putting the value into biosimilar decision making

Autoimmunity Reviews xxx (2014) xxx–xxx

AUTREV-01536; No of Pages 7

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Autoimmunity Reviews

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Review

Putting the value into biosimilar decision making
The judgment value criteria
Mirhelen Mendes de Abreu a,⁎, Vibeke Strand b, Roger Abramino Levy c, Denizar Vianna Araujo c

a Department of Medicine, Universidade Federal de São Carlosb Adjunct Division of Immunology/Rheumatology, Stanford University School of Medicinec Department of Medicine, Universidade do Estado do Rio de Janeiro

⁎ Corresponding author at: Federal University of São CaE-mail addresses: [email protected] (M. Mendes

1568-9972/$ – see front matter © 2014 Elsevier B.V. All rihttp://dx.doi.org/10.1016/j.autrev.2014.01.051

Please cite this article as: Mendes de AbreuM10.1016/j.autrev.2014.01.051

a b s t r a c t
a r t i c l e i n f o
Article history:Received 15 December 2013Accepted 7 January 2014Available online xxxx

Keywords:BiosimilarsValue in healthImmunogenicityDecision processValue chain

Uncertainties remain the key issue surrounding biosimilars, although decisions regarding their use must bemade. The challenges for policymakers, doctors, patients and others seeking to navigate in the uncharted watersof biosimilars must be clarified. At the most basic level, scientific understanding of the issue remains limited andwhenmaking decisions, policymakersmust consider all those affected by health policy decisions, particularly theultimate recipients of these medicines: the patients.The biosimilar-value chain relies onmeasurement of comparabilities. The goal is to demonstrate how, fromamo-lecular perspective, closely similar they are or are not andhowpotential small differencesmay be relevant to clin-ical outcomes. To critically understand these points, this conceptual paper will present a knowledge-value chainand discuss each dimension assigning value in the decision making process re-utilization of biosimilars.

© 2014 Elsevier B.V. All rights reserved.

Contents

1. Introduction - Defining the value of biosimilars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02. The biosimilar-value chain framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

2.1. Mapping the knowledge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.2. Concepts and terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.3. Manufacturing process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.4. Challenges of measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 02.5. Knowledge creation and destruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

Professional behavior based on experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Uncertainties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Patients' roles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

2.6. Knowledge integration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Regulatory aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Aspects related to the product's quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

2.6. Knowledge replication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0The need for the biological reference products during comparison . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Design of efficacy studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Characteristics of safety studies including immunogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Definitions of extrapolation to original labeled indications of the BRP . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Pharmacovigilance and traceability plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0The need to differentiate between labels and information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

2.8. Knowledge performance and innovation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03. What are the criteria to value biosimilars? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

3.1. EMA judgment value criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.2. USA judgment value criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

rlos, Medicine Department, Av. Washington Luis, Km 235, SP 310, São Carlos, SP 13565-905, Brazil.de Abreu), [email protected] (V. Strand), [email protected] (R.A. Levy), [email protected] (D.V. Araujo).

ghts reserved.

, et al, Putting the value into biosimilar decisionmaking, Autoimmun Rev (2014), http://dx.doi.org/

http://dx.doi.org/10.1016/j.autrev.2014.01.051

mailto:[email protected]





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2 M. Mendes de Abreu et al. / Autoimmunity Reviews xxx (2014) xxx–xxx

3.3. Latin America judgment value criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 03.4. Brazil judgment value criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

4. Final considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

1. Introduction - Defining the value of biosimilars

Value should always be defined around the customer and, in a well-functioning health care system, the creation of value for patients shoulddetermine the rewards for all other participants in the system [1].Achieving high value for patients must become the overarching goalof health care delivery, with value defined as health outcomes achievedper dollar spent. This goal is whatmatters for patients and unites the in-terests of all participants in the system. If values improve, patients,payers, providers, and suppliers can all benefit while the economic sus-tainability of the health care system increases [2–4].

Over the past fifteen years, biologic agents have revolutionized thetreatment of many rare and life threatening illnesses, such as autoim-mune diseases [5]. Biologic agents (or biologics) refer broadly to sub-stances produced by living cells, which are used in the treatment orprevention of diseases. They include a wide range of substances, includ-ing monoclonal antibodies, soluble receptors, cell based therapies andvaccines and work by influencing cellular processes and/or cytokinesthat result in or down modulate a disease [6,7].

Biologic agents have a recent history of success in treating chronicand life-threatening disease [8]. With anticipated expiration of patentsand/or data protection for a large group of original biologic agents, anew generation of products designed to be “highly similar” to the orig-inally licensed products has emerged. For these products to be licensed,manufacturers depend in part on prior information on the safety and ef-ficacy of the biologic reference product (BRP). Thewell-established clin-ical experience and safety profile of the reference products mustcontribute to the development of biosimilar products (BSPs).

Key concerns around biosimilars involve the balance between safetyversus cost and the issue of informed and shared patient choice. In gen-eral, regulatory guidelines emphasize safety and equivalent pharmaco-kinetics, pharmacodynamics and efficacywhile reimbursement policiesemphasize cost [9,10]. This may lead us into policies such as forcedswitching or interchangeability of biosimilars for BRPs, which have im-portant consequences for patients of which they and their health careproviders may not be aware. Experts on biosimilars and health technol-ogy assessment have been emphasizing the need for such knowledgewhen they contemplate the availability of factual and unbiased informa-tion to prescribers and patients. Somemay see the use of biosimilars as asimple technical issue whereas the arrival of these new innovativeproducts poses both practical and ethical questions. To address thesequestions, this paper will present some of the key issues regardingbiosimilars and discuss their potential implications on health carefrom the perspectives of patient–physician encounters to macro issuesfacing decision makers [11]. To do so, we outline a framework of abiosimilar-value chain in different health systems, consideringmanufacturing, clinical and regulatory aspects and how these issueshave been managed, according to different values and economicviewpoints.

2. The biosimilar-value chain framework

Value is emerging as a concept— perhaps the only concept— that allstakeholders in health care embrace [12]. Providers, patients, payers,and policymakers all support the goal of improving outcomes anddoing so as efficiently as possible. No one can oppose this goal and ex-pect long-term success, just as no one in a for-profit company can resist

Please cite this article as: Mendes de AbreuM, et al, Putting the value into10.1016/j.autrev.2014.01.051

decisions expected to enhance long-term shareholder value. Such avalue framework offers a unifying orientation for provider organizationsthat might otherwise be stymied by constituents' fighting for biggerpieces of a shrinking pie.

How then is the concept of value translated into realistic use ofbiosimilars? As often true inmedicine itself, the critical first step ismea-surement. Provider organizations need to capture data on outcomes rel-evant to patients, as well as costs per patient over meaningful episodesof care. These data are essential for assessingwhether value is attained?or improving.

The biosimilar-value chain relies on measurement of comparabil-ities [13]. To critically understand these points, we will discuss thevalue of biosimilars in the context of how Landry et al. postulate theknowledge-value chain to be in health care [14].

“The knowledge-value chain is a non-linear concept and is based on themanagement of five dyadic capabilities: mapping and acquisition, crea-tion and destruction, integration and sharing/transfer, replication andprotection, and performance and innovation.”

2.1. Mapping the knowledge

Mapping knowledge refers to the understanding and awareness thatan organization has with respect to its knowledge resources and theirlimitations. Based on the results of a knowledge mapping and acquisi-tion diagnostic, one could examine the gaps in knowledge and chal-lenges that may exist between what a public health organizationcurrently knows regarding biosimilars and that which it must know toimplement its mandate and what it currently knows.

To better understand the potential values of a biosimilar, the firststep is to map the concepts and definitions that are used for this discus-sion. Also, a broad view of manufacturing process, that is the core of thebiosimilars' value, needs to be fully described, including what is mea-sured to determine biosimilarity and/or comparability. Finally, howcountries are measuring each outcome and managing these challengesand gaps are presented.

2.2. Concepts and terminology

TheWorld Health Organization (WHO) defines biosimilar or SimilarBiotherapeutic Products as “a biotherapeutic product which is similar interms of quality, safety and efficacy to an already licensed referencebiotherapeutic product” (RBP). Biosimilars should be developed strictlyin accordance with the WHO definition, which requires comparativeprocedures used for reference products. It is alsomandated by regulato-ry authorities, such as the European Medicines Agency (EMA) and USFood and Drug Administration (FDA). These stringent processes ensurethat no clinically meaningful differences exist between biosimilar andreference product in terms of ‘safety, purity and potency’ (FDA), or‘quality, safety and efficacy’ (EMA).

Physicians must be aware of the distinction between “bio-alike”,“me-too” or “follow on biologics” and ‘true’ biosimilars that meetWHO, EMA and FDA standards, as well as differences betweenbiosimilars and these other biological copies. Also, it is important to em-phasize that biosimilars are not, per se generic drugs, by definition, andthus regulatory requirements differ.

biosimilar decisionmaking, Autoimmun Rev (2014), http://dx.doi.org/



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Differences in terminologymight reflect how such a country is man-aging— and valuating— biosimilars and the like. In this aspect, regula-tory aspects differ between countries, since not all countries can affordto follow a regulatory pathway outlined by EMA and/or FDA. In thatcase, such as in Brazil, legislation is now in place to obviate such regula-tory review. In other countries in Central and South America and cer-tainly China, there is no regulatory pathway in place. In thesecountries, different terms need to be used, such as “bio-alike” or “bio-wannabe”.

The term generic drug is used to describe small-molecule chemicalentities that are structurally and therapeutically equivalent to an origi-nal drug whose patent and/or data protection period has expired. Dem-onstration of pharmacokinetic bioequivalence is generally adequate andsufficient to infer therapeutic equivalence between generic and refer-ence drugs. However, this approach is not adequate for development,evaluation, and licensing of biosimilars. As with any drug developmentprogram, development of a biosimilar requires a step wise approach,starting with the characterization and evaluation of the quality attri-butes, e.g. structure, pharmacokinetics and pharmacodynamics of theproduct, followed by clinical efficacy, safety and immunogenicitystudies.

Second-generation biological or biobetter is a structurally and func-tionally altered biological product resulting in improved or differentbiological activity from the reference. In certain circumstances, such asequivalent efficacy but superior safety and/or less immunogenicity,this may still be considered a biosimilar [15]. Finally, there is the me-too biologic, also called non-innovator biologic. This category is a biologi-cal product developed with the same target antigen but withoutdemonstrated comparability by PK, PD, efficacy, safety and/or immuno-genicity to the reference product.

2.3. Manufacturing process

Biologic proteins are synthesized in living organisms to treat variousdiseases, often by genetically modified cell constructs or cell lines [16].Recombinant technology is often used to insert desirable genes or re-move undesirable ones within a living cell or via a vector such as avirus, prompting production of a specific protein to treat a disease.Thus biotechnology has led to development of today's most importantmedicines, including cloning of naturally occurring proteins such ashuman insulin for diabetes, erythropoietin to stimulate the productionof red blood cells in the treatment of chronic anemia and G-CSF for neu-tropenia and monoclonal antibodies and soluble receptors for cancer,rheumatoid arthritis and systemic lupus erythematosus [17].

The genetic code of a chosen protein, such as human insulin ormonoclonal antibody, is identified and replicated by combining differ-ent segments of DNA to build a functional DNA sequence [18]. TheDNA sequence is introduced into the host cell of a living organism,such as bacteria, yeast or mammalian cells, altering the cell's geneticmakeup and coding it to produce the chosen protein. Genetically mod-ified cell lines are carefully selected and cultured in large bioreactors be-fore the biologic product is extracted through complex and lengthypurification processes. Even minor alterations may lead to changes incell behavior and differences in the structure, stability or other qualityaspects of the end product, commonly due to differences in glycosyla-tion patterns. Any of these differences have the potential to affect thetreatment's safety, efficacy and immunogenicity.

2.4. Challenges of measurement

Biosimilars present challenges because of their high level of com-plexity [19]. The complex tertiary and quaternary structures of biologicproducts are largely determined by the production process (choice ofthe cell type, production, fermentation, purification, formulation, stor-age and packaging). Consequently, seemingly minor variations inthese processes can significantly and critically affect, for example, the

Please cite this article as: Mendes de AbreuM, et al, Putting the value into b10.1016/j.autrev.2014.01.051

extent of aggregation and post-translational modifications, which canlead to serious implications such as loss of potency e.g. efficacy and/orefficacy, undesirable immunogenic responses (immunogenicity) aswell as other adverse events.

Although few biosimilars have been formally approved by EMA, in-cluding only one monoclonal antibody, analytical studies have demon-strated heterogeneity of erythropoietin biosimilars (e.g., chemical andmolecular structure and efficacy) produced in different countries [20].In addition, those analytical studies failed to demonstrate comparabilityof these products to the originator (i.e., each biosimilar product differedin composition and none consistently met specifications). Clinical stud-ies were also unable to prove equivalent or non-inferiority, safety andefficacy of the biosimilar products to the recombinant human erythro-poietin originator and there were significant occurrences of pure redcell aplasia, attributed to aggregate formation due to changes in formu-lation and use of a tungsten plunger in administration syringes. This ex-ample served to illustrate the importance of preclinical and clinicalcomparability studies to establish analytical and bioanalytical equiva-lency between biosimilars and originators.

One of the fundamental challenges in designing experiments to es-tablish physiochemical and structural comparability of the biosimilaris that a small degree of heterogeneity in its physiochemical naturemay be inevitable, and similar differences are likely to be inherent inthe originator itself, due to improvements in manufacturing processessince approval of the originator. It is a fundamental regulatory require-ment that all biosimilarity studies include concurrent analysis of multi-ple batches of the originator. However, this can be a significantchallenge as current batches of originator products are now so large asto account for an entire year's use. Thus determination of the variabilityof the biosimilar will have narrower comparability requirements thanwhen the originator product was approved.

2.5. Knowledge creation and destruction

The knowledge-creation capability refers to the capacity to combineknowledge (tacit, explicit, individual and collective, internal and exter-nal) to develop new knowledge. Knowledge creation is typically associ-ated with research and development activities. Knowledge-destructioncapability is the capacity to eliminate pieces of knowledge or disentan-gle their interconnectedness. Knowledge destruction frequently pavesthe way for creation and innovation. Three aspects of value can be con-sidered as targets for creation and destruction on biosimilar-valuechain: professional behavior based on experience; uncertainties and pa-tients' roles.

Professional behavior based on experienceDoctors are already familiarwith the concept and cost benefits of ini-

tiating treatment with generic versions of non-biologic agents in manyconditions including RA. However, they will need to trust and believethat regulatory approved biosimilars are an effective, safe and cheaperalternative to originator biologics.

UncertaintiesThe biosimilars debate represents decisions made with uncer-

tainties, which are the key issues within the value chain. There is grow-ing interest in health decision making when made in the presence ofuncertainties. Little is known about the optimal approaches to oroutcomes of communicating uncertainties about risks and benefits oftreatments. Consequently, all health decisionmakers will face consider-able challenges involving decisions re-using biosimilars.

A crucial point in large patient and provider populations is the levelof co-pays: unless they are significantly lower there will be littleincentive for biosimilar use. The possibility of moving biosimilars to aseparate formulary tier is an option, but one that is likely to be heavilydependent on the perception of safety concerningmonoclonal antibod-ies and soluble receptors. Lack of experience with these types of

iosimilar decisionmaking, Autoimmun Rev (2014), http://dx.doi.org/




biosimilars and the novelty of this regulatory pathway have led to anatural conservatism in consideration of prescribing approachesamong many physicians. This learning curve has yet to be establishedand overcoming safety and efficacy concerns will be paramount to theacceptance of biosimilars. Usage will vary by therapeutic area but it islikely to limited to small groups of new patients initially, with closemonitoring of outcomes before more widespread use is considered.

Patients' rolesIncreasingly vocal regarding treatment decisions, patients are also

more focused on broader and affordable access to treatment. However,it is likely that they will be heavily influenced by physician guidanceconcerning use of biosimilars and they may not be aware whetherthey are being treatedwith a biosimilar or an originator product. Societyis thus facing two revolutionary health care paradigms: patient partici-pation in their health care plans and use of biosimilars. These issues in-volve information exchange, discussion of values and consequences toclinical and ethical perspectives.

Use of biosimilars continues under debate andmacro-level decisionsare beingmade, although the evidences in several policy health dimen-sions are scarce, including consequences of their administration forclinical outcomes. These consequences involve ethical dimensionswhich have implications on values and preferences. It is not clearwhich is feasible and best approach to guide discussions on biosimilarsfrom society's perspective. To address these questions, a possibilitymayinclude use of decision aids to improve discussion of biosimilars inpatient–physician encounters.

2.6. Knowledge integration

Knowledge integration is the capacity to transform a public healthorganization's knowledge resources into actionable knowledge. It maytake into account the organization's strengths, weaknesses and oppor-tunities aswell as threats posed to the organization. Knowledge integra-tion remains a challenge regarding biosimilars. It defines how analyticaland clinical studies might be interpreted and those outcome measuresselected to demonstrate biosimilarity. As care activities are interdepen-dent, value for patients is often revealed only over time and manifestedin longer-termoutcomes such as sustainable recovery, need for ongoingtherapy, or occurrences of treatment-associated adverse events. Theonly way to accuratelymeasure a biosimilar's value, then, is to track pa-tient outcomes and costs longitudinally, that is: regulatory mandatedclinical studies and post marketing surveillance.

Clinical studiesDetermining the group of relevant outcomes to measure for a

biosimilar in amedical condition should follow several principles to im-prove its value-chain comprehension [21]. To adequately measure itsvalue in health, outcomes should include those health circumstancesmost relevant to patients. They should cover both near-term andlonger-term health, addressing a period sufficiently long to encompassthe ultimate results of care. Additionally, outcome measures should in-clude sufficient assessment of risk factors or initial conditions to allowfor risk adjustment.

Outcomes for anymedical condition can be arrayed in a three-tieredhierarchy, in which the top tier is generally the most important andlower-tier outcomes involve a progression of results contingent on suc-cess at the higher tiers [22]. Each tier of the framework contains twolevels, each involving one or more distinct outcome dimensions. Foreach dimension, success ismeasuredwith the use of one ormore specif-ic metrics. In this hierarchy framework, Tier 1 is the health status that isachieved. Tier 2 outcomes are related to the recovery process and its cycletime. Tier 3 is the sustainability of healthwhich is recurrences of originaldisease manifestations and/or longer-term complications.

Tomeasure health status variations according to use of biologic prod-ucts and biosimilars means to investigate their effectiveness and safety


profiles. As rheumatic diseases are chronic conditions, effectivenessand safety can be established by the degree of health or recoveryachieved or retained at the peakor steady state,whichnormally includesdimensions such as freedom from disease and relevant aspects of func-tional status. To demonstrate this in comparativeness effectiveness stud-ies, WHO determines the precise scope and magnitude of the studiesbased on “residual uncertainty” about the product's biosimilarity.

The second level in Tier 2 is the treatment process. As dosage regi-men and duration of treatment are influenced by pharmacokineticand pharmacodynamics parameters, they aremeasured in all biosimilarclinical studies. WHO acknowledges that, “in certain circumstances,”these studies “may provide sufficient clinical data to support a demonstra-tion of biosimilarity.” Applicants must scientifically justify all aspects oftheir study design, including temporal length of the study, selection ofsubjects, dosage levels, and route of administration.

Outcomes to measure sustainability of health (Tier 3) are divided intwo levels. The first level includes recurrences of original disease mani-festations and/or longer-term complications. The second level capturesnew health problems created as a consequence of treatment. When re-currences or new illnesses occur (as a treatment consequence), all out-comes must be remeasured.

Measurement, in the case of Tier 3, can also explicitly comparetradeoffs among outcomes. For example, achieving more complete re-covery may require more concentrated treatment and/or confer ahigher risk of complications, as immunogenicity. Mapping thesetradeoffs, and seeking ways to reduce them, is an essential part of thecare-innovation process for the biosimilar-value chain, although evi-dence regarding their potential risks is still scarce.

Measurement efforts for biosimilar-value should begin with at leastone outcome dimension at each tier, and ideally one at each level. As ex-perience increases and available data infrastructure grow, the numberof dimensions (and measures) can be expanded. However, they maybe anchored to WHO recommendations for clinical studies, as theywill guide the regulatory aspects.

Regulatory aspectsGuidelines established by WHO's Expert Committee on Biological

Standardization (ECBS) serves as a basis for establishing national re-quirements for production, quality control, and general regulation of bi-ologic medicines [23,24]. An increasing range of biosimilars are beingdeveloped and licensed in many countries, and the WHO formally rec-ognized the general need for evaluation and regulation guidelines in2007 [25]. EMA and FDA have issued formal guidelines and guidancesdiscussing their characterization, assessments of PK/PD, determinationof similar efficacy, immunogenicity and comparable safety. Only anoriginal product that was licensed with a complete dossier can serveas a BRP. This does not refer to measurement standards such as interna-tional, pharmacopoeial, and national standards or benchmarks.

Aspects related to the product's qualityWHO guidelines state that the quality comparison showingmolecu-

lar similarity is indispensable to provide justification for prediction thatthe safety profile and clinical efficacy of the BRP will apply to thebiosimilar. Small differences in manufacturing processes can affect gly-cosylation patterns and thus pharmacokinetics, pharmacodynamics, ef-ficacy, immunogenicity and/or safety of biosimilars.

Ideally, the development of a biosimilar involves a complete analysisof the BRP, followed by engineering of amanufacturing process that pro-duces a product that is very similar to the BRP in all attributes that couldimpact its clinical performance. A biosimilar is derived from an indepen-dent cell line, using newer manufacturing processes, independent con-trols and more sophisticated characterization processes that wereavailable for the reference product. Extensive knowledge about the rela-tionships between the biochemical, physico-chemical, and biologicalproperties of the product and its clinical results facilitates developmentof a biosimilar. To compare and assess biosimilarity, the manufacturer





should perform a complete physico-chemical and biological analysis ofthebiosimilar andcompare itwith theBRP. All aspects of product qualityand heterogeneity should be assessed. A complete quality dossier ofboth medications and active ingredients is always necessary, whichmeets standards required by the National Regulatory Agencies (NRAs)for BRPs.

The primary structure of the biosimilar and BRP must be identical.The learning curve for biosimilars is essentially still building in US buthas been established in Europe based on recent approval of a monoclo-nal anti-TNF.

2.6. Knowledge replication

The capacity to replicate knowledge may improve the efficacy andefficiency of biologic interventions and the decision regarding incorpo-ration of biosimilars into a therapeutic armamentarium. To addressthese issues, WHO defines the attributes that should be included in allbiosimilar studies:

a. The need for comparison to the BRPb. Design of efficacy studiesc. Characteristics of safety studies including immunogenicityd. Definition of extrapolation to original indications for the BRPe. Pharmacovigilance and traceability planf. Need to differentiate between labels and information

These attributes are the knowledge that must be shared or trans-ferred to provide a template or guideline for decisions and actions re-garding biosimilar use. Knowledge replication includes identificationof attributes that are replicable, how these attributes can be recreated,and characteristics of the contexts in which they can be replicatedsuccessfully.

The need for the biological reference products during comparisonAccording toWHOguidelines, the BRP is crucial for the licensing of a

biosimilar. Complete information on the BRP provides the basis for es-tablishing the safety, quality, and effectiveness standards to which thebiosimilar is compared, but this characterization must be made by thedeveloper of the biosimilar since such information remains confidentialbetween the originator of the BRP and regulatory agencies. The BRP alsoprovides the standards for dosage and administration methods, andmust be used in comparison studies required to support licensing. Thesame BRP should be used throughout all testing.

When submitting to the National Regulatory Agency (NRA), thebiosimilar manufacturer should provide justification for its choice ofBRP. Traditionally, the NRA has requested the use of a nationally li-censed reference product for the licensing of generic drugs, as alsotrue for biosimilars. The chosen BRP should have been marketed foran appropriate period and have a large volume of commercial use sothat demonstration of similarity supplies a substantial body of data inrelation to acceptable safety and efficacy. More importantly, the BRPmust be licensed based on data demonstrating complete quality, safetyand efficacy.

Design of efficacy studiesWHO guidelines state that the efficacy between biosimilar and the

BRP must be demonstrated in randomized controlled clinical trial(s)with adequate statistical evidence. Clinical trials are preferably doubleblind, or at least observer-blind. In the absence of blinding, a carefuland complete justification will be required to demonstrate that thestudy results are free of significant bias.

Equivalence definitions (which require 95% confidence intervals forlower and upper limits of comparison) must be clearly defined forcomparisons of efficacy, pharmacokinetics and immunogenicity. Non-inferiority testingdesigns (which require only one limit)maybe consid-ered if justified on the basis of clinical relevance, but typicallywill not besufficiently stringent. The limits selected should be based on prior


randomized clinical trials of the BRP and represent the greatest differ-ence in efficacy that would not be of consequence in clinical practice.Treatment differences within this limit would then be, by definition, ac-ceptable because they should not be clinically relevant.

Characteristics of safety studies including immunogenicityWHOguidelines declare that the pre-licensing safety datamust be ob-

tained via testing on a sufficient number of patients to adequately charac-terize the safety profile of the biosimilar. The comparison with the BRPshould include the type, frequency and severity of events/adverse reac-tions. For cases inwhich similarity is demonstrated in confirmatory phar-macokinetics/pharmacodynamics studies and safety data relevant to thetarget population cannot be deduced, it is still necessary to provide drugsafety data in the target population.

In addition, biosimilar safety information must be comparative. It isexpected that the data obtained from randomized controlled trialsshould detect both frequent and short-term adverse reactions. Thisdata is usually sufficient for pre-licensing, but in general, closemonitor-ing of clinical safety in the post-commercialization phases is necessaryas well.

The immunogenicity of biologic products should always be investi-gated prior to licensing. Even if the efficacy and safety of a biosimilarand a BRP are proved to be similar, immunogenicity may still differ. Im-munogenicity is the ability of substance to activate an immune responseor reaction, such as the development of specific antibodies, T cell re-sponses, allergic or anaphylactic reactions and infusion or injectionsite reactions. The formulation, the recipient, manufacturing or storageconditions of monoclonal antibodies may influence the product's im-munogenicity profile thereby modifying the protein's conformationalstructure and/or extraction of impurities which can act as immunologi-cal adjuvants or provoke alterations such as aggregation formation.

The European Medicines Agency (EMA) launched in 2012 a guide-line related to the monoclonal antibodies (guideline on immunogenicityassessment of monoclonal antibodies intended for in vivo clinical use)[26]. The European guideline focusesmainly on aspects related to unde-sired immunogenicity risks with use of monoclonal antibodies (mAbs).The European Medicines Agency recommends that the companiesrequesting monoclonal antibodies (mAbs) registrations show a RiskManagement Plan (RMP) to guarantee not only risk identification andcharacterization, but also risk minimizing, monitoring and mitigationstrategies for post-marketing surveillance. Similar requirements are ev-ident in recently issued FDA guidance documents.

Definitions of extrapolation to original labeled indications of the BRPWHO guidelines state that, if the similarity between the biosimilar

and BRP is convincingly demonstrated, the biosimilar can be approvedfor use for other clinical indications in which the biosimilar was not di-rectly tested as long as themanufacturer provides appropriate scientificjustification for such an extrapolation. The following conditionsmust bemet: a model of sensitive clinical testing should be used that is able todetect potential differences between the biosimilar and the BRP; themechanism of action must be clinically relevant and highly similarand/or have the same receptor(s) involved; the safety and immunoge-nicity of the biosimilar must have been sufficiently characterized andhave no safety issues for which clinical data is not supplied; if the effica-cy trial used a non-inferiority design and demonstrated acceptable safe-ty and efficacy of the biosimilar compared with the BRP, the biosimilarapplicant must provide convincing arguments that the findings can beapplied to extrapolated indications. If these pre-requirements are notmet, then themanufacturer must submit their own clinical data to sup-port each desired indications.

Pharmacovigilance and traceability planThe WHO guideline is categorical about the need for careful moni-

toring in addition to determination of clinical safety of these products





in all approved indications and ongoing risk-benefit evaluation in thepost-commercialization phase.

The manufacturer should submit a safety and pharmacovigilanceplanwhen submitting the request formarketing authorization. It shouldbe in accordancewith the principles of pharmacovigilance plan found inrelevant guidelines such as the ICHE2E [27]. Safety specifications shoulddescribe the BRP's potential or known safety issues, the class of sub-stance and/or any other information specific to the biosimilar. Thepharmacovigilance plan should specify activities and planned post-commercialization methods based on security specifications. Measuresto minimize risks such as educational material for patients and/or phy-sicians can be expected to enhance safe use of the biosimilar.

Any specific safety monitoring imposed on the BRP or class of prod-uct should be incorporated into the pharmacovigilance plan for thebiosimilar. Moreover, additional potential risks identified during analy-ses of biosimilar testing results should be subject to additional surveil-lance procedures. Post-commercialization surveillance reports shouldinclude all information about the tolerability of the product receivedby the holder of the commercial authorization. Information should beevaluated scientifically and should include the frequency and causalityof adverse events.

At the time ofmarketing authorization,manufacturersmust guaran-tee that they have an appropriate pharmacovigilance system in place,including services of a qualified person responsible for monitoringpharmacovigilance and the necessary means for notification to regula-tory authorities of adverse reactions that may occur in any countrywhere the product is marketed. After the marketing authorization isgiven, it is the NRA's responsibility to closely monitor the manufac-turers' compliance with their responsibilities, and particularly, theirpharmacovigilance obligations.

Furthermore, as with any biological product, an adequate systemis required to guarantee specific biosimilar identification (i.e. trace-ability). The NRA should provide an adequate legal framework forpharmacovigilance and ensure the ability to identify any biologicagent marketed in its territory that is subject to adverse reaction re-ports. This implies that an adverse reaction report for any biologicproduct must include International Nonproprietary Name (INN)[28], as well as other important indicators such as the owner name(brand), manufacturer, batch number, and country of origin.

The need to differentiate between labels and informationBiosimilars should be clearly identifiable by a unique trademark.

When an International Nonproprietary Name (INN) is set, the INNshould also be mentioned. WHO policy for INNs should be followed.The provision of a batch number is essential, since this is an importantpart of the manufacturing information and is critical for traceability incases where problems are encountered in a product.

Prescription information for the biosimilar should be as similar aspossible to the BRP's. This is particularly important for dosage andsafety-related information, including contraindications, warnings andadverse side effects. However, if the biosimilar is less prescribed thanthe BRP, several sections of the text can be omitted, unless it is impor-tant to inform doctors and patients about certain risks due to, for exam-ple, off-label use. In such cases, the prescription information shouldclearly state that the biosimilar is not indicated for use in specific situa-tions and state the reasons why.

2.8. Knowledge performance and innovation

The assessment of knowledge performance is the capacity to assessto what extent the replication of knowledge delivers desired outputsand outcomes. The innovation capability is the capacity to develop abetter understanding of the knowledge application process to achievesuperior outcomes for the final beneficiaries of knowledge translation.It will be related to the criteria that each public health organizationwill use to define value of biosimilars.


The opportunity afforded by biosimilars can be considered from twodifferent standpoints: either as ameans of protecting current value or asa source for new value generation. Unlocking the potential ofbiosimilars will require a focused strategy along the entire value chain,from optimizing the clinical development program through developingthe most suitable strategy for commercialization. Balancing the trade-offs between in-house versus strategic alliances will be essential forachieving cost efficiencies and speeding up time tomarket, with furthertailoring by geography to cope with a heterogeneous landscape. Entryinto pharmerging markets, as Latin America, for example, will bestrongly governed by partnerships with local players.

3. What are the criteria to value biosimilars?

3.1. EMA judgment value criteria

The European Medicines Agency is responsible for conducting eval-uation of marketing authorization applications for drugs in Europeancountries. The European Union (EU) has the most advanced biosimilarregulatory framework with global guidance and specific guidance forthe products. European Medicines Agency (EMA) issued a guidelineoutlining the regulation of monoclonal antibodies in 2012 which fo-cusedmainly on aspects related to risk estimation of undesirable immu-nogenicity (immune response) with clinical use of monoclonalantibodies (mAbs) [29]. Recently, EMA recommended marketing ap-proval for an anti-TNFmAb biosimilar, with extrapolation to all current-ly approved indications for the BRP.

3.2. USA judgment value criteria

On February 9, 2012, the United States Food and Drug Administra-tion (FDA) issued three draft guidance documents, outlining approachesfor demonstration of biosimilarity, under Section 351(k) of PublicHealth Services Act of the Biologic Price Competition and InnovationAct of 2009. These guidances are in accordance with guidelines issuedby EMA and WHO [30].

3.3. Latin America judgment value criteria

The regulations of Argentina, Peru, Chile, Guatemala, Panama andCosta Rica follow WHO guidelines. Other countries, such as Cuba,Mexico, Venezuela and Brazil, have regulations that take into account in-ternational standards combined with local features. In Colombia, a draftdecree is under revision and the debate is ongoing. Some countries havealready approved SBPs. Mexico, Chile, Ecuador, Bolivia, and Peru marketSBPs of rituximab, and Colombia markets an SBP of etanercept [31].

3.4. Brazil judgment value criteria

On December 17, 2010, the Collegiate Board of Directors of the Na-tional Health Surveillance Agency (ANVISA) published the CollegiateBoard of Directors' Resolution [RDC] no. 55 with the purpose of estab-lishing the minimum requirements for registration of “new biologicproducts” and “biologic products” in the country to assure the quality,safety, and efficacy of these agents [32]. RDC no. 55 establishes two dif-ferent regulatory measures for product registration. One measure forthe development by comparison “that may be used by a biologic prod-uct to obtain registration before the regulatory authority in which thepractice of comparison was used in terms of quality, efficacy and safety,between the product developed to be the compared and the comparatorbiologic product”. Another method is called individual developmentmeasure, “that may be used by a biologic product to obtain registrationbefore the regulatory authority in which the submission of total dataon development, production, quality control, and non-clinical and clini-cal data is required to demonstrate quality, efficacy and safety of theproduct in compliance with what is set forth by this Resolution.”





Some important items of RDC no. 55 of ANVISA are not in compli-ance with WHO recommendations. This Resolution does not provideclarification on the need of an identical molecular structure for abiosimilar in relation to BPR or on the definition of rules for biocompat-ibility determination.

An item of concern is related to the omission about conduct of phase3 comparative randomized clinical trials (non-inferiority, clinical equiv-alence, or superiority) for the registration of blood products, vaccines,and biologic products for oncology indication [33].

4. Final considerations

Biosimilar development is a long-term game. To achieve thebiosimilar-value chain, the knowledge-management strategy shouldaddress the five dyadic capabilities of knowledge-value chain and for-mulate objectives and success factors for each capability. However,each public health organization or communitywill arrive at its own par-ticular trade-offs between the five perspectives in order to achieve itsstrategic biosimilar-translation goals.

Consensus on biosimilars can bedeveloped for each public health or-ganization. This consensus can extend beyond the creation of a positionpaper. It can be a task force to build a knowledge platform regardingbiosimilar use to allow discussions of comparisons with biologic agents.

Other strategy to be considered is the development of decision sup-ports to help decision-makers understand the trade-offs posed bybiosimilars. Evidence shows that people have difficultiesmaking consis-tently good decisions when they are facing unfamiliar problems involv-ing value-based trade-offs between advantages and disadvantages ofalternatives. They are especially useful in situations that involve twoor more decisionmakers, a mixture of tangible and intangible consider-ations, or both. An effective market access strategy will be vital for suc-cessful entry: the value proposition is complex and will need to addressthe full range of stakeholders — including payers, physicians and pa-tients all of whose opinion will be critical.

Take-home messages

• Biosimilar development is a long-term game.• The knowledge-management strategy for biosimilar use should ad-dress the five dyadic capabilities.

• The biosimilar-value chain relies on measurement of comparability.• Differences in terminology might reflect how each country ismanaging — and valuating — biosimilars and the like.

• Regulatory pathways differ between countries.

References

[1] Porter M. What is value in health care? NEJM 2010;363(26):2477–81.[2] Porter ME. Defining and introducing value in health care. Evidence-based medicine

and the changing nature of health care: 2007 IOM annual meeting summary.Washington, DC: Institute of Medicine; 2008. p. 161–72.

[3] Leardini G, Rigon C. The impact of the profile of biologics on treatment costs.Autoimmun Rev 2013;12(8):842–7.

[4] Modena V, Bianchi G, Roccatello D. Cost-effectiveness of biologic treatment for rheu-matoid arthritis in clinical practice: an achievable target? Autoimmun Rev2013;12(8):835–8.

[5] Caorsi R, Federici S, Gattorno M. Biologic drugs in autoinflammatory syndromes.Autoimmun Rev 2012;12(1):81–6 [Review].


[6] Xiao Yann C, Wake A, Gouty D. Analytical and bioanalytical assay challenges to sup-port comparability studies for biosimilar drug development. Bioanalysis2013;5(5):517–20.

[7] Ben-Horin S, Kopylov U, Chowers Y. Optimizing anti-TNF treatments in inflammato-ry bowel disease. Autoimmun Rev 2014;13(1):24–30.

[8] Narayanan S, Kruse NA, Reichmann G, Thorpe R, Giezen C, Gravanis I, et al.Biosimilars: what clinicians should know. Blood 2012;120:5111–7.

[9] Engelberg AB, Kesselheim AS, Avorn 1 J. Balancing innovation, access, and profits —market exclusivity for biologics. N Engl J Med 2009;361:1917–9.

[10] Roccatello D. Novel diagnostic approaches and cost-benefit balance of treatment ofimmune-mediated and rare disease in the era of biologic drugs: lessons from the15th Turin Congress on Immune Pathology and Orphan Disease. Autoimmun Rev2013;12(8):793–5.

[11] Grabowski H, Cockburn I, Long G. The market for follow-on biologics: how will itevolve? Health Aff (Millwood) 2006;25:1291–301.

[12] Abreu MM, Gafni A, Ferraz MB. Development and testing of a decision board to helpclinicians present treatment options to lupus nephritis patients in Brazil. ArthritisRheum 2009;61:37–45.

[13] Cockburn I, Lerner J. The cost of capital for early-stage biotechnology ven-tures. In: Pisano G, editor. Science business: the promise, the reality andthe future of biotech. Cambridge, MA: Harvard Business School Press; 2006.p. 115.

[14] Landry R, Amara N, Pablos-Mendes A, Shademani R, Gold I. The knowledge-valuechain: a conceptual framework for knowledge translation in health. Bull WorldHealth Organ 2006;84:597–602.

[15] http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/06/WC500144124.pdf. [accessed 8/27/13].

[16] Brinks V, Hawe A, Basmeleh AH, Joachin-Rodriguez L, Haselberg R, SomsenGW, et al. Quality of original and biosimilar epoetin products. Pharm Res2011;28(2):386–93.

[17] Schneider CK. Biosimilars in rheumatology: the wind of change. Ann Rheum DisMarch 2013;72(3):315–8.

[18] Schneider CK, Schäffner-Dallmann G. Typical pitfalls in applications for marketingauthorization of biotechnological products in Europe. Nat Rev Drug Discov2008;7:893–9.

[19] Dörner T, Strand V, Castañeda-Hernández G, Ferraccioli G, Isaacs GI, Kvien TK, et al.The role of biosimilars in the treatment of rheumatic diseases. Ann Rheum Dis2013;72:322–8.

[20] Health Canada guidance document—comparative bioavailability standards: formula-tions used for systemic effects. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/bio/gd_standards_ld_normes-eng.php. [Accessed in October 2013].

[21] Scheinberg MA, Kay J. The advent of biosimilar therapies in rheumatology—“o bravenew world”. Nat Rev Rheumatol 2012;8:430–6.

[22] Institute of Medicine. Performance measurement: accelerating improvement.Washington, DC: National Academies Press; 2006.

[23] WHO reference materials for cytokines/growth factors and endocrinological sub-stances. http://www.who.int/bloodproducts/Catalogue/en/index.html.

[24] Elkayam O, Pavelka K. Biologic registries in rheumatology: lessons learnedand expectations for the future. Autoimmun Rev 2012;12(2):329–36[Review].

[25] Joung J, Robertson JS, Griffiths E, Knezevic I. WHO informal consultation on regula-tory evaluation of therapeutic biological medicinal products held atWHOHeadquar-ters, Geneva, 19–20 April 2007. Biologicals 2008;36(4):269–76.

[26] EuropeanMedicines Agency. Guideline on immunogenicity assessment of monoclo-nal antibodies intended for in vivo clinical use. Available in http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/11/WC500099362.pdf.

[27] ICH efficacy guidelines. Pharmacovigilance planning (E2E); 2004.[28] Meeting report on WHO informal consultation on international nonpropri-

etary names (INN) policy for biosimilar products, 4–5 September, Geneva,2006 (INN working report 07.211). http://www.who.int/medicines/services/inn/BiosimilarsINN_ReportSept2006.pdf.

[29] http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/06/WC500144941.pdf. [Accessed 12/10/13].

[30] http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. [Accessed 8/27/13].

[31] Desanvicente-Celis Z, Caro-Moreno J, Enciso-Zuluaga M, Anaya JM. Similarbiotherapeutic products in Latin America. Regulation and opportunities for patientswith autoimmune diseases. Biosimilars 2013;3:1–17.

[32] Centro Latino-Americano e do Caribe de Informação em Ciências da Saúde.Resolução – RDC n%º 55. Available from http://bvsms.saude.gov.br/bvs/saudelegis/anvisa/2010/anexo/anexo_res0055_16_12_2010.pdf . [AccessedOctober 26, 2013. Portuguese].

[33] Araujo DV. Consideraciones Regulatorias sobre Productos Biológicos em Brasil. ValueHealth Reg Issues 2012;1:254–6.




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