GIENSWORKSHOPS 2014/PHARMACOECONOMYThérapie

DOI: 10.2515/therapie/2015003

© 2015 Société Française de Pharmacologie et de Thérapeutique

† Articles, analyzes and proposal from Giens workshops are those of the authors and do not prejudice the position of their parent organization.

Biosimilars: from Technical to PharmacoeconomicConsiderationsDanièle Girault1, Jean-Hugues Trouvin2, Corinne Blachier-Poisson3, François Gary4, Didier Laloye5,and participants of round table N°3 of Giens XXX : Jean-François Bergmann6, Nicole Casadevall7 , Cécile Delval8,Rima De Sahb Berkovitch9, Jean-Yves Fagon10, Marta Gersberg11, Catherine Lassale12, Philippe Lechat13,Claire Le Jeunne14, Jean-Louis Montastruc15, Jean-Louis Prugnaud7, Christelle Ratignier-Carbonneil16

and Cécile Rey-Coquais17†

1 Laboratoire Novartis Pharma, Rueil Malmaison, France2 Université Paris Descartes, Faculté de Pharmacie, France3 Laboratoire Amgen, Neuilly-sur-Seine, France4 Laboratoire Sandoz, Levallois Perret, France5 Hospira France, Meudon la Forêt, France6 Hôpital Lariboisière, AP-HP, Paris, France7 Hôpital Saint Antoine, AP-HP, Paris, France8 ANSM, Saint Denis, France9 Laboratoire MSD, Courbevoie, France10 CEPS, HEGP, Paris, France11 Marta Gersberg Conseil, Chatou, France12 LEEM, Paris, France13 Hôpital Saint Louis, AP-HP, Paris, France14 Hôpital Cochin, AP-HP, Paris, France15 CHU ; Faculté de Médecine, Toulouse, France16 CNAMTS, Paris, France17 Laboratoire Pfizer, Paris, France

Text received January 8th, 2015; accepted January 12th, 2015

Abstract – A biosimilar is a biological medicinal product claimed to be similar to a reference biological medicinal product.Its development plan includes studies comparing it with the reference product in order to confirm its similarity in terms ofquality, preclinical safety, clinical efficacy, and clinical safety, including immunogenicity. Biosimilars differ from genericsboth in their molecular complexity and in the specific requirements that apply to them. Since patents on many biological medi-cinal products will expire within the next 5 years in major therapeutic areas such as oncology, rheumatology and gastroen-terology and as those products are so costly to the French national health insurance system, the availability of biosimilars wouldhave a considerable economic impact. The round table has issued a number of recommendations intended to ensure that theupcoming arrival of biosimilars on the market is a success, in which prescribing physicians would have a central role in infor-ming and reassuring patients, an efficient monitoring of the patients treated with biologicals would be set up and time to marketfor biosimilars would be speeded up.

Abbreviations: see end of article.

Keywords:biosimilarpharmaceuticals;traceability; riskmanagement;substitution;health care costs

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1. Introduction

Biosimilars became a topical issue and a matter of public inte-rest in France in September 2013 when an article in the 2014French Social Security Finance bill introduced the principle ofsubstitution by pharmacists for biosimilars. Having previouslyreceived relatively little attention, biosimilars suddenly became ahot topic, with public authorities, industry representatives, acade-mics and the media, all rushing to discuss the scientific issues andthe potential value of biosimilars in containing escalating healthcosts. In this controversial climate, the 2014 Giens meeting dedica-ted one of the round tables to address both the scientific and econo-mic aspects of biosimilars, listening to the points of view of all inte-rested parties, in order to propose a series of balancedrecommendations to help ensure that the upcoming arrival of biosi-milars on the French market would occur under optimal conditions.In the first part of this article, we describe the regulatory definitionof a biosimilar, an important prerequisite for understanding thesubject: this definition was proposed to make a clear distinctionbetween copies of chemical medicinal products (so-called gene-rics) and copies of biological medicinal products (so-called biosi-milars). This distinction has consequences for the development ofbiosimilars, which we set out in the second part. We then addressthe economic aspects: general financial issues, the problems sur-rounding market access in France, and the conditions required forsuccessful biosimilar market uptake, drawing on the lessons learntfrom previous experience with introduction of the generics for che-mical medicinal products. The article concludes with our fiverecommendations.

2. Definitions, origin of the concept of biosimi-lar medicinal products

Abiosimilar isabiologicalmedicinalproductclaimedtobesimi-lar to a “reference” biological medicinal product,[1] the quality,safety, and efficacy profile of which has been proved, through anappropriate development plan, to be “similar” to the profile of thereference product. Because a copy of a biological molecule can onlybe similar, rather than strictly identical to the reference product, dueto differences in the biological source and the manufacturing process,it is called a “biosimilar”, a contraction of the official term given inArticle 10 of European Directive 2001/83/EC:[2] “biological medi-cinal product which is similar to a reference biological product”.

The European Commission and its groups of experts proposed,along with the “biosimilar” status, the concept of comparabilityand a development approach that is more demanding than the onethat applies to developing a generic medicinal products: “where abiological product which is similar to a reference biological pro-duct does not meet the conditions in the definition of generic medi-cinal products, owing to, in particular, differences relating to rawmaterials or differences in manufacturing processes of the biological

medicinal product and the reference biological medicinal product,the results of appropriate pre-clinical tests or clinical trials rela-ting to these conditions must be provided”.[2] This wording makesa clear distinction between generics and biosimilars, and stipulatesthat the development plan for a biological medicinal productrequires more supporting studies than required for a generic (thelatter being essentially based on the identity of the chemical mole-cule and proof of bioequivalence), mainly to take account of theintrinsic variability of these complex molecules (see below).

This definition of biosimilars therefore makes a clear distinc-tion between copies of chemical medicinal products and copies ofbiological medicinal products and has implications for patient andprescriber information, substitution or interchangeability andfinally on traceability and medical records, as discussed at theGiens round table.

As theEuropeanMedicinesAgency(EMA)states, “Abiosimilarmedicine is a biological medicine that is developed to be similar to anexisting biological medicine (the ‘reference medicine’). Biosimilarsare not the same as generics, which have simpler chemical structuresand are considered to be identical to their reference medicines”.[3]

To understand the term “biosimilar”, proposed for copies ofactive substances of biological origin, it is important to know thedefinition of a biological medicine and a number of physicochemi-cal, biological and structural characteristics of these molecules thatmake them more difficult to copy.

2.1. Definition of a biological medicinal product

Biological medicinal products are defined in Annex 1, Part I ofEuropean Directive 2001/83/EN:[1] “A biological medicinal pro-duct is a product, the active substance of which is a biological subs-tance. A biological substance is a substance that is produced by orextracted from a biological source and that needs for its characte-risation and the determination of its quality (quality profile, inclu-ding impurities, variants, degradation products, etc.) a combinationof physico-chemical-biological testing, together with the produc-tion process and its control”. This definition confirms the well-known dogma that holds that a biological substance is described inpart by the process through which it is obtained, or in other words“the process makes the product”.

From a regulatory perspective, the classification of a product asa biological medicinal product requires specific variables to bemeasured to determine its quality, given the molecular complexityof these substances and the processes through which they are deri-ved. The final quality and inter-lot reproducibility of biologicalproducts are more difficult to control and demonstrate than for che-mically synthesized products.

2.2. The particularities of biological molecules

Active substances of biological origin feature a series of charac-teristics both at the molecular level and as regards their manufacturing

Biosimilars: from Technical to Pharmacoeconomiy 3

process that set them apart from small chemical entities.[4] Firstly,biological substances are macromolecules with a molecular massranging from tens to one hundred kilodaltons (whereas the molecu-lar mass of aspirin, a well-known small chemical entity, forexample is 180 daltons) leading to molecular structures that are 20to 800 times more complex than chemical substances. Such macro-molecules cannot be synthesized chemically and require the use ofa biological source. Biological medicines are mostly proteins (hor-mones, cytokines, growth factors, monoclonal antibodies),although a few are complex glycans (heparin, low molecular massheparin). Their three-dimensional spatial organization must bemaintained in order to keep their biological activity, whereas che-mically synthesized molecules have a flat structure with much lessflexibility.

In addition to their basic molecular structure, additional attri-butes that add further level of complexity, and especially for pro-teins, must be mentioned, such as glycosylation, sulfation, amida-tion, and disulfide bridges. These structural modifications are madeduring the process of biosynthesis in the producing cells, leading todiversity and variability in the molecules produced, termed “micro-heterogeneity”. This means that a single production lot containsvarious “isoforms” and “variants”, the qualitative and quantitativedistribution of which will vary and the limits of this variability hasto be managed and controlled through appropriate process controltests and end-product testing. Thus, the concept of a “single mole-cule” that applies to chemical active substances, cannot be appliedto biological substances, and instead one must think of the productas a “molecular population” of the molecule of interest. Many ofthe issues and challenges posed by biological medicines thereforerely on controlling the molecular profile, intrinsic variability, andreproducibility for each production campaign. It is important tomaintain consistency in the quality profile, despite its complexityand microheterogeneity, because it determines two importantaspects of the product clinical profile:– the efficacy profile and therapeutic response, which depend onmaintaining the molecule three-dimensional structure and, whereappropriate, its glycosylation profile, and more generally its qua-lity attributes. Differences in glycosylation profile, or poor glyco-sylation pattern, or partial degradation during purification orformulation and storage, may impact negatively the efficacy andsafety profile, although these molecular alterations may not be de-tected by the analytical procedures applied during the control testsperformed on each lot of production of the medicine;– the safety profile and especially the risk of immunologicalreactions: macromolecules can be immunogenic, especially whenthe exogenous molecule contains “non-self” motifs. This immuno-genic potential, when administered to humans, must be checked,because any immune reaction could have adverse effects, rangingfrom loss of activity (due to the development of neutralizing anti-bodies) to intolerance (especially hypersensitivity or anaphylaxis),although the development of antibodies does not systematicallyresult in loss of activity or intolerance. In addition to this intrinsic

immunogenicity, which in most cases would already have been ex-tensively documented through the clinical experience acquiredwith the reference biological medicinal product, there is a risk ofdeveloping a “neo-antigenic” profile, due to the presence of newantigenic motifs on the copied molecule, generated by modifica-tion of its molecular profile, usually through a less suited produc-tion/purification process, or a poor pharmaceutical formulation,leading to potential degradation during process or storage of themedicinal product (see below). This risk cannot always be detec-ted by standard analytical procedures but will be detected by thepatient’s immune system capable to detect such neo-epitopeswhich may then disrupt the immunological tolerance previouslydeveloped to the reference product of acceptable quality.

The biological source from which these biological substancesare produced or extracted also causes variability in the quality pro-file. The development of a biosimilar requires the development ofa new manufacturing process, which may differ considerably fromthe process used by the manufacturer of the reference product: forexample, for recombinant proteins, there could be differences in theexpression system and in particular the genetically modified cellline, production conditions, culture media, or contact time. Theextraction or purification conditions selected by the new manufac-turer may also differ, depending on the company’s experience andknow-how in biological engineering processes.

As mentioned above, these differences in the production pro-cess may have significant effects on the quality profile, and theirimpact on safety and efficacy must be determined.

One final factor to take into account is the difficulty in charac-terizing, analyzing, and testing, for each production batch, themany quality parameters that qualify the “molecular population”profile described above. The tests performed prior to release eachlot of a medicinal product intended for clinical use must be capableto verify and confirm these various quality attributes, qualitativelyand quantitatively. No single analytical procedure can test the entireprofile and, as the European definition stipulates, “a combination ofphysico-chemical-biological testing” will have to be used, espe-cially since, despite advances in analytical methods, some areas ofthe molecule remain inaccessible to routinely used analyticalmethods and to the detection of small differences that occasionallyoccur, in particular from one production lot to another. In conclu-sion, each lot will exhibit a degree of “intrinsic variability” that canbe neither predicted nor verified, and the only way to ensure thatinter-lot variability does not exceed acceptable limits is throughprocess control and validation of critical steps. The problems posedby the analysis of biological products also apply to the “compara-bility exercise” to compare the quality profiles of a biosimilar andits reference product (cf. section 3).

To summarize, biological substances differ from substances ofchemical origin in their complex structure and microheterogeneity,their production process, and the complexity of the analyticalmethods required for their characterization and quality control.This complexity results in inter-lot “variability”, which must be

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controlled to ensure that it does not compromise the efficacy andsafety profile when either the reference medicine or its biosimilaris administered to patients.

3. The development of a biosimilar and stillpending issues

Marketing authorization (MA) applications for biosimilarsmust meet the regulatory requirement of Article 10 of the direc-tive[2] that states that “the results of appropriate pre-clinical testsor clinical trials relating to these conditions must be provided”.

The development of biosimilars mainly involves demonstra-ting the “pharmaceutical quality” of the biosimilar, in which thedeveloper must establish and describe the new production and puri-fication process, and quality control strategy in order to show thatit is capable of producing the therapeutic “copy” in a reproduciblemanner and to an acceptable quality standard. The copy must thenbe compared with the original “reference” molecule to show that,under these new production conditions, the copy is similar to thereference molecule. This comparability exercise endeavors to iden-tify all the possible differences in all the “quality attributes” thatdefine the purity and biological activity profile.

The comparability exercise must use the entire battery of ana-lytical methods mentioned above, using specific and sensitivemethods to estimate the degree of “similarity” between the biosimi-lar and the reference molecule. The applicable regulations and gui-delines[1,3,5,6] clearly specify that the quality attributes of the bio-similar are not expected to be identical to those of the referenceproduct. Indeed, if the production process uses a different biologi-cal source (for example if the producing cell line is from anotheranimal species) the impurities generated by the process will differboth qualitatively and quantitatively. Many other molecular charac-teristics may also differ, such as the glycosylation profile or the pro-portion of N-terminal and C-terminal amino acid sequencevariants, in particular for monoclonal antibodies. This is clearlyillustrated in the European Public Assessment Report (EPAR) onthe biosimilars Inflectra® and Remsima®, which are copies of themonoclonal antibody infliximab (Remicade®) used as the refe-rence medicinal product.[7]

Once the originator and biosimilar molecules have been com-pared and the molecular differences identified, the nonclinical andclinical development plan of the biosimilar will be adapted accor-dingly to demonstrate that these differences do not alter the efficacyand safety profile. The nonclinical and clinical studies will essenti-ally compare the reference molecule with its biosimilar, includingmeasurement of the relevant pharmacodynamic and pharmacoki-netic parameters, in both in vitro or animal studies and one or moreclinical pharmacology/pharmacokinetic studies or sometimes a cli-nical efficacy study, in a population sensitive enough to detect dif-ferences in efficacy or safety with a relatively limited sample size.The requirements in terms of clinical studies vary depending on the

class of product, its molecular complexity and the degree of simi-larity established between the originator and the biosimilar.

For reference products licensed for several indications, there isalso the issue of the legitimacy of granting MA to the biosimilar forall of these indications when the clinical development only investi-gated its efficacy/safety profile in one indication. This issue hasbeen debated at length in the various guidelines and again veryrecently.[8] It is most controversial when the indications involvedifferent physiological systems (rheumatology, gastroenterologyand dermatology, for example) and when the clinical trial todemonstrate equivalence was conducted in an indication that onlyrepresents one of the systems concerned. The same is true whendifferent populations are concerned, such as adult and pediatricindications. The most recent example of debate around extrapola-tion of indications can be found with the biosimilar of infliximab.[7]

The development plan of a biosimilar is therefore based on thenotion of comparative studies at the three levels of quality, safety,and efficacy in order to confirm that the differences observed in thequality profile of the drug substance and/or drug product will haveno impact on the clinical efficacy and safety profile establishedmany years earlier for the reference product. However, such a deve-lopment plan does not evaluate other aspects such as, in particularthe risk of immunogenicity when substituting one product for theother or when alternating products, for example switching a patientwho has been using the reference product to a biosimilar, switchingback to the original product several months later, or switching to anew biosimilar of the same reference product.

The risks of cross-immunogenicity induced by switching, thata substitution policy would enable are not currently covered by thedevelopment plans proposed in the European guidelines. This sug-gests that active surveillance should be put in place when biosimi-lars enter the market. It is noteworthy that this risk is taken onboardin the risk management plan scheduled for the biosimilar of inflixi-mab.[7] As regards the risk management plan, in addition to thepotential risk of immunogenicity, usually associated with biologi-cal drugs, it is important to bear in mind that, unlike generic drugs,biosimilars are considered “new medicinal products” and therefore,when MA is granting, obligations are imposed to establish a speci-fic pharmacovigilance plan, including traceability and post-marke-ting surveillance, to compensate for the uncertainties identified atthe time of evaluation.

All of these scientific and regulatory requirements imposed onthe development of a biosimilar clearly show that we are dealingwith a new type of “copy” that is very different from a generic drug.The specific regulations that apply to biosimilars make them muchcheaper to develop than the reference drug (a limited number ofnonclinical studies are performed and the clinical developmentconsists only of pharmacodynamic/pharmacokinetic and phase 3studies in a “model” indication) but much more expensive to deve-lop than a generic drug, on account of these additional nonclinicaland clinical studies, on top of the expense of developing a new pro-duction system for a complex biological molecule. As a rough

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Biosimilars: from Technical to Pharmacoeconomiy 5

indication, it costs € 3-5 million to submit an MA applicationfor a generic drug, € 100-250 million for a biosimilar and€ 1 000 million for the complete development of a new molecule.With the current financial pressure on European health systems, theappeal of drugs that cost less to develop but have an equivalent risk-benefit profile is obvious.

4. Biosimilars: an economic opportunity

The French healthcare system faces the two-fold challenge ofdemand for health spending rising faster than gross domestic pro-duct (GDP) and a structural deficit for the past 30 years. In thiscontext, any medical technology that offers equivalent medicalbenefit at a lower cost will be welcomed by payers.

The innovative biological medicines (hereafter named “biolo-gicals”) market is now a major economic issue in France andEurope. Eight of the top ten drugs by turnover in France’s hospitalsector and four in the retail pharmacy sector are biologicals. Totalturnover for biologicals in France was € 7 billion in 2013, represen-ting a 2.5% increase on 2012, despite the recession in the market asa whole.[9] The number of biological medicines registered is alsoincreasing every year (173 in 2013 versus 115 in 2004), with theadvent of increasingly innovative biologicals for the treatment ofcostly diseases (cancer, autoimmune diseases, etc.).

The commercialization of biosimilars for these costly diseasesoffers two economic advantages in the short term: it broadens therange of products available, including similar drugs at a lower pricefor biologicals dispensed by retail pharmacies, and it stimulatescompetition thereby driving down the prices of originator drugs. Inthe long term, it encourages pharmaceutical companies that deve-lop originator drugs to continue their research and develop futureinnovations.

The first biosimilars were introduced in France in 2007 andhave already generated savings. Biosimilar penetration by volumerepresents: 35% for growth hormone with respect to the referencemolecule and 13% of the whole class; 75% for granulocyte colonystimulating factor (GCSF) with respect to the reference moleculeand 20% of the class; and 36% for erythropoietins for the referencemolecule and 10% of the class. These figures show that biosimilarshave taken a significant market share and clearly signal growingconfidence in biosimilars among physicians and pharmacists. It isnoteworthy that in France, unlike other European countries such asGermany, no specific incentives were introduced to foster the deve-lopment of these first biosimilars.

But the major economic advantage of biosimilars for our heal-thcare system is still to come, because the patents on the biologicalswith the highest turnover are due to expire within the next 3 to5 years. Most of these are monoclonal antibodies used in a varietyof therapeutic areas such as oncology, hematology, rheumatology,and gastroenterology, in which the launch of the originator pro-ducts in the last ten years transformed the treatment of these

diseases. It is difficult to evaluate the potential savings these biosi-milars could provide because they depend on pricing policies andincentives.

5. Market access for biosimilars:are new rules necessary?

Although the rules for granting MA for biosimilars are specificand distinct from those applying to generics, the opportunity of aspecific procedure for market access has yet to be addressed. Todate, neither the French National Authority for Health (Haute Auto-rité de Santé, HAS), whose Transparency Committee issues opi-nions on reimbursement to the Minister of Health, nor the FrenchEconomic Committee on Healthcare Products (Comité Econo-mique des Produits de Santé, CEPS) in charge of pricing policy forreimbursable drugs has a specific policy on biosimilars.

The Transparency Committee currently applies the same eva-luation rules to biosimilars as to any new molecule. Whereas ageneric, if identical to an originator drug, is exempt from evaluationby the Transparency Committee, allowing pricing negotiations tostart immediately after MA to accelerate market introduction, nosuch fast-track procedure exists or is under consideration for biosi-milars. The Transparency Committee has only evaluated eight bio-similars so far. As per current policy, they were evaluated as newmedicinal products through a simplified procedure. The Transpa-rency Committee’s assessment in each of these eight cases was thesame: the actual benefit (service médical rendu, SMR) was identi-cal to the reference biological medicine and the rating was noimprovement in actual benefit versus the reference product (amé-lioration du service médical rendu, ASMR). This approach is bothconsistent (all biosimilars are treated the same) and logical (they

Fig. 1. Key factors for the success of biosimilars.

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6 Girault et al.

are “copies” of a reference product). As the number of biosimilarswill increase and more long-term data be collected, the HAS’s posi-tion could change, leading to the development of a specific andeven simplified procedure for biosimilars.

The CEPS has yet to set a pricing policy for retail biosimilars.For hospital biosimilars, current guidelines are to reduce the priceof the reference product by 10%, to align the price of the biosimilar,and to review the price of the biosimilar soon after (one year later).The final pricing policy adopted will depend on how biosimilars areevaluated by the HTA body. The two options could be either as newproducts that provide no improvement versus existing treatments(ASMR 5), or as pure generics. Is there a need for a third optionwith specific rules to be created?

The costs involved in developing biosimilars are unlikely toallow alignment with the rules on generics (launch price 60% lowerthan the originator product). But it seems important to providestable, transparent rules so that manufacturers can predict the via-bility and sustainability of developing and launching a biosimilaron the French market. A new pricing model (launch price and long-term policy) therefore needs to be considered.

6. What is required for the successfulintroduction of biosimilars in France?

To answer this question, it is interesting to analyze past expe-rience with generics and learn from both the successes and the fai-lures.

Since their introduction in France in the 1980s, generics havesuffered from a lack of recognition by both the health care profes-sionals and patients. France is one of the last remaining countriesin the world where the quality and sometimes even the efficacy ofgeneric drugs are questioned. Even today “generics still have lowermarket shares than in neighboring Germany or England”.[10]

Looking back, it is clear that several factors contributed to thissituation: the lack of consistent information from scientific andpublic authorities aimed at health care professionals and patients toreassure them about the quality of generics; the focus on economicrationale; the inconsistent messages given to the public; the ten-dency for French physicians to prescribe new drugs (referred to asthe “structure effect” in the 2013 CEPS report); the reluctance oflearned societies; the restricting effect of the repertoire or “positivelist” the lack of incentives for physicians. The development ofgenerics in France was mainly relying on the right of the pharma-cists to substitute generics for originator drugs through financialincentives and on incentives for patients to accept generic substitu-tion Thus, the relative failure of France’s generics policy was dueto its focus on financial incentives and the complete lack of posi-tive, educational information provided by public authorities.

Biosimilars were first mentioned in French health policy in theCEPS/LEEM (LEEM is French pharmaceutical industry association,Les Entreprises du Médicament) framework agreement, signed on

December 5th, 2012,[11] which stated that “the signatories acknowle-dge the strong opportunity that biosimilars represent contributingto the funding of therapeutic innovation”.

The French Strategic Council for Healthcare Industries(Conseil Stratégique des Industries de Santé [CSIS] July 5th,2013), reactivated under the leadership of the Prime Minister, sum-marized the combined objectives of a biosimilars policy to set up(measure 13: Biosimilars):[12] “To ensure patient safety while pro-viding savings for the national health care system and enabling thedevelopment of biosimilars market in France”. The proposed inter-ventions included “Establishing a specific framework that wouldfacilitate biosimilars commercialization on the French market, andexpand their use among prescribers and patients”.

The fact that Article 47 of the 2014 French Social SecurityBudget Law (Loi de Financement de la Sécurité Sociale, LFSS)introduced the possibility of allowing pharmacists to deliver a bio-similar instead of the reference biological medicine at initiation oftreatment, even before the CSIS’s working group has been set up,accelerated the involvement of each stakeholder on this topic. Theuse of terms such as “reference list of groups of similar biologicaldrugs” and the “right to substitute” created confusion with genericsand raised concerns that the same mistakes would be made.[13]

In September 2013, the French National Agency for Medicinesand Health Products Safety (Agence Nationale de Sécurité duMédicament et des Produits de Santé, ANSM) published a reporton biosimilars and recommended that “once a product has beenadministered to a patient it must not be switched, in order to mini-mize the risk of immunization and ensure traceability forpharmacovigilance follow-up”.[14]

The CSIS Biosimilars working group, which started meetingin early 2014 and brings together manufacturers, the Ministries ofHealth and Industry, health agencies, the French National HealthInsurance Fund (Caisse Nationale d’Assurance Maladie, CNAM)and health care professionals, identified the technical and practicalhurdles to an optimal introduction of the “substitution right”, butabove all emphasized the need to create a favorable environmentfor prescribing and dispensing biosimilars, relying mainly on themedical profession in order to build patient confidence in these pro-ducts. Introducing the right to substitute in retail pharmacies from2014 was premature and could have been counterproductive.

In the Giens round table, as in the CSIS working group, therewas consensus to support the idea that physicians are the corner-stone to inform and reassure patients, both at the start of treatmentand for any switching once treatment is underway.

One major initiative to support health professionals in theirefforts to build confidence in biosimilars would be for public autho-rities to issue information and documentations about these pro-ducts, adapted to each targeted audience (health care professionalsor patients), with the involvement of learned societies and patients’associations, that would be provided by all of the players inFrance’s healthcare system (ANSM, HAS, Ministry of Health,CNAM, complementary health insurance companies, etc.).

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Biosimilars: from Technical to Pharmacoeconomiy 7

Health agencies have a major role to play in this communica-tion initiative: the ANSM in establishing the list of biological medi-cines (originator molecules and biosimilars), providing all healthprofessionals with exhaustive information, and the HAS in drawingup pharmacoeconomic recommendations for each class to raiseawareness among health care professionals of the most efficientalternatives, and in disseminating good practice guidelines.

In addition, any incentives to encourage the development ofbiosimilars must take into account how these products are prescri-bed and dispensed, and how these pathways differ between retail orhospital pharmacies.

For biosimilars used in health establishments, the establish-ment’s Pharmacy and Therapeutics Committee play an essentialrole in the products jointly chosen by clinicians and pharmacists tobe listed and described in the hospital formulary.

The proposals put forward to expand the use of biosimilars inhospitals include: including biosimilars in good practice agree-ments (contrats de bon usage); providing financial incentives forprescribers or departments, such as share between the payor and thehospital the savings, referred to as the reimbursable drug price dif-ference (écart médicament indemnisable, EMI) for drugs includedon the “expensive drugs list” (liste en sus); conducting clinical tri-als; and developing patient education about these therapies. Ifrebates were not targeted or savings not reallocated to the prescrib-ers, these incentives would undoubtedly be less impactful.

For biological medicines dispensed on an ambulatory basis,prescribing physicians must keep control over the choice of treat-ment, and pharmacists just reinforce communication to the patients.Incentives on the model of prescribing targets for prescribers (alongthe lines of France’s pay-for-performance scheme) should beexplored, for medicines prescribed in a doctor’s office and also thoseprescribed in hospital but dispensed by retail pharmacies.

7. The round table’s proposals/recommendations

The round table issued a number of recommendations toensure that the development of the biosimilars market is a success,focused on informing healthcare professionals and patients aboutthese products and their particularities, monitoring biosimilar treat-ments, including recording which product is dispensed and conduc-ting post-marketing surveillance, as well as clear-cut market accessprocedures.

7.1. The value of a register of the biological medicinesavailable on the market

It is probably fair to say that many physicians, retail and hos-pital pharmacists, and patients do not have a clear idea of what bio-logical medicines are and their particularities. The round table

recommends the publication of an exhaustive list of biologicalmedicines for reference purposes. This list could be drawn up by aregulatory agency, in a similar way to the register of medicinal pro-ducts already published on the ANSM website.

7.2. The value of keeping a pharmaceutical record forevery patient treated with a biological medicine,with a sufficiently long memory period to coverthe treatment durations involved

In order to implement the ANSM’s recommendations on bio-similar treatment initiation, all pharmacists must have access to thetreatment history of each patient treated with a biological medicine.The round table recommends that a pharmaceutical record be set upfor each patient whenever treatment with a biological medicine isinitiated, that can be updated every time a biological medicine isdispensed by a retail or an hospital pharmacy. A pharmaceuticalrecord similar to the traceability system already in place for bloodproducts will ensure that patients’ treatment history is available forall patients who receive a biological medicine. It will also avoid therisk of switching between products, be it from the reference pro-duct to a biosimilar, from one biosimilar to another, or from a bio-similar to the reference product. Given the long treatment durationsinvolved, these pharmaceutical records will have to be saved for along time, whereas treatment records are currently held for only afew months. Both retail pharmacies and hospital pharmacies mustbe able to access these records, to record any substitution madewhen the first hospital prescription was issued and to ensure thatthe same product is delivered subsequently in retail pharmacies, inaccordance with ANSM recommendations.[14]

7.3. The value of high-quality post marketing surveillancefor biosimilars

In addition to the risk management plans established for allnew medicines when MA is granted, we propose that all patientsfor whom a biological medicine is prescribed (a reference productor a biosimilar) be included in a prospective registry, as is alreadythe case in some countries (Nordic countries for example). Thiswould enable longitudinal follow-up of patients treated with thesedrugs, and analysis of safety data as well as the treatments receivedin real life. Permission from the French Data Protection Authority(Commission Nationale Informatique et Libertés, CNIL) is requi-red to set up this kind of registry, and it occurred to many membersof the round table that inclusion in these registries could be a pre-condition for reimbursement (usually in full) of these expensivetreatments. These registries or observational studies, similar to thepost-marketing studies conducted at the request of the FrenchTransparency Committee for many biological medicines, will help

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8 Girault et al.

generate data on the safety and efficacy of these drugs in real-lifepractice, including comparative data on the reference product andits biosimilars. They will provide the data required to build healthcare professionals’ and patients’ confidence in the use of biosimi-lars alongside their reference molecules.

7.4. The value of a simplified procedure for accessto reimbursement for biosimilars

We propose a fast-track Transparency Committee procedure toevaluate the reimbursement conditions for biosimilars, the detailsof which remain to be determined, to enable price negotiations withthe CEPS to start earlier and to accelerate access to the French mar-ket. The CEPS should draw up stable, transparent rules as soon asthe HTA evaluation procedure that precedes price setting has stabi-lized.

7.5. The value of communication with physicians,pharmacists and patients, in addition to incentivesto use biosimilars

The use of biosimilars in healthcare practice will not increasewithout transparency and prior communication with healthcareprofessionals.

Not to underestimate the impact that incentives can have, wha-tever incentives are introduced for prescribing biosimilars, the suc-cess of any policy to encourage the use of biosimilars must bebased on communication: it is essential to build physicians’, phar-macists’ and patients’ confidence in biosimilars, especially insevere diseases such as cancer or certain autoimmune conditionswhere therapeutic choices are limited. Biosimilars are not generics,and it is currently neither recommended nor conceivable for phar-macists to automatically dispense a biosimilar in substitution of areference product, as they have to do for generic drugs. Recentexperience in France with generics has demonstrated that commu-nication towards healthcare professionals and patients will have tobe redesigned in order to gain their trust and encourage physiciansto gradually introduce biosimilars into their prescribing strategies.Only appropriate communication can help establish biosimilars asa cheaper alternative to reference biological medicines. We proposethat didactic documents aimed at patients, prescribers and pharma-cists be prepared. Ideally they would be drawn up in partnershipwith learned societies and patient advocacy groups, when theyexist, in order to best meet the needs and expectations of eachgroup. It is essential that prescribers be fully informed about biosi-milars, so that they can inform their patients. Prescribers must alsobe told which product was eventually dispensed to the patient,especially if the pharmacist substitutes a biosimilar for the refe-rence product on treatment initiation. This information is necessary

at least to ensure that the prescriber will prescribe the same productat the time of treatment renewal. Finally, prescribers should beencouraged in contributing to the pharmacovigilance system, inparticular through their obligation of spontaneous reporting.

8. Conclusions

The gradual and successful introduction of biosimilars intohealthcare strategies must be based on three key factors: confidencebuilt on a robust MA dossier, including proof of equivalence, bac-ked up by data on the product’s quality, safety and efficacy, and onpost-marketing surveillance, pharmacovigilance notifications andtraceability/recording at the patient level, enabling their long-termsafety to be monitored and the impact of switching to be assessed;consistent information aimed at health professionals and patients,involving public authorities, manufacturers and learned societies;and financial incentives, initially focused on physicians, who arebest placed to build patients’ confidence in biosimilars. These threefactors are deeply intertwined: confidence will only be establishedby following all of these steps and by involving prescribing physi-cians, pharmacists and patients. Eventually, the scientific data col-lected will show whether the precautionary measures that prohibitautomatic substitution or interchangeability between biosimilarsand reference products, currently proposed, should be maintainedor can be lifted.

Acknowledgements

We wish to thank all of the participants in round table N°3, aswell as Professor Jacques-Eric Gottenberg (Strasbourg UniversityHospital), Marie Claude Laubignat (Teva), Frédéric Rupprecht(Sanofi), and Professor Hervé le Louet (Mondor University Hospi-tal, AP-HP Paris Hospitals) who, although they were unable toattend, contributed to the preparation of the topics addressed in thisround table.

Conflicts of interest. Danièle Girault, Corine Blachier, FrançoisGary, Didier Laloye, Rima De Sahb Berkovitch, and Cécile ReyCoquais are employees of pharmaceutical companies (innovativeand/or biosimilar products); Catherine Lassale is an employee ofLEEM.

The other authors have no conflicts of interest to declare inrelation to this article.

Abbreviations. ANSM: French National Agency for Medicinesand Health Products Safety (Agence Nationale de Sécurité duMédicament et des produits de santé); ASMR: improvement inactual benefit (the French rating of the extent to which a treatmentimproves the situation of patients compared with existing treatments,

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Biosimilars: from Technical to Pharmacoeconomiy 9

amélioration du service médical rendu); CEPS: French EconomicCommittee on Healthcare Products (the national health productspricing committee: Comité Economique des Produits de Santé);CME: a health establishment’s Pharmacy and Therapeutics Com-mittee (Commission Médicale d’Etablissement); CNAM: FrenchNational Health Insurance Fund (Caisse Nationale d’AssuranceMaladie); CNIL: French Data Protection Authority (CommissionNationale Informatique et Libertés) ; COMEDIMS: a healthestablishment’s Pharmacy and Therapeutics Committee coveringmedicines and sterile medical devices (COmité du MEdicament etdes DIspositifs Médicaux Stériles); CSIS: French Strategic Coun-cil for Healthcare Industries (Conseil Stratégique des Industriesde Santé); EMA: European Medicines Agency; EMI: reimburs-able drug price difference (the proportion of the saving that a hos-pital can charge to the French national health insurance systemwhen the price it negotiates for certain expensive drugs is lowerthan the officially agreed price [écart médicament indemnisa-ble]); EPAR: European Public Assessment Report; EPO: erythro-poietin (a cytokine stimulating in vivo production of red bloodcells); GCSF: granulocyte colony stimulating factor (a cytokinestimulating in vivo production the white blood cell granulocytelineage); GDP: gross domestic product; HAS: French NationalAuthority for Health (Haute Autorité de Santé); LEEM: Frenchpharmaceutical industry association (Les Entreprises du Médica-ment); LFSS: French Social Security Finance Law (loi definancement de la Sécurité Sociale); MA: marketing authoriza-tion; SMR: actual benefit (the French rating of the medical bene-fit provided by a treatment, given the severity and seriousness ofthe disease, the safety and efficacy of the treatment, and itsimpact on public health [service médical rendu]).

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Correspondence and offprints: Danièle Girault, Laboratoire NovartisPharma, 2-4 rue Lionel Terray, BP 308, 92506 Rueil Malmaison, France.E-mail: daniele.girault@novartis.com

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