3. Regulatory Requirements: Biosimilar versus Generic Drugs

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PD = pharmacodynamics; PK = pharmacokinetics.
Source: US Food and Drug Administration5,8,18-20; Kozlowski S.21

The development process for biosimilars compared with their reference products is often referred to as “the world turned upside down” (Figure 4).22 Analytical characterization is a large part of biosimilar development, including both structure and function assessment.1 The amino acid sequence of the primary structure must be confirmed, and higher order structures and conformation must be determined. Post-translational modifications are inherent in all biologics and must be identified.5 Aggregation characteristics and size must be determined.5 Binding and biological activity, both in vitro and in vivo, contribute to the overall characterization of the prospective product.5 Characterizing each of these molecular attributes requires multiple investigations using sophisticated methods. Because the design specification includes both physicochemical and biological characterization, multiple iterations of process change, and repetition of these characterization analytics are often required, contributing to the extensive effort demanded early in development.5,21,23 When design specification is completed, validation in preclinical studies and clinical PK/pharmacodynamic studies is undertaken. Clinical trials comprise the peak of the biosimilar development pyramid, which acquire data to support the safety, efficacy, and immunogenicity of the biosimilar product.5

Figure 4. Biosimilar versus Originator Product Development

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Source: US Food and Drug Administration Advisory Committee GP 2015 (Etanercept) Meeting Materials. 2016. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM513088.pdf.

Extrapolation of Indications

Extrapolation of data from a clinical trial of a biosimilar performed in 1 indication may be used to support approval of the biosimilar for other indications for which the reference product is already licensed.5 Several conditions must be satisfied to receive approval of an application for indication extrapolation. The mechanism of action (MoA) must be the same for each condition for which approval is sought.5 For example, rituximab targets the CD20 antigen on the surface of B lymphocytes, mediating B-cell lysis.24 The MoA specifics are more complicated.5 For a biosimilar to claim the same MoA as its reference product, it requires establishing that all known characteristics of the MoA are the same.5 The targets/receptors for each activity/function of the product; binding, dose/concentration response, and pattern of molecular signaling following receptor binding; relationships between product structure and target/receptor interactions; as well as the location and expression of the target/receptors, are all aspects of the MoA that must be demonstrated to be the same in the biosimilar as in the reference product.5 In addition to providing supporting evidence for the MoA, the biosimilar sponsor must provide data acquired from different patient populations of the product’s PK and biodistribution, immunogenicity, and expected toxicities across indications.5 The application must support that differences between conditions do not necessarily preclude extrapolation. If the totality of evidence supports that there are no differences in efficacy or safety, extrapolation may be justified.25

Despite the provision for indication extrapolation, sponsors often choose to investigate their biosimilar product in more than 1 therapeutic area. For example, data from a 24-week phase 1/2 study of the rituximab biosimilar PF-05280586 in patients with rheumatoid arthritis (RA) were reported in 2016,26 and data from an extension of the study that included transitioning from the reference product to PF-05280586 were reported in 2018.27 The sponsor recently completed REFLECTIONS B328-06, a phase 3 study comparing PF-05280586 with the EU rituximab product in more than 300 patients with low tumor burden follicular lymphoma.28 No results have been published, although the sponsor announced that PF-05280586 met its primary endpoint of equivalence with the reference product for overall response rate.29 It was suggested that having clinical data for more than 1 indication may be useful to support evidence submitted for indication extrapolation.29

Interchangeability

Interchangeability is the ability to switch to an approved biosimilar from its reference biologic without prescriber consent.30 This can be possible only if the clinical result after the switch is the same as if the patient had remained on the reference product.30 The FDA released draft guidance on demonstrating interchangeability in 2017, but none of the biosimilars approved at this time has been given interchangeability status.31 The draft guidance received 53 comments during the response period, with individual submissions often including numerous observations and recommendations.32 One commenter recommended that the FDA clarify, although an interchangeability designation requires additional data, that it does not represent a higher quality product or one with greater safety and efficacy than products receiving a biosimilar designation.33 Another concern is the use of PK as a surrogate for immunogenicity, recommending that the totality of the evidence should include all aspects of treatment that can be affected by changes in immunogenicity, including safety and efficacy.33 These activities demonstrate the dedicated involvement of key players in striving to ensure that valid guidance supports biosimilar development.

FDA: Biosimilar Product Development Program

The FDA created the Biosimilar Product Development Program to facilitate development of biosimilar and interchangeable products, providing detailed, product-specific advice to manufacturers.34 Enrollment in the program reached 68 on July 1, 2018, with meeting requests to discuss development of biosimilars for 31 different reference products.34

Consensus Recommendations for Biosimilar Use in Rheumatological Diseases

The emergence of biosimilars for treating rheumatologic diseases prompted the formation of an international multidisciplinary task force on biosimilars in 2016.35 An evidence- and consensus-based statement was developed, comprising 5 overarching principles and 8 recommendations to help guide clinicians in their use of biosimilars.35 The first overarching principle emphasizes that treatment of rheumatic diseases is based on a shared decision-making process between patients and their rheumatologists.35 A related recommendation states that no switch to or among biosimilars should be initiated without the prior awareness of the patient and the treating health care provider.35

Ten of these 13 items were based on the lowest level of evidence.35 Two items that were supported by randomized controlled trials (RCTs, level 1b) recommend that approved biosimilars can be used to treat appropriate patients in the same way as their reference product and that currently available evidence indicates that a single switch from the reference product to 1 of its biosimilars is safe and effective.35 They state that there is no scientific rationale to expect that switching among biosimilars of the same reference product would result in a different clinical outcome; however, patient perspectives must be considered.35 Level 2b evidence (cohort study or low-quality RCT) has supported the recommendation that it is not necessary to measure antidrug antibodies (ADAs) in clinical practice in a setting where no clinically significant differences in immunogenicity have been detected between biosimilars and their reference products.35

Currently Approved Biosimilars in the United States

After the first biosimilar (filgrastim-sndz) received FDA approval in 2015, 11 additional biosimilars have been approved, of which 7 were approved in 2017-2018 (Table 3).31,36 The 12 biosimilars are based on 8 reference products, and currently only 4 of these agents are being marketed.36 Despite their 2016 approvals, etanercept-szzs and adalimumab-atto are not yet marketed in the United States.36 Although a European launch of adalimumab-atto is anticipated in late 2018, the current plans are for a US launch in 2023.37 The maker of infliximab-qbtx does not plan to have a US launch, after the company received approval for its infliximab-dyyb in 2016, which is currently on the market.38

Table 3. US Food and Drug Administration-approved Biosimilars

REFERENT (APPROVAL YEAR)

BIOSIMILAR

BIOSIMILAR APPROVAL YEAR

Adalimumab (2002)

Adalimumab-adaz

Adalimumab-adbm

Adalimumab-atto

2018

2017

2016

Bevacizumab (2004)

Bevacizumab-awwb

2017

Epoetin alfa (1989)

Epoetin alfa-epbx

2018

Etanercept (1998)

Etanercept-szzs

2016

Filgrastim (1991)

Filgrastim-aafi

Filgrastim-sndz

2018

2015a

Infliximab (1998)

Infliximab-abda

Infliximab-dyyb

Infliximab-qbtx

2017a

2016a

2017

Pegfilgrastim (2002)

Pegfilgastrim-jmdb

2018a

Trastuzumab (1998)

Trastuzumab-dkst

2017

aMarketed in the United States.
Note: Bold/italics denote approval for treating rheumatic diseases.
Source: Data from US Food and Drug Administration31; Biosimilar Review & Report.36

The FDA designates nonproprietary names that are included in the license for all biologic products.39 The nonproprietary biosimilar name follows the convention of having a core name comprising the name of the originator product, with a hyphenated 4-letter unique and meaningless suffix.39

The paucity of biosimilars that have been approved in the United States is in stark contrast to their status in Europe where, to date, 50 biosimilars have received approval, including 2 based on rituximab.40 As part of the development program for the rituximab biosimilars, several parallel group clinical trials that included safety and efficacy endpoints were performed in up to 372 (CT-P10) and 627 (GP2013) patients.41 Both of these agents were also submitted to the FDA for approval, with indications for non-Hodgkin’s lymphoma and RA, with efficacy data included for both indications.44 The FDA rejected the submission for CT-P10 in April 2018, which was partly related to the FDA issuance of a Warning Letter to the manufacturer in January 2018 in response to numerous Current Good Manufacture Practices violations.43 The company resubmitted its application to the FDA in May 2018. The application for GP2013 was rejected in May 2018.44 The sponsor announced it will engage in further discussions with the FDA in keeping with its intention to receive approval in the United States for its rituximab biosimilar.44

Biosimilar Clinical Trials

Despite the presence of guidelines for the regulatory pathways that are in place, the peak of the pyramid comprising the clinical trials of biosimilar products contains studies that span several designs.41,45 Parallel group designs, which may have 3 arms to allow comparison of the biosimilar with both the EU and the US reference products, are common.41,45 Some designs include switching, with parallel groups re-randomized to continue or switch treatments after nonstandard durations of the initial parallel group treatment.41,45 Data from crossover studies, including 2, 3, and 4 crossovers, have been submitted.41,45 The heterogeneity among designs shows the flexibility in the regulatory guidance and can complicate comparisons among studies of biologics for the same reference product. All these designs yielded data that supported approval of the biosimilars.

NOR-SWITCH RCT: Switching From Infliximab to Infliximab-dyyb

The noninferiority phase 4 NOR-SWITCH trial in Norway randomized adult patients on stable treatment with infliximab for ≥6 months to continue infliximab or switch to the infliximab biosimilar infliximab-dyyb (CT-P13) following a similar treatment regimen.46 The primary endpoint was disease worsening during 52 weeks of follow-up.46 Of 482 randomized patients, 408 in the per-protocol analysis included 32% with Crohn’s disease, 19% with ulcerative colitis, 19% with spondyloarthritis (SpA), 16% with RA, 6% with psoriatic arthritis (PsA), and 7% with chronic plaque psoriasis.46 Disease worsening occurred in 26% of infliximab and 30% of infliximab-dyyb group patients for an adjusted treatment difference of -4.4% (95% confidence interval [CI] -12.7-3.9), which was within the protocol-specified noninferiority margin of 15%.46 The study was not powered to show noninferiority in the individual disease subgroups.46

Adverse events (AEs) were similar between the infliximab and infliximab-dyyb group, occurring in 70% and 68% of patients, respectively.46 Serious AEs (SAEs) were observed in 10% and 9% of patients, respectively, and AEs led to discontinuation of 4% and 3% of patients, respectively.46  

DANBIO: Switching From Infliximab to Infliximab-dyyb

A guideline-adherent, nonmedical switch from infliximab to infliximab-dyyb trial performed in Denmark included 802 patients with RA (n=403), PsA (n=120), and axial SpA (n=279) who had received infliximab treatment for a median of 6.8 years.47 Disease activities 3 months before and after the switch were compared in the study cohort, and crude and adjusted retention rates of study participants were compared with a historical cohort, which noted that disease activities were similar before and after the switch.47 Crude 1-year infliximab-dyyb retention during a median follow-up of 413 days was similar to that of the historic controls (84.1% vs 86.2%; P=.22; adjusted rate ,83.4% vs 86.8%; P=.03).47 Patients whose previous infliximab treatment was >5 years had longer retention on infliximab-dyyb.47 In the 16.5% of patients who withdrew, 54% were due to lack of effect and 28% to AEs.47 

Infliximab versus Infliximab-abda

A phase 3, multicenter, international RCT compared infliximab with infliximab-abda in 584 biologic-naïve patients with moderate to severe RA, despite methotrexate (MTX) therapy.48 Equivalence was supported by achievement of the primary endpoint—ACR20 at week 30—by 64.1% of patients in the infliximab-abda group and 66.0% in the infliximab group.48 The dose escalation design allowed stepwise increments in both groups, starting at week 30, based on the investigator’s clinical judgment.49 Efficacy, safety, immunogenicity, and radiographic progression from baseline were similar until week 54.49 At week 54, patients previously receiving infliximab were rerandomized to continue the reference product or switch to infliximab-abda until week 70, with efficacy, safety, and immunogenicity assessed until week 78.50 Efficacy was sustained in all groups, and efficacy, safety, and immunogenicity profiles were comparable among groups.50 No treatment-emergent issues or clinically relevant immunogenicity was noted in patients who switched from infliximab to infliximab-abda.50

Infliximab versus Infliximab-qbtx

A parallel, international equivalence RCT evaluated the efficacy, safety, PK, and immunogenicity of infliximab compared with the biosimilar infliximab-qbtx (PF-06438179/GP1111) in 650 biologic-naïve patients with moderately to severely active RA, despite MTX treatment.51 The primary endpoint was ACR20 response rate at week 14, with equivalence defined as a symmetric equivalence margin of ± 13.5% for the 95% CI of the treatment difference.51 Equivalence was supported by ACR20, achieved by 61.1% of infliximab-qbtx and 63.5% of infliximab group patients, with the 95% CI of the difference -9.92% to 5.11%.51 Disease Activity Score 28-joint count–C reactive protein (DAS28–CRP) scores were similar between groups.51 Data through week 30, comprising treatment period 1, revealed that efficacy and immunogenicity were similar for patients who underwent protocol-defined dose escalation after 14 weeks and between treatments for patients without dose escalation.51 There were no clinically meaningful safety differences between treatments.51

The study included 2 additional treatment periods to provide outcomes data following switching from the reference product to the biosimilar.51 At week 30, patients on infliximab were rerandomized to continue blinded treatment with infliximab or initiation of infliximab-qbtx for 24 weeks during treatment period 2.51 During treatment period 3, starting at week 54, all patients received open-label infliximab-qbtx. The last treatment dose was given at week 70, with the end of treatment and safety follow-up at week 78.51

Of 566 patients entering treatment period 2 at week 30, 280 continued GP1111, 143 continued infliximab, and 143 were switched from infliximab to GP1111.52 At each of the 38, 46, and 54-week visits, ACR20 rates and DAS28–CRP scores were comparable between groups, as were incidences of treatment-emergent adverse events (TEAEs), SAEs, and infusion-related reactions. Post-dose ADA rates were comparable between groups.52

EGALITY Plaque Psoriasis RCT: Switching From Etanercept to Etanercept-szzs

EGALITY was a 52-week, equivalence, international RCT that randomized 531 patients with moderate to severe chronic plaque-type psoriasis to self-administer etanercept or its biosimilar etanercept-szzs (GP2015).53 At week 12, patients with ≥50% improvement in the Psoriasis Area and Severity Index (PASI 50) were re-randomized to remain on the once-weekly dosing schedule or to undergo 3 switches between etanercept and etanercept-szzs until week 30.53 From week 30 to week 52, patients remained on their most recent treatment.53 The primary endpoint was the difference in PASI 75 response rates at week 12.53

The PASI 75 difference between the biosimilar and etanercept was -2.3% (95% CI: -9.85 to 5.30), which was within the prespecified 18% margin.53 The 52-week incidence of TEAEs was similar between treatments that were continued throughout the trial and switching between the agents revealed similar safety profiles.53  

EQUIRA Rheumatoid Arthritis RCT: Switching From Etanercept to Etanercept-szzs

The subsequent phase 3, 48-week EQUIRA study of etanercept-szzs had a different switching protocol than the EGALITY study.54 In treatment period 1, patients with moderate to severe RA, with inadequate response to MTX, were randomized to etanercept or etanercept-szzs for 24 weeks of subcutaneous treatments.55 The change from baseline in DAS28–CRP (the primary endpoint) supported equivalence between etanercept-szzs and its reference product.55 Other efficacy outcomes and safety profiles were comparable between the 2 groups.54,55  

At week 24, patients in the etanercept-szzs group who had at least a moderate response continued etanercept-szzs treatment.54 Patients in the reference etanercept group with at least a moderate response were switched to receive etanercept-szzs.54 Treatment period 2 continued to 48 weeks, at which time the mean change in DAS28–CRP from baseline and other efficacy outcomes were comparable between the continued and switched groups.55 In addition, the switch to the biosimilar had no apparent safety impacts.54 

Adalimumab versus Adalimumab-atto

A phase 3, international, 26-week equivalence study compared adalimumab with adalimumab-atto (ABP 501) in 526 patients with moderately to severely active RA, despite MTX treatment.56 Equivalence was defined as having a 90% CI for the risk ratio (RR) of ACR20 at week 24 between 0.738 and 1.355.56 ACR20 at week 24 was 72.4% and was 74.6% for adalimumab and adalimumab-atto (RR 1.039; 90% CI, 0.954-1.133), fulfilling equivalence criteria.56 Changes from baseline DAS28–CRP, ACR50, and ACR70 were also similar between groups.56 The AEs and laboratory abnormalities were similar between groups.56 Antidrug antibodies were observed in 38.2% and 38.3% of adalimumab and adalimumab-atto group patients.56 

VOLTAIRE-RA: Adalimumab-adbm Equivalence and Switching

The pivotal phase 3 VOLTAIRE-RA trial compared adalimumab with adalimumab-adbm (BI 695501) in patients with moderate to severe RA.57 At week 24, patients taking the reference product were re-randomized to continue treatment or switch to adalimumab-adbm for the remainder of the 48-week study.57 Outcomes were similar between treatments at 48 weeks, and the single switch from the reference to the biosimilar product had no effects on efficacy, safety, or immunogenicity.57 

VOLTAIRE-RL: Adalimumab-adbm Autoinjection

Two phase 1 studies (VOLTAIRE-AI and VOLTAIRE-TAI) in healthy volunteers observed similar administration success, immunogenicity, and AEs in subjects randomized to a single administration of adalimumab-adbm using an autoinjector (AI) or prefilled syringe.58 VOLTAIRE-RL enrolled patients with moderately to severely active RA who had no experience at drug self-administration using an AI or pen in a single-arm study to monitor self-injection success using the AI.59 Almost all (216/218; 99.1%) of the 4 injections using the AI were successful—that is, the full content of the AI was injected into the body.59 Injection site reactions were reported by 6.5% of patients.59 

VOLTAIRE X: Switching Between Adalimumab and Adalimumab-adbm in Psoriasis

The phase 3 VOLTAIRE X is underway to assess PK similarity between patients with moderate to severe chronic plaque psoriasis receiving adalimumab continuously compared with those who alternate repeatedly between adalimumab-adbm and adalimumab.60,61 Secondary outcomes include additional PK measures, efficacy, safety, and immunogenicity.60,61 The study was launched in 2017, with a targeted enrollment of 240 participants and an estimated completion date of 2020. VOLTAIRE-X is the first interchangeability study in the United States.62

Adalimumab versus Adalimumab-adaz

A phase 3, randomized, double-blind, controlled, 51-week study included a 17-week initial treatment period for patients with clinically stable but active plaque psoriasis.63 In the first 17 weeks, patients were treated with either adalimumab or adalimumab-adaz. In the second part of the study, patients were randomly assigned to 1 of 4 treatment groups—2 groups continued their originally assigned treatment, whereas 2 underwent alternating therapy between the novel drug and the originator drug every 6 weeks until week 35.63 In the third part of the trial, patients were returned to their initial treatment group.63

Efficacy was evaluated using the PASI 75. After week 17, 75.2% of the patients treated with adalimumab-adaz reached PASI 75 response rates compared with 67.8% of those treated with adalimumab.63 After week 51, 84.5% reached PASI 75 response rate in the adalimumab-adaz arm compared with 79.6% in the adalimumab arm.63

Adverse events and immunogenicity profiles were comparable for both treatment groups.63

The FDA granted approval for adalimumab-adaz in October 2018 due to clinical trial equivalence to adalimumab.64

Barriers to Biosimilar Adoption

Biosimilars are expected to have a significant impact on the US biologic market, despite dissimilarity with payer policies and practices in other markets. However, adoption of biosimilars is associated with several unresolved issues.65 Market access can be affected by complex contracting dynamics. Regulatory and legal uncertainties continue, particularly in the setting where individual states may have different legislation regarding switching from the reference product to the biosimilar.65

Post-marketing pharmacovigilance is required to provide real-world data on switching outcomes. Registries should be clearly defined to ensure adequate data are acquired.65

Robust data on multiple switches in the real world are needed. Acquiring these data is complicated by payer policies and state legislation affecting treatment of patients who move among states.65

A survey of awareness, knowledge, and perceptions of biosimilars, created by the Biosimilars Forum, was conducted toward the end of 2015 to obtain responses from US specialty physicians who prescribe biologics.66 Among 421 responding rheumatologists, 83% correctly identified whether named drugs used by their specialty were biologics.66 Regarding biosimilars, which at that time had become available in the past year, 56% of rheumatologists believed there were no biosimilars available in the United States, and 66% disagreed with the statement that biosimilars will be safe and appropriate for use in naïve and existing patients.66 Almost half of respondents (48%) believed that biosimilars would be less safe than the reference product because of approval through an abbreviated pathway.66

Clinicians need to be familiar with the availability of and clinical data associated with biosimilars. They must understand the policies that affect their use and the advocacy that is needed. They must be able to work with their patients to navigate through these issues and constraints to ensure optimum patient management is provided.

Summary

The advent of biosimilars has been paralleled by the development of guidelines regulating their production. As more experience is acquired, reviewing applications for approval of biosimilar drugs, and more marketplace experience data become available, the development of more meaningful and evidence-based standards is anticipated. The US biologics market is sluggish compared with the single-payer markets in other countries.1 However, biosimilar development activities continue to expand while working toward resolution of issues that are barriers to their use in the United States. The consensus that biosimilars can offer cost and access benefits, while providing similar safety and efficacy compared with their reference products prevails, as reflected in a recent special article on biosimilars from the American College of Rheumatology.67

References

  1. Schiestl M, Zabransky M, Sorgel F. Ten years of biosimilars in Europe: development and evolution of the regulatory pathways. Drug Des Devel Ther. 2017;11:1509-15.
  2. Declerck P, Danesi R, Petersel D, Jacobs I. The language of biosimilars: clarification, definitions, and regulatory aspects. Drugs. 2017;77(6):671-7.
  3. Dorner T, Kay J. Biosimilars in rheumatology: current perspectives and lessons learnt. Nat Rev Rheumatol. 2015;11(12):713-24.
  4. Dorner T, Strand V, Cornes P, et al. The changing landscape of biosimilars in rheumatology. Ann Rheum Dis. 2016;75(6):974-82.
  5. US Food and Drug Administration. Scientific considerations guidance demonstrating biosimilarity to a reference product. Guidance for industry 2015. https://www.fda.gov/downloads/drugs/guidances/ucm291128.pdf. Accessed September 2, 2018.
  6. Harbour PJ. Emerging health care issues: follow-on biologic drug competition. https://www.ftc.gov/sites/default/files/documents/public_statements/emerging-health-care-issues-follow-biologic-drug-competition/090611fobtestimony.pdf. Accessed September 14, 2018.
  7. Anour R. Biosimilars versus 'biobetters'—a regulator's perspective. Generics and Biosimilars Initiative Journal. 2014;3(4):166-7.
  8. US Food and Drug Administration. What Are Generic Drugs? https://www.fda.gov/Drugs/ResourcesForYou/Consumers/QuestionsAnswers/ucm144456.htm. Accessed September 2, 2018.
  9. Wolf DC. Biosimilars in Crohn's disease and ulcerative colitis. Inflamm Bowel Dis. 2016;22(4):994-7.
  10. Montgomery MS. Generics And biosimilars: mapping the biosimilars regulatory approval pathway against the Hatch-Waxman Act and projecting futures effects on the biologics market and patent protection. University of Pittsburgh Law Review. 2014 Spring;75:387-408.
  11. Markus R, Liu J, Ramchandani M, Landa D, Born T, Kaur P. Developing the totality of evidence for biosimilars: regulatory considerations and building confidence for the healthcare community. BioDrugs. 2017;31(3):175-87.
  12. European Medicines Agency. Guideline on similar biological medicinal products. 2005. https://www.ema.europa.eu/documents/scientific-guideline/guideline-similar-biological-medicinal-products_en.pdf. Accessed September 16, 2018.
  13. Kumar R, Sigala S. Biosimilars: regulatory status and implications across the world. J Pharmacovigil. 2016;S3:e002.
  14. European Medicines Agency. Guideline on similar biological medicinal products. 2014. https://www.ema.europa.eu/documents/scientific-guideline/guideline-similar-biological-medicinal-products-rev1_en.pdf. Accessed September 19, 2018.
  15. European Medicines Agency. Multidisciplinary: biosimilar. https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/multidisciplinary/multidisciplinary-biosimilar. Accessed September 19, 2018.
  16. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1). 2014. https://www.ema.europa.eu/documents/scientific-guideline/guideline-similar-biological-medicinal-products-containing-biotechnology-derived-proteins-active_en-0.pdf. Accessed September 19, 2018.
  17. US Food and Drug Administration. Biosimilars guidances. https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/General/ucm444891.htm. Accessed September 19, 2018.
  18. US Food and Drug Administration. Code of federal regulations: Title 21; Chapter I; Subchapter D.  https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.21. Accessed September 14, 2018.
  19. US Food and Drug Administration. Generic drug development. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm142112.htm. Accessed September 14, 2018.
  20. US Food and Drug Administration. S6 preclinical safety evaluation of biotechnology-derived pharmaceuticals. https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm304390.htm. Accessed September 14, 2018.
  21. Kozlowski S. US FDA perspectives on biosimilar biological products. Presented at: 2014 Biotechnology Technology Summit; June 13, 2014; Institute for Bioscience & Biotechnology Research, University of Maryland; Rockville, MD.
  22. McCamish M. GP015 Etanercept Introduction and Concept. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM513088.pdf. Accessed September 16, 2018.
  23. da Silva A, Renard D. Role of pharmacokinetics: Pharmacodynamics in biosimilar assessment. In: Bonate P, Howard D, eds. Pharmacokinetics in Drug Development. Problems and Challenges in Oncology. Vol 4. Basel, Switzerland: Springer; 2016:175-188.
  24. Rituximab [Package insert]. South San Francisco, CA: Genentech, Inc.; 2018.
  25. Lim S. Overview of the regulatory framework and FDA’s guidance for the development and approval of biosimilar products in the US. 2017. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM572144.pdf. Accessed September 14, 2018.
  26. Williams JH, Hutmacher MM, Zierhut ML, et al. Comparative assessment of clinical response in patients with rheumatoid arthritis between PF-05280586, a proposed rituximab biosimilar, and rituximab. Br J Clin Pharmacol. 2016;82(6):1568-79.
  27. Cohen SB, Burgos-Vargas R, Emery P, Jin B, Cronenberger C, Vazquez-Abad MD. An extension study of PF-05280586, a potential rituximab biosimilar, versus rituximab in subjects with active rheumatoid arthritis. Arthritis Care Res (Hoboken). 2018;70(11):1598-1606.
  28. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02213263. Accessed September 17, 2018.
  29. Pharmaceutical Technology. https://www.pharmaceutical-technology.com/comment/pfizers-rituximab-biosimilar-edges-closer-approval/. Accessed September 17, 2018.
  30. Ebbers HC, Chamberlain P. Interchangeability. An insurmountable fifth hurdle? Generics and Biosimilars Initiative Journal. 2014;3(2):88-93.
  31. US Food and Drug Administration. Center for Drug Evaluation and Research. List of licensed biological products. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM560162.pdf. Accessed September 17, 2018.
  32. Regulations.gov. Considerations in demonstrating interchangeability with a reference product. https://www.regulations.gov/docketBrowser?rpp=25&so=DESC&sb=commentDueDate&po=0&dct=PS&D=FDA-2017-D-0154. Accessed September 17, 2018.
  33. Regulations.gov. Comments on FDA's Draft Guidance titled “Considerations in Demonstrating Interchangeability With a Reference Product,” Docket No. FDA-2017-D-0154. https://www.regulations.gov/document?D=FDA-2017-D-0154-0024. Accessed September 17, 2018.
  34. US Food and Drug Administration. Biosimilars action plan: balancing innovation and competition. July 2018. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM613761.pdf?utm_campaign=FDA Releases Biosimilars Action Plan - Drug Information Update&utm_medium=email&utm_source=Eloqua. Accessed September 17, 2018.
  35. Kay J, Schoels MM, Dorner T, et al. Consensus-based recommendations for the use of biosimilars to treat rheumatological diseases. Ann Rheum Dis. 2018;77(2):165-74.
  36. Biosimilar Review & Report. Biosimilar approval status. https://biosimilarsrr.com/us-biosimilar-filings/. Accessed September 17, 2018.
  37. Mintz.com. Approved and pending biosimilar applications. https://www.mintz.com/newsletter/2018/Documents/Status-of-Biosimilar-Applications_June-2018--.pdf. Accessed September 19, 2018.
  38. Brennan Z. https://www.raps.org/regulatory-focus%E2%84%A2/news-articles/2017/12/pfizer-not-planning-us-launch-of-its-second-remicade-biosimilar-approved-by-fda. Accessed September 19, 2018.
  39. US Food and Drug Administration. Nonproprietary naming of biological products. Guidance for industry. January 2017. https://www.fda.gov/downloads/drugs/guidances/ucm459987.pdf. Accessed September 9, 2018.
  40. Biosimilars approved in Europe. 2018; http://www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe. Accessed September 17, 2018.
  41. Mielke J, Jilma B, Jones B, Koenig F. An update on the clinical evidence that supports biosimilar approvals in Europe. Br J Clin Pharmacol. 2018;84(7):1415-31.
  42. RJ Health Systems. Rituximab Biosimilars – 2018 Drug Pipeline Review. http://rjhealthsystems.com/2018/01/17/2018-drug-pipeline-rituxan-rituximab-biosimilars/. Accessed September 17, 2018.
  43. Generics and Biosimilars Initiative. http://www.gabionline.net/Biosimilars/News/Celltrion-resubmits-biosimilar-rituximab-to-FDA. Accessed September 17, 2018.
  44. Althoff E. https://www.sandoz.com/news/media-releases/sandoz-receives-complete-response-letter-us-fda-proposed-biosimilar-rituximab. Accessed September 17, 2018.
  45. Mielke J, Jilma B, Koenig F, Jones B. Clinical trials for authorized biosimilars in the European Union: a systematic review. Br J Clin Pharmacol. 2016;82(6):1444-57.
  46. Jorgensen KK, Olsen IC, Goll GL, et al. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. Lancet. 2017;389(10086):2304-16.
  47. Glintborg B, Sorensen IJ, Loft AG, et al. A nationwide non-medical switch from originator infliximab to biosimilar CT-P13 in 802 patients with inflammatory arthritis: 1-year clinical outcomes from the DANBIO registry. Ann Rheum Dis. 2017;76(8):1426-31.
  48. Choe JY, Prodanovic N, Niebrzydowski J, et al. A randomised, double-blind, phase III study comparing SB2, an infliximab biosimilar, to the infliximab reference product Remicade in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis. 2017;76(1):58-64.
  49. Smolen JS, Choe JY, Prodanovic N, et al. Comparing biosimilar SB2 with reference infliximab after 54 weeks of a double-blind trial: clinical, structural and safety results. Rheumatology (Oxford). 2017;56(10):1771-9.
  50. Smolen JS, Choe JY, Prodanovic N, et al. Safety, immunogenicity and efficacy after switching from reference infliximab to biosimilar SB2 compared with continuing reference infliximab and SB2 in patients with rheumatoid arthritis: results of a randomised, double-blind, phase III transition study. Ann Rheum Dis. 2018;77(2):234-40.
  51. Cohen SB, Alten R, Kameda H, et al. A randomized controlled trial comparing PF-06438179/GP1111 (an infliximab biosimilar) and infliximab reference product for treatment of moderate to severe active rheumatoid arthritis despite methotrexate therapy. Arthritis Res Ther. 2018;20(1):155.
  52. Alten R, Tseluyko V, Hala T, et al. Efficacy, safety and immunogenicity from week 30 to week 54 in a randomised, double-blind phase iii study comparing a proposed infliximab biosimilar (PF-06438179/GP1111) with reference infliximab. Abstract FRI0137. Ann Rheum Dis. 2018;77(Suppl 2):612-3.
  53. Griffiths CEM, Thaci D, Gerdes S, et al. The EGALITY study: a confirmatory, randomized, double-blind study comparing the efficacy, safety and immunogenicity of GP2015, a proposed etanercept biosimilar, vs. the originator product in patients with moderate-to-severe chronic plaque-type psoriasis. Br J Dermatol. 2017;176(4):928-38.
  54. Matucci-Cerinic M, Schulze-Koops H, Buch M, et al. Switch between reference etanercept (ETN) and gp2015, an etanercept biosimilar, did not impact efficacy and safety in patients with moderate-to-severe rheumatoid arthritis: 48-week results from the phase 3 EQUIRA study. Abstract FRI0129. Ann Rheum Dis. 2018;77(Suppl 2):609.
  55. Kavanaugh A, Allanore Y, Kucharz E, Babic G. Etanercept biosimilar GP2015 has equivalent efficacy and safety to etanercept originator in patients with moderate to severe rheumatoid arthritis: the phase 3 Equira study. Presented at: 2017 ACR/ARHP Annual Meeting; November 7, 2017; San Diego, CA. Abstract 2797.
  56. Cohen S, Genovese MC, Choy E, et al. Efficacy and safety of the biosimilar ABP 501 compared with adalimumab in patients with moderate to severe rheumatoid arthritis: a randomised, double-blind, phase III equivalence study. Ann Rheum Dis. 2017;76(10):1679-87.
  57. Cohen S, Alonso-Ruiz A, Klimiuk PA, et al. Biosimilar Candidate BI 695501 and adalimumab reference product have similar efficacy and safety in patients with moderately-to-severely active rheumatoid arthritis (RA): 1-year results from a phase iii study. Presented at: 2017 ACR/ARHP Annual Meeting; September 18, 2017; San Diego, CA. Abstract 2442.
  58. Ramael S, Van Hoorick B, Tiessen R, et al. Similar pharmacokinetics of the adalimumab (Humira) biosimilar BI 695501 whether administered via subcutaneous autoinjector or prefilled syringe (VOLTAIRE)-AI and VOLTAIRE)-TAI): Phase 1, randomized, open-label, parallel-group trials. Rheumatol Ther. 2018 Jun 29 [Epub ahead of print]. doi:10.1007/s40744-018-0119-1.
  59. Cohen S, Klimiuk PA, Krahnke T, Assudani D. Successful administration of BI 695501, an adalimumab biosimilar, using an autoinjector (AI): results from a phase II open-label clinical study (VOLTAIRE)-RL). Expert Opin Drug Deliv. 2018;15(6):545-8.
  60. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03210259, September 2, 2018.
  61. Biosimilars Resource Center. Interchangeability study for adalimumab biosimilar underway. https://www.biosimilarsresourcecenter.org/interchangeability-study-adalimumab-biosimilar-underway/. Accessed September 16, 2018.
  62. Jahnke U. Advances and challenges facing the biosimilars market. https://clarivate.com/blog/advances-challenges-facing-biosimilars-market/. Accessed September 16, 2018.
  63. Blauvelt A, Blauvelt A, Lacour JP, Fowler JF, Jr, et al. A phase III confirmatory study comparing GP2017 with reference adalimumab in patients with moderate-to-severe chronic plaque psoriasis: 51 week results from the ADACCESS study. Presented at: European Academy of Dermatology and Venereology Annual Congress; September 13-17, 2017; Geneva., Switzerland
  64. Healio.com. https://www.healio.com/rheumatology/rheumatoid-arthritis/news/online/%7Bebc9eef8-4f04-43fe-b875-7510cfaeb82e%7D/fda-approves-hyrimoz-third-humira-biosimilar
  65. Simmons-Stern N, Danosi C, Haber A, Greenaway J, Scaife JG. The state of US biosimilars market access: payer perceptions of past, present, and future hurdles to adoption. http://www.trinitypartners.com/files/5815/1638/4057/The_State_of_US_Biosimilars_Market_Access.pdf. Accessed September 20, 2018.
  66. Cohen H, Beydoun D, Chien D, et al. Awareness, knowledge, and perceptions of biosimilars among specialty physicians. Adv Ther. 2017;33(12):2160-72.
  67. Bridges SL, Jr, White DW, Worthing AB, et al. The science behind biosimilars: entering a new era of biologic therapy. Arthritis Rheumatol. 2018;70(3):334-44.
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