Biosimilars report

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Biosimilars report

  1. 1. October 2010Biosimilars: Surveying theMarket LandscapeA FirstWord Dossier Market Intelligence Report
  2. 2. Biosimilars: surveying the market landscapeBiosimilars: surveying the market landscape: Biosimilars: surveying the market landscapePublished October 2010© Copyright 2010 Doctor’s Guide Publishing LimitedAll rights reserved. No part of this publication may be reproduced or used in any form or byany means graphic, electronic or mechanical, including photocopying, recording, taping orstorage in information retrieval systems without the express permission of the publisher.This report contains information from numerous sources that Doctor’s Guide PublishingLimited believes to be reliable but for which accuracy cannot be guaranteed. Doctor’s GuidePublishing Limited does not accept responsibility for any loss incurred by any person whoacts or who fails to act as a result of information published in this document. Any views andopinions expressed by third parties and reproduced in this document are not necessarily theviews and opinions of Doctor’s Guide Publishing Limited
  3. 3. Biosimilars: surveying the market landscapeContentsExecutive summary ............................................................................................... 1Introduction .......................................................................................................... 3Biosimilars are not generics .................................................................................... 5 Manufacturing .................................................................................................... 6 Safety and immunogenicity ................................................................................. 7 Automatic substitution and naming .................................................................... 8 Development ..................................................................................................... 9 Marketing ......................................................................................................... 10 Market acceptance.......................................................................................... 11 Patents ............................................................................................................ 12Regulatory picture ................................................................................................ 12 EU ................................................................................................................... 13 Guidelines ..................................................................................................... 14 Substitution ................................................................................................... 15 Data exclusivity ............................................................................................. 15 Pre-approval trials .......................................................................................... 15 Post-marketing surveillance (pharmacovigilance) ............................................... 16 Extrapolation ................................................................................................. 18 Monoclonal antibodies ..................................................................................... 19 USA ................................................................................................................. 21 Legislation ..................................................................................................... 22 Substitution/interchangeability ......................................................................... 23 Data exclusivity ............................................................................................. 23 Extrapolation to other indications ..................................................................... 24 Patent information exchange ........................................................................... 24 Biological products approved as drugs .............................................................. 25October 2010 i All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  4. 4. Biosimilars: surveying the market landscape Other markets .................................................................................................. 26 Global biosimilars strategy .............................................................................. 28Target biopharmaceutical products ......................................................................... 30 Somatropin (growth hormone) ........................................................................... 33 Epoetin (erythropoietin)..................................................................................... 34 Filgrastim ........................................................................................................ 37 Insulin ............................................................................................................. 39 Interferon alfa .................................................................................................. 41 Interferon beta ................................................................................................. 43 Low-molecular-weight heparins .......................................................................... 45 Monoclonal antibodies and anti-inflammatory fusion proteins ................................. 47 Immunomodulators – anti-TNF antibodies ......................................................... 49 Cytotoxic mAbs ............................................................................................. 49 Follitropin (follicle-stimulating hormone; FSH) ...................................................... 50 Vaccines .......................................................................................................... 50 Enzymes .......................................................................................................... 51 Imiglucerase ................................................................................................. 51 Blood coagulation factors ................................................................................... 52Biosimilars companies .......................................................................................... 53 Generics manufacturers ..................................................................................... 53 Sandoz ......................................................................................................... 54 Teva ............................................................................................................ 55 Hospira ........................................................................................................ 56 Stada ........................................................................................................... 57 Mylan ........................................................................................................... 58 Watson ......................................................................................................... 58 Actavis ......................................................................................................... 58ii October 2010 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  5. 5. Biosimilars: surveying the market landscape Apotex .......................................................................................................... 59 Other generics manufacturers .......................................................................... 59 Innovator pharmaceutical companies ................................................................... 60 Merck & Co. ................................................................................................... 60 Pfizer ............................................................................................................ 61 GlaxoSmithKline ............................................................................................. 61 Eli Lilly .......................................................................................................... 62 AstraZeneca .................................................................................................. 62 Companies in India and other emerging markets ................................................... 62 Biocon .......................................................................................................... 63 Dr Reddy’s .................................................................................................... 64 Reliance Life Sciences ..................................................................................... 64 Intas............................................................................................................. 65 Wockhardt ..................................................................................................... 65 Ranbaxy (Daiichi Sankyo)................................................................................ 65 Cipla ............................................................................................................. 66 Other markets ............................................................................................... 66Future prospects .................................................................................................. 67Index .................................................................................................................. 70October 2010 iii All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  6. 6. Biosimilars: surveying the market landscape This Page Left Blankiv October 2010 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  7. 7. Biosimilars: surveying the market landscapeExecutive summaryCheaper biological drugs are an economic and healthcare necessity. Yet only recently haveaccelerated approval pathways for lower-cost versions of off-patent biologics come intoexistence. Biosimilar competition is now possible in all the major markets, including theUSA, the EU, Japan, Canada and Australia. But biosimilars are far more complex thangenerics. The residual lack of stakeholder confidence that surrounded standard generics insome markets may be even tougher for biosimilars to overcome.The balancing act by the regulatory agencies must weigh safety and effectiveness againsteconomics. The regulatory system needs to ensure that biosimilars are as safe andeffective as the reference product. But is this even possible for such complex molecules?Economically, there is a need to balance the incentive to innovate with the need for lowerprices and greater access.In Europe, an abbreviated approval pathway for biosimilars has existed since 2006, withthe simplest of the biological medicines seeing competition for several years. In March2010, the USA—the largest potential biosimilars market—created legislation that allowsthe creation of a pathway for abbreviated approval. This report summarises the currentregulatory situation in the EU and the USA, and touches on the situation in emergingmarkets. This is put into context by considering the differences between biosimilars andgenerics.In the market for traditional drugs, relatively few compounds account for adisproportionate share of sales and profits. The same is true for biological medicines. As inthe traditional generic drug market, it is these outstanding performers that will attract themost interest from biosimilars manufacturers, where the number of entrants is stronglyrelated to the size of the branded product’s sales before entry. The biosimilars marketedso far are mostly simple, first-generation biological products such as somatropin, epoetinand filgrastim. The report looks at the markets for these products and other first-generation biological drugs, and considers the biosimilars that have already beenapproved.These incursions into biosimilars are only the first wave. The monoclonal antibodies arethe products that manufacturers believe will reap the biggest rewards. However, they aremore complex than the first-generation biologicals. Even pioneering EU regulators will notissue a draft guideline until the end of 2010. The report considers the issues surroundingOctober 2010 1 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  8. 8. Biosimilars: surveying the market landscapebiosimilar monoclonal antibodies and highlights those that are likely to be the first targetsfor biosimilars manufacturers.Who are the successful biosimilar manufacturers likely to be? Since biosimilars are verydifferent from traditional generics, it’s an open question. Obtaining approval is expensiveand can be complicated; the costs of setting up manufacturing are high and distributionmay be complex. Once approved, substitution in pharmacies is not permitted and the pricediscounts are much lower than for traditional generics. Brand development is importantand direct marketing to small numbers of specialists is required. These are not the skillstraditional generics manufacturers have. This report looks at the early entrants to themarket and others who might follow, and offers an overview of companies in emergingmarkets such as India, who have their eye on the European and US markets.2 October 2010 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  9. 9. Biosimilars: surveying the market landscapeIntroductionSince the 1976 formation of Genentech—the first biotechnology company—more than 150biopharmaceutical products have been marketed world-wide 1, which are estimated toaccount for around ten percent of the global pharmaceutical market 2. The US GenericPharmaceutical Association (GPhA) estimates that by 2012, nearly half the productsapproved by the US Food and Drug Administration (FDA) will be biological medicines 3.Biological medicines treat some of the most devastating diseases; those that areuntreatable by other means, such as genetic disorders, and those for which currenttherapies have serious drawbacks, such as cancer and rheumatoid arthritis. However,these benefits come at huge cost. In a New York Times article, Anthony D. So and SamuelL. Katz said that biological medicines cost around 20 times as much as standard drugs,with 28 percent of 2008 sales from the pharmaceutical industry’s top 100 products comingfrom biological products. That share is expected to rise to 50 percent by 2014 4, and will nodoubt continue to increase because the diseases they treat are often long-term conditionsassociated with the growing ageing population.Lowering the cost of medicines is seen by governments and the World Health Organization(WHO) as an economic and healthcare necessity. As with the uninsured in the UnitedStates, much of the developing world’s population is denied access to medicines becauseof their cost. In European countries, health technology assessment agencies (such as theUK’s National Institute for Health and Clinical Excellence [NICE] and Germany’s Institutefor Quality and Efficiency in Healthcare [IQWiG]) restrict access to expensive medicinessuch as biological products on cost–benefit grounds. Generic medicines have been thetraditional route to reducing the drugs bill—in the USA generic pharmaceuticals fill75 percent of the prescriptions dispensed, but consume just 22 percent of total drugspending 5.Many first-generation biological medicines—those that copy or closely resembleendogenous human proteins such as insulin, growth hormone and interferons—have either1 Misra A. Are biosimilars really generics? Expert Opin Biol Ther 2010;10:489–94.2 European Generic Medicines Association. Biosimilar Medicines: FAQ. http://www.egagenerics.com/FAQ-biosimilars.htm3 Generic Pharmaceutical Association. Biogenerics: GPhA position. http://www.gphaonline.org/issues/biogenerics4 So AD, Katz SL. Biologics boondoggle. New York Times 2010, March 7.http://www.nytimes.com/2010/03/08/opinion/08so.html?_r=15 Generic Pharmaceutical Association. Press release Jul 26, 2010. http://www.gphaonline.org/media/press-releases/2010/generic-medicines-saved-us-health-care-system-1396-billion-2009-824-billioOctober 2010 3 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  10. 10. Biosimilars: surveying the market landscapelost patent protection or soon will do. In theory, the door is open to generic competition.However, biological medicines are far more complex than traditional generic drugs andcannot be exactly copied. They cannot therefore be approved via the same abbreviatedprocedures as standard generic drugs. The term ‘generics’ has been avoided for thisreason and ‘similar biological products’ (biosimilars) and ‘follow-on biological products’ 6have been used in the EU and USA, respectively, to describe ‘generic’ biological medicines.It is therefore essential to examine the issues around biosimilars and the currentregulatory situation around the world-wide, the biological products that are likely to betargets for biosimilar competition and profile the companies that are in the best position totake advantage of this new market.6 The term ‘follow-on biological products’ is often used in the USA to mean improved, next-generation products.For this report the term ‘biosimilars’ will be used to mean products intended to be as similar as possible to anexisting product, whichever market is being discussed.4 October 2010 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  11. 11. Biosimilars: surveying the market landscapeBiosimilars are not genericsManufacturers of standard generic medicines can seek approval for their products viaabbreviated registration procedures in Europe and the USA. To gain approval in this way, ageneric drug must contain the same active ingredients as the innovator drug; be identicalin strength, dosage form and route of administration; have the same indications; bebioequivalent (a surrogate marker for therapeutic interchangeability); meet the samebatch requirements for identity, strength, purity and quality; and be manufactured underthe same standards of good manufacturing practice required for innovator products.Biological medicines cannot meet all these requirements because they are much morecomplex than traditional generic drugs. Demonstrating bioequivalence representssomething of a challenge, especially for the more complex biologics. Some of the majordifferences between standard generics and biosimilars are presented in Table 1.Table1. Comparison of generic and biosimilar drugs Generics BiosimilarsProperties Small (<500Da) Large (5000-300,000Da) Usually stable Often unstable; may require specific formulation Easy to fully characterize Hard to characterizeManufacturing Chemical synthesis Fermentation in living cells Simple Complex isolation and purification steps Cheap Sensitive to manufacturing changes Process affects product Relatively expensiveDevelopment Limited trials required, usually Substantial development work only Phase I PK/PD studies required – cell lines etc. Extensive Phase I and III clinical trialsOctober 2010 5 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  12. 12. Biosimilars: surveying the market landscape Generics BiosimilarsMarketing Large price discounts Smaller price discounts; price sensitivity is product-specific No or limited detailing to physicians Detailing to specialist physicians required Key role of wholesalers and payers Method of delivery can be a key differentiator Special delivery device not usually necessary No automatic substitution Automatic substitution in possible Specialist distribution often in some pharmacies required Simple to distributeRegulation Must be identical to reference Must be highly similar to product reference product Substitutable/interchangeable Not automatically substitutable Abbreviated procedure is Abbreviated approval applicable to all drugs requirements vary depending on the drugIt is fundamental to the approval process for a standard generic drug that it contains thesame active ingredient as the reference product. Achieving identical bioequivalence isrelatively easy to achieve for small, stable molecules that are produced by chemicalsynthesis and can easily be characterised but much harder for biological drugs. Biologicaldrugs have an inherently microheterogeneous structure, which can be affected by changesto the expression system, culture medium, pH, temperature and so on. The regulatoryauthorities therefore address the concept of biosimilarity, which allows a product to beapprovable via an abbreviated pathway while not being completely identical to thereference product.ManufacturingWith conventional drugs there is no relationship between the manufacturing process andthe characteristics of the final product. However, for biological drugs the process and theproduct are inextricably linked. For example, filgrastim (granulocyte colony-stimulatingfactor; G-CSF) produced in Chinese hamster ovary cells (the most commonly usedmammalian manufacturing system for recombinant proteins) is glycosylated (has attachedsugar molecules), unlike that produced in Escherichia coli. A change in glycosylation orother post-translational modifications can to lead to the protein folding differently. This6 October 2010 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  13. 13. Biosimilars: surveying the market landscapemay have no relevant clinical effect, but it may affect the way the protein binds to itsreceptor and alter efficacy and safety, particularly immunogenicity. It may also have aneffect on solubility, which could affect the pharmacokinetics and pharmacodynamics of theprotein (i.e. its absorption and tissue distribution). This could also affect the degradationprofile and how quickly the protein is cleared from the body.The issue is highlighted by Genzyme’s attempt to scale up production of alglucosidase alfa(Myozyme), an enzyme replacement therapy for Pompe disease. Genzyme wished to moveproduction to a new plant with greater capacity, but the FDA ruled that the productmanufactured in the larger facility was sufficiently different from the original product as torequire a new Biologics License Application (BLA). This was because of concerns that theglycosylation of the protein had been altered to such an extent that the product wasmaterially different from the previous version. The product from the larger facility waseventually approved in May 2010, as Lumizyme.Another issue is that the manufacturing process’ complexity means that the originator’sprocedure will be patented and any biosimilar manufacturer will have to work around thepatent or, more likely, patents.Safety and immunogenicityThe major safety issue with biological drugs is their ability to produce an immune response(immunogenicity). Biological medicines are produced in living cells and are thereforerecognised as foreign by the human immune system. The resulting immune response mayhave no consequences, but could lead to allergic reactions, infusion reactions especiallyafter the first dose, the induction of neutralising antibodies and loss of effectiveness.Neutralising antibodies can be important when they act against an essential endogenousprotein. This is demonstrated by the extremely rare occurrence of pure red cell aplasia(PRCA) after subcutaneous epoetin administration in patients with kidney failure, in whichantibodies are induced to the recombinant epoetin and the patient’s own erythropoietin.The condition requires transfusions for survival.The immunogenicity of a product can be changed by any factor that alters its three-dimensional structure, including changes in glycosylation. Furthermore, any impurities canbe immunogenic in their own right or enhance the immunogenic activity of the product, aswhen acting as an adjuvant). Thus any change to the formulation or manufacturingprocess, which would have to happen for the production of a biosimilar, could haveOctober 2010 7 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  14. 14. Biosimilars: surveying the market landscapeconsequences for the safety profile. This was seen when the incidence of PRCA increasedin renal patients receiving Johnson & Johnson’s epoetin alfa subcutaneously. This followeda minor manufacturing change to replace human serum albumin with polysorbate 80. Thepolysorbate 80 caused organic compounds to leach from the rubber stopper of the prefilledsyringe. These compounds were involved in the induction of antibodies to the patients’own erythropoietin, resulting in PRCA 7.Automatic substitution and namingAn issue linked to immunogenicity and safety is automatic substitution, which allows andsometimes requires pharmacists to dispense generic drugs in place of prescribed innovatorproducts without the knowledge or consent of the treating physician. This is often allowedwith traditional generic medicines on the basis that they are identical to the brandedproduct. However, it has been argued that if patients receive several biological productsover the course of therapy, depending on whichever is the cheapest at the time ofdispensing, it will be impossible to link an adverse event to a specific product. This willconfound the pharmacovigilance assessment required for approval by the biosimilarpathway (see ‘Post-marketing surveillance’ in the ‘Regulatory picture’ section).Moreover, it has been suggested that biosimilars should carry a different international non-proprietary name (INN) to their reference product to prevent inadvertent substitution.INNs are issued by the WHO on the advice of an international panel of experts, andfacilitate worldwide pharmacovigilance by ensuring that all adverse event reports arelinked with the correct drug. However, it has been argued that as biosimilars are notidentical to the product for which the name was granted, the INN should not be relied onas the only method of identifying a biological medicine. The EMA supports this view,stating in its Guideline on Similar Biological Medicinal Products ‘in order to supportpharmacovigilance monitoring, the specific medicinal product given to the patient shouldbe clearly identified’ 8.For example, epoetin zeta is the INN for a recently introduced biosimilar epoetin product.The name reflects a difference in glycosylation and differentiates it from the original7 Boven K, Knight J, Bader F, Rossert J, Eckardt KU, Casadevall N. Epoetin-associated pure red cell aplasia inpatients with chronic kidney disease: solving the mystery. Nephrol Dial Transplant 2005;20(Suppl 3):iii33–40.8 Mellstedt H, Niederwieser D, Ludwig H. The challenge of biosimilars. Ann Oncol 2008;19:411.8 October 2010 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  15. 15. Biosimilars: surveying the market landscapeepoetin alfa. Another suggestion is that biosimilars should always be commercialised witha brand name or the INN plus the manufacturer’s name 9. The use of unique INNs forbiosimilars would preclude automatic substitution and would probably be supported by theinnovator industry, as it would present a further barrier to substitution.According to the US Federal Trade Commission (FTC), a lack of automatic substitution willslow the rate at which a biosimilar can acquire market share and thereby increase itsrevenues 10. In the traditional generics market, where automatic substitution is allowed insome markets, the market share of the incumbent drops dramatically with the first genericentrant.DevelopmentTraditional generic drugs do not generally require preclinical or clinical trials to determinetheir efficacy and safety. As long as the generic product is bioequivalent to the innovatorproduct, its safety and efficacy is presumed to be the same. All that is needed todemonstrate bioequivalence are Phase I pharmacokinetic/pharmacodynamic studiesconducted with healthy volunteers to prove that the generic product delivers the sameamount of drug over the same time period as the reference product. Because biosimilarscannot be identical to the reference product, they will usually require extensive clinicaltrials in addition to Phase I. For more details on the clinical data required by the EUbiosimilar pathway, see ‘EU: Pre-approval trials’ under ‘Regulatory picture’.The extent to which additional clinical trials are required depends on many factors, notleast the product itself and how well it is characterised. If a clinically-relevant end pointcorrelated with efficacy is available, trials can be shorter and require fewer patients. Someexamples include glucose levels for insulin, haemoglobin levels for epoetin and neutrophillevels for filgrastim. A therapeutic marker may not exist at all for some products, such asmonoclonal antibodies; trials for products for diseases such as cancer will need muchlonger studies with more patients.These additional requirements will mean higher development costs for biosimilar medicinescompared with standard generics. Costs are difficult to estimate accurately becausedifferent products require widely differing amounts of development work. However, the9 Zuñiga L, Calvo B. Biosimilars: pharmacovigilance and risk management. Pharmacoepidemiol Drug Saf2010;19:661–669.10 Emerging Health Care Issues: Follow-on Biologic Drug Competition. Federal Trade Commission; June 2009.http://www.ftc.gov/os/2009/06/P083901biologicsreport.pdfOctober 2010 9 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  16. 16. Biosimilars: surveying the market landscapeFTC estimates that developing a biosimilar will cost $100 to 200 million and take eight to10 years. This is considerably higher than for a standard generic medicine, which the FTCestimates costs $1 to $5 million and takes three to five years to develop. This is stillconsiderably cheaper than the $1 billion widely quoted for developing an innovator drug.According to David E. Wheadon of the Pharmaceutical Research and Manufacturers ofAmerica (PhRMA), biosimilar manufacturers still have strong incentives to enter themarket, including the ability to support their application with the innovator’s data 11.MarketingThe business model for a standard generics manufacturer is the regular launch of newproducts to maintain growth. In this market, the barriers to entry are few and low. Thereare many competitors and price competition is intense, with discounts of 80 to 90 percent.Standard generic drugs require limited or no detailing to physicians, and wholesalers andpayers have the key role. It will not be possible to follow this business model forbiosimilars, which may be better viewed as specialty generics, at least in highly-regulatedmarkets. Specialty generics have higher barriers to market entry because they may bedifficult to manufacture, have a complex patent or regulatory environment, or havespecialised marketing requirements. Competition between specialty generic medicines isnot based primarily on price. Products are marketed under separate brand names and alsocompete on product differentiation such as delivery systems and promotion likesponsorship of education 12.In Europe, where a mechanism for approving biosimilar products has been in place since2006, price reductions have mostly been a modest 25 to 30 percent. However, pricesensitivity appears to be product- and market-specific. In Germany for example, where thegenerics market is well established, biosimilar somatropin is more heavily discounted.Although the price discounts may be smaller compared with traditional generic drugs, thehigh price of treatment with many biological drugs—Roche’s Herceptin (trastuzumab)costs $48 000 per year 13—means that payers will see reasonably large savings.11 Wheadon DE. N Engl J Med 2009;362:661.12 Specialty Generics: Climbing the pharmaceutical value chain. FirstWord; July 2010.13 Emerging Health Care Issues: Follow-on Biologic Drug Competition. Federal Trade Commission; June 2009.http://www.ftc.gov/os/2009/06/P083901biologicsreport.pdf10 October 2010 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  17. 17. Biosimilars: surveying the market landscapeThe FTC believes that the specialty pharmaceutical characteristics of biosimilars are likelyto limit market share. Specialty drugs, including biologicals, are commonly used to treatpatients with severe, chronic diseases and terminal conditions. The drugs are primarilyinjected or infused and are combined with ancillary medical services and products thatrequire training for proper handling and administration. Because most biological productsare delivered to patients in clinics, hospitals, doctors’ offices or other medically supervisedsettings, shifting to another product is typically more costly because it requires restockinginventory and retraining nurses and healthcare providers 14. As a result, the FTC suggeststhat only two or three companies will try to compete with each biological drug, in whichcase price competition will be limited. However, once a medical facility has beenpersuaded to switch, there will be an advantage for the biosimilar manufacturer as all thepatients at that facility will follow.Market acceptanceIn the EU, the initial acceptance of biosimilars has generally been low but this variesgreatly from country to country. “[Biosimilar] epoetin penetration in Germany, forexample, has now reached around 60% of the market (by volume), Suzette Kox, SeniorDirector Scientific Affairs for the European Generic Medicines Association (EGA) toldFirstWord. Kox believes that “the situation is now rapidly changing. The adoption rate isexpected to increase significantly in the future as the experience and confidence in thisnew category of products grows day by day.”Difficulty gaining market share is likely to be common because of concerns aboutdifferences in safety and efficacy between the innovator product and the biosimilar.Physicians may be reluctant to switch their patients from an innovator product to abiosimilar because of the risk that they will react differently to the biosimilar. Conveniencewill be an issue for patient—receiving a second-generation product are unlikely to want toswitch to a first-generation product with a less convenient dosing regimen. This may limitbiosimilar market opportunities to newly-diagnosed patients. Careful marketing toprescribers will therefore be important to ensure adequate market penetration. Thereputation of the manufacturer is likely to carry significant weight. Those with an existingreputation in the field such as a supplier of other specialty medicines may prosper.14 Emerging Health Care Issues: Follow-on Biologic Drug Competition. Federal Trade Commission; June 2009.http://www.ftc.gov/os/2009/06/P083901biologicsreport.pdfOctober 2010 11 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  18. 18. Biosimilars: surveying the market landscapeThe perspectives of organised patient groups in therapeutic areas with high usage ofbiological drugs will also be important in driving or limiting demand for biosimilars. Forexample, those denied access to anticancer monoclonal antibodies on cost–benefit groundsby health technology assessment agencies, such as the UK’s NICE, may welcome theavailability of cheaper versions.PatentsThe innovator pharmaceutical industry has suggested that, as biological drugs are socomplex, it is relatively easy to ‘design around’ their patents. However, the FTC believesthere is no evidence that biological drug patents have been designed around morefrequently than those claiming small-molecule drugs 15. For example, Amgen controls theUS epoetin market and on the basis of its patents has successfully challenged competitorsattempting to enter the market with novel epoetin variants, notably Roche’s Mircera.Innovator biological products are covered by suites of patents protecting not only theproduct (if it is not naturally occurring) but the production process (the technology,vectors and cell lines) and the formulation or delivery system. These are often morenumerous and varied than for small-molecule branded products. A major issue forbiosimilars manufacturers will be how to balance the need to assure the regulator thattheir product is highly similar to the reference product, yet make a product that is differentenough so as not to infringe any patents covering the reference product. This is aparticular problem in the US, where drug patent infringement suits are commonplace. Forthose patents that cannot be worked around, biosimilars manufacturers will have to paylicensing fees to the originators.The large number of patents covering a biological drug makes it difficult to determinewhen it is no longer protected. The potential for litigation against biosimilarsmanufacturers may therefore be greater than for traditional generics manufacturers.Regulatory pictureThe balancing act to be managed by the regulatory agencies weighs safety andeffectiveness against economics. The regulatory system needs to ensure that biosimilars15 Emerging Health Care Issues: Follow-on Biologic Drug Competition. Federal Trade Commission; June 2009.http://www.ftc.gov/os/2009/06/P083901biologicsreport.pdf12 October 2010 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  19. 19. Biosimilars: surveying the market landscapeare as safe and effective as the reference product. But is this even possible? Economically,a balance must be struck between the incentive to innovate and ensure a steady supply ofnovel therapies with the need for lower prices and greater access.In Europe, an abbreviated approval pathway for biosimilars exists. Even the simplest ofthe biological medicines have seen competition for several years. In the USA where thereis the largest potential market, legislation allowing the creation of a pathway forabbreviated approval was created in March 2010.EUIn October 2005, a legal framework for the development of biosimilars in the EU wasenacted, with the first biosimilar medicines gaining approval in April 2006. Since then, 14products have been approved under the pathway: two somatropins, five epoetins andseven filgrastims. Only five have been rejected or withdrawn: one interferon alfa-2a, oneinterferon beta-1a and three insulin products. The system is deemed to be working well.According to Suzette Kox of the EGA, “from our standpoint, the pathway for the firstbiosimilar molecules is well established, works well and delivers. It is broadly believedwithin the industry and amongst regulators to be a success.”EU approvals are dealt with on a case-by-case basis. In other words, the degree ofsimilarity required is flexible, depending on the product. For example, Lilly’s Humatrope(somatropin) is produced in Escherichia coli. The biosimilar product Valtropin(Biopartners/LG Life Sciences) is produced in yeast and so must be different in at leastsome respects. It has been approved by the EU as biosimilar, although it is not yetmarketed due to problems sourcing the delivery device. Another example is epoetin. Allavailable epoetins vary in their glycosylation pattern, but are accepted by the EU asbiosimilar, as the differences are deemed to be within the range seen in the naturalproduct.October 2010 13 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  20. 20. Biosimilars: surveying the market landscapeGuidelinesEU guidelines require biosimilar drugs to have a reference biological drug that is approvedin the EU for the intended indication and for which the data protection period has expired.Clinical testing must be carried out to support the approval. Tailored post-marketingpharmacovigilance or risk management must be carried out to monitor the potentialemergence of immunogenicity issues. The aim is to ensure a product is similar to thereference product in terms of quality, safety and efficacy.All biological drugs, including biosimilars, are assessed by the EMA’s Committee forMedicinal Products for Human Use (CHMP), which has developed both overarching andproduct-specific guidelines. The first general guideline 16, issued by the CHMP in October2005, introduces the concept of similar biological products and the basic principles appliedto gaining approval. Among other things, it states that for a product to be considered abiosimilar, it must have the same amino acid sequence as the reference product. Thesecond guideline 17, which came into effect in June 2006, specifies the quality requirementsregarding manufacturing processes, the analytical methods to assess comparability,factors to consider when choosing a reference product and physicochemical and biologicalcharacterisation of the biosimilar. The third guideline 18 was also issued in June 2006. Thenon-clinical section covers the pharmacotoxicological assessment, while the clinical sectionaddresses the requirements for pharmacokinetic, pharmacodynamic, efficacy and safetystudies, with emphasis on the evaluation of immunogenicity.Several product-specific guidelines 19 have subsequently been issued for granulocytecolony-stimulating factor (filgrastim), human growth hormone (somatropin) and humaninsulin. All were adopted in April 2006. Recombinant epoetin was adopted in July 2006,low-molecular-weight heparin in October 2009 and interferon alfa in Apr 2009. Concept16 European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on similar biologicalmedicinal products. CHMP/437/04. London: EMEA; 2005.http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003517.pdf17 European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on similar biologicalmedicinal products containing biotechnology-derived proteins as active substance: quality issues.EMEA/CHMP/BWP/49348/2005. London: EMEA; 2006.http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003953.pdf18 European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on similar biologicalmedicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues.EMEA/CHMP/BMWP/42832/2005. London: EMEA; 2006.http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003920.pdf19 All the product-specific guidelines, plus consultation documents and guidelines relevant to all biologicalmedicines can be found at:http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c&murl=menus/regulations/regulations.jsp&jsenabled=true14 October 2010 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  21. 21. Biosimilars: surveying the market landscapepapers on monoclonal antibodies were released Oct 2009, follicle-stimulating hormone andrecombinant interferon beta were both released March 2010. The first draft monoclonalantibodies guideline is expected by the end of 2010.SubstitutionThe EMA does not assess the interchangeability or substitutability of a biosimilar.Substitution practice varies by country. For example, all biological medicines are excludedfrom substitution in Spain, while in France biosimilars will not be registered in theDirectory of Generics, which is a requirement to authorise substitution by pharmacists. Atleast 15 European countries now prevent the automatic substitution of biological drugswith biosimilars.Data exclusivityThe other side of the generic coin is fostering innovation. Innovator companies need tohave sufficient time before generic competition starts to make a return on theirinvestment. This is achieved in the EU (and the USA, see below) by a period of dataexclusivity, during which companies making generic drugs cannot rely on the originator’sdata to support their application, as they must do to prove similarity. The period of dataexclusivity was enacted with EU Directive 2004/27/EC. For generic or biosimilar productsthat reference products with marketing applications submitted before late 2005, thisperiod is ten years or six years in some cases. In the case of generics or biosimilars thatreference products with marketing applications submitted after late 2005, there is aneight-year data exclusivity period during which a marketing application for a biosimilarcannot be submitted, followed by a two-year period of market exclusivity when no genericapplications are approvable. The ten-year period may be extended for an additional year,for a total of 11 years of data exclusivity, with respect to a new indication that constitutesa significant clinical benefit.Pre-approval trialsThe philosophy of biosimilar approval ensures that the product is comparable to anapproved reference biological product in terms of quality, efficacy and tolerability. Thisrequires comparative quality studies and non-clinical and clinical efficacy and tolerabilitystudies.October 2010 15 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  22. 22. Biosimilars: surveying the market landscapeBecause of the differences between biopharmaceutical products, the approval processvaries according to the product. The comparability programme is clearly defined andagreed upon in advance with the EMA, which defines the set of non-clinical and clinicaldata necessary to demonstrate comparability. The extent of the data required variesaccording to the type and complexity of the medicine involved, and each biosimilarmedicine is assessed on a case-by-case basis. In particular, the amount of clinical dataavailable may depend on the inherent variability of efficacy end points and the availabilityof validated surrogate markers 20. Typically, one study in a single population during alimited time interval or 12 months will be deemed sufficient to demonstrate comparableefficacy and tolerability.Comparative non-clinical pharmacokinetics, safety pharmacology, reproduction toxicology,mutagenicity and carcinogenicity studies are not required as these will have been done forthe reference product and, if approved, the biosimilar will be demonstrably comparable tothe reference product.Because biopharmaceuticals have been associated with serious adverse events, EMAguidelines 21 require all biological drugs to undergo immunogenicity testing. Biosimilars arenot exempt from this requirement as the relatively minor alterations that will necessarilyoccur from the reference product can have a major effect on the product’simmunogenicity.Post-marketing surveillance (pharmacovigilance)Although pre-authorization clinical studies can demonstrate that a biosimilar drug hascomparable efficacy and tolerability to the reference drug, this could be established byonly one study in a single population during a 12-month limited time interval, and mayeven allow extrapolation to all other approved indications of the reference product. Thismay not be sufficient to identify the full safety profile of the biosimilar, which may differfrom the reference drug in nature, seriousness or incidence of adverse reactions. Thepotential for immunogenicity may not occur until several months after treatment hasstarted. As a result, biosimilar manufacturers must develop a risk management systemand submit a risk management plan (EU-RMP) with their application.20 Surrogate marker – a laboratory measurement or a physical sign used as a substitute for a clinicallymeaningful end point that directly measures how a patient feels, functions or survives.21 European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on immunogenicityassessment of biotechnology-derived therapeutic proteins. EMEA/CHMP/BMWP/14327/2006. London: EMA; 2007.http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003946.pdf16 October 2010 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  23. 23. Biosimilars: surveying the market landscapeA risk management system is defined in the relevant guideline as ‘a set ofpharmacovigilance 22 activities and interventions designed to identify, characterise, preventor minimise risks relating to medicinal products, and the assessment of the effectivenessof those interventions’ 23. An EU-RMP is not specific to biosimilars and is required by theEMA with the marketing authorisation for any product containing a new active substance,and in several other situations. However, they are not generally required for traditionalgeneric drugs.An example of the problem is the pure red cell aplasia (PRCA), which can occur in patientsreceiving subcutaneous epoetin alfa (see ‘Safety and Immunogenicity’ above). PRCA is avery rare event taking months to years of epoetin treatment to develop. In the limitedclinical trials required for the approval of biosimilar epoetin with a minimum of 300patients, PRCA may not be detected as too few patients are likely to be included to detectsuch a rare event. The EMA guideline for the approval of biosimilar epoetin 24 requires 12-month immunogenicity testing.Professor Paul Declerck of the Katholieke Universiteit Leuven questions whether thecurrent criteria for comparability of biosimilars and their reference products are valid. Hecalls for long-term clinical investigations and systematic monitoring of the efficacy andtolerability of biosimilars 25. “The minimum number of required patients in clinical studiesfor approval of biosimilars is exclusively based upon statistical grounds to be able to provethat the product is as effective as the reference. This (small) number is, however, notsufficient to draw any conclusion with respect to possible adverse events (which occur at amuch lower frequency). Therefore, to my opinion, the RMP for biosimilars should not beconsidered as a classical RMP but should really be considered as an active, post-approvalcommitment.” He also believes that the mere fact that there is an RMP is often used toconclude erroneously that safety is virtually fully proven and that the RMP is only a ratherroutine commitment.22 Pharmacovigilance describes the detection, assessment, understanding and prevention of adverse effects afterthe launch of a product onto the market.23 European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on risk managementsystems for medicinal products for human use. EMEA/CHMP/96268/2005. London: EMA; November 2005.http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004888.pdf24 European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on non-clinical andclinical development of similar biological medicinal products containing recombinant erythropoietins (Revision).EMEA/CHMP/BMWP/301636/2008 London: EMA; March 2010.http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/04/WC500089474.pdf25 Declerck PJ, Darendeliler F, Góth M, Kolouskova S, Micle I, Noordam C, et al. Curr Med Res Opin2010;26:1219–29.October 2010 17 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  24. 24. Biosimilars: surveying the market landscapeProf. Declerck also expressed concern that although the RMP is imposed by the EMA, thespecific details of the RMP are discussed and eventually approved at a national level. Thiscould result in a heterogeneous approach between member states and may compromisethe strength of the pharmacovigilance.ExtrapolationData extrapolation—the approval of a drug for indications or situations in which it has notbeen evaluated in clinical trials—is permitted for biosimilars if an ‘adequate’ scientificexplanation is provided and the mechanism of action in the new indication is the same asthe original indication, but usually only for same route of administration. For example, theEMA’s revised biosimilar epoetin guideline says: “Since the mechanism of action of epoetinis the same for all currently approved indications and there is only one known epoetinreceptor, demonstration of efficacy and safety in renal anaemia will allow extrapolation toother indications of the reference medicinal product with the same route ofadministration.”Thus, biosimilar epoetins are approved not only for the primary indication—the treatmentof anaemia associated with renal failure—but also for chemotherapy-induced anaemia andto increase the yield of autologous blood from patients before they undergo major electiveorthopaedic surgery. The dosages required to achieve the desired response may varyconsiderably between indications and are highest in the oncology indications. The lack of aclinical trial in each indication may well lead to reluctance by physicians to prescribe forthe extrapolated indications or for a patient population in which there has beenextrapolation, such as in children. It is notable that the converse route—approval for theoncology indication being extended to renal—has not been implemented, and undoubtedlyreflects the fears that risk of PRCA would not be picked up in the immune-compromisedoncology patient population.Epoetin can be administered intravenously or subcutaneously. The pharmacokinetics anddose requirements usually differ for each route. Furthermore, subcutaneous administrationin renal failure is associated with PRCA (see ‘Safety and immunogenicity’ above). The EMAguideline requires that similar efficacy between the test and reference products be ensuredfor both routes of administration. This can be achieved either by performing separateclinical trials for each route or by performing a clinical trial for one route and providingadequate bridging data for the other. Adequate bridging data could be comparative single-18 October 2010 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  25. 25. Biosimilars: surveying the market landscapedose and multiple-dose PK/PD data in an epoetin-sensitive population of healthyvolunteers. The guideline suggests that since comparative immunogenicity data will alwaysbe required for subcutaneous use, if applied for, the most reasonable approach would beto perform a clinical trial using subcutaneous epoetin and to provide PK/PD bridging datafor the intravenous route. The biosimilar epoetins approved to date are for intravenousadministration. The biosimilar epoetins approved to date are for intravenousadministration, and at least one instance of immunogenicity occurred during a trial inwhich the biosimilar was administered subcutaneously 26.To extend the approval of currently approved epoetin biosimilars to the subcutaneousroute in the renal indication; manufacturers must conduct a full clinical trial demonstratingcomparable efficacy and safety to the reference product, as products were initiallyapproved only for intravenous use in this indication. (Comparative immunogenicity trialscould not be performed because subcutaneous use of the reference product wascontraindicated at the time of the studies 27).Monoclonal antibodiesMonoclonal antibodies (mAbs) are far more complex than first-generation biologicalproducts. The first-generation drugs are comparatively simple molecules resemblingendogenous human proteins (e.g. somatropin or epoetin) whose modes of action are wellunderstood. Monoclonal antibodies are around three times heavier and often consist offour protein chains rather than one. Furthermore they are novel constructs that do notsubstitute for endogenous proteins. Their mechanism of action is often incompletelyunderstood. It has therefore been asked whether the development of biosimilar mAbs ispossible. In theory, the biosimilar approval process is applicable to more complexmolecules; the EMA guidelines state as much.EMA guidance on quality for manufacturers of mAbs already exists 28, but it was thoughtthere was insufficient guidance on non-clinical and clinical issues. Before establishing abiosimilar guideline, the Biosimilar Medicinal Products Working Party (BMWP) issued a26 GaBi Online (October 2009) Safety study for subcutaneous epoetin alfa biosimilar Binocrit/Epoetin alfaHexal/Abseamed suspended http://www.gabionline.net/Biosimilars/News/Safety-study-for-subcutaneous-epoetin-alfa-biosimilar-Binocrit-Epoetin-alfa-Hexal-Abseamed-suspended27 Schellekens H. Clin J Am Soc Nephrol 2008;3:174–8.28 European Medicines Agency. Guideline on development, production, characterization and specifications formonoclonal antibodies and related products. London: EMA; 2008. CHMP/BWP/157653/07.http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003074.pdfOctober 2010 19 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  26. 26. Biosimilars: surveying the market landscapeconcept paper aimed at gathering opinions 29. The discussion period ended in January2010, and an EMA spokeswoman told FirstWord that a draft guideline will be released forexternal consultation by the end of 2010. The guideline is eagerly awaited. At the 8th EGAInternational Symposium on Biosimilar Medicines held in London in early September 2010,Greg Perry, Director General of the EGA, said that “if healthcare systems are to continueto function long-term, we must address the importance of biosimilar monoclonal antibodiesnext. Science for monoclonal antibodies is already here today and our industry isexpecting a workable guideline.”The concept paper indicates that the approach to establishing biosimilarity might bedifferent for mAbs with different modes of action. The paper draws a distinction betweenimmunomodulators (e.g. anti-TNF-alpha mAbs such as etanercept and infliximab);cytotoxic mAbs with or without receptor modulation (e.g. anti-CD20, anti-EGFR or anti-Her2 mAbs such as rituximab and trastuzumab) and others that do not fall into thesecategories, such as antimicrobial mAbs such as palivizumab, which targets respiratorysyncytial virus. The often incomplete understanding of mAbs`mechanism furthercomplicates the picture, exemplified by the TNF-alpha antagonists etanercept andinfliximab. Etanercept is a fusion protein consisting of the p75 binding unit of the TNF-alpha receptor and the Fc portion of human IgG1, whereas infliximab is a chimaeric anti-TNF-alpha IgG1 antibody. Although they are both TNF antagonists, infliximab is effective inCrohn’s disease, whereas etanercept is not. This would suggest that extrapolation ofefficacy from one indication to another will have to be on a case-by-case basis.There are many other issues to be resolved, among them whether or not such complexmolecules can be replicated, if the structure of two monoclonal antibodies can be rapidlyand reliable proved to be the same, if there are differences are they significant and towhat extent of clinical trials are required? Considering the first issue, it is fundamental tothe EU biosimilars pathway that a protein will only be considered as a biosimilar, if it hasthe identical amino acid sequence to the reference product. However, not all parts of themAb molecule are necessary for mediating the mechanism of action—there are regionsthat act as a framework—and it has been asked whether minor structural differences be29 European Medicines Agency. Concept paper on the development of a guideline on similar biological medicinalproducts containing monoclonal antibodies. London: EMA; 2009.EMEA/CHMP/BMWP/632613/2009.http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/11/WC500014438.pdf20 October 2010 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  27. 27. Biosimilars: surveying the market landscapeacceptable, if adequately justified 30. The EMA was not in a position to make a statementon this, other than to say that the issue of an identical amino acid sequence is animportant one that may evolve in future in the light of experience.With respect to clinical trials, mAbs are used in different ways from first-generationbiological drugs.Although used in patients with cancer, epoetin and filgrastim do not treatthe cancer itself but the symptoms anaemia and neutropenia.. Because of this, there areclinically relevant surrogate end points that can be measured in clinical trials, such ashaemoglobin and neutrophil levels. The availability of sensitive and rapidly measurablesurrogate end points is less likely for mAbs used in cancer and rheumatoid arthritis.Although clinical trials will need to be larger and longer, the issue is how large and howlong they will be. According to the Generics and Biosimilars Initiative, it is one thing torequire a trial for efficacy in a particular clinical indication. But if equivalence/non-inferiority studies were required against a reference product, they might require manymore patients than stand-alone trials showing efficacy. This would depend on the attitudeof regulators toward the specific biosimilar product 31.USAUntil March 2010, there was no US legislation allowing the FDA to provide a mechanism forthe approval of biosimilars, known there as follow-on protein products. And although thelegislation has now been passed, the FDA has not yet issued guidance.The marketing of biological products in the USA usually requires a biologics licence issuedunder the Public Health Service (PHS) Act, whereas small-molecule pharmaceuticals arehandled under the Food, Drug and Cosmetic (FDC) Act. In 1984, Congress passed theDrug Price Competition and Patent Term Restoration Act or the Hatch–Waxman Act. TheAct amended the FDC Act to create a simple, inexpensive pathway for FDA approval ofbioequivalent generic drugs (the abbreviated new drug application; ANDA). The Hatch–Waxman Act made no amendments to the PHS Act and there has been no abbreviatedapproval process for competitors to the original version of a biological product. The PHSAct has now been amended by part of the 2010 healthcare reform legislation to provide30 GaBIonline: Generics and Biosimilars Initiative. How far does similarity go?http://www.gabionline.net/Biosimilars/Research/How-far-does-similarity-go31 GaBIonline: Generics and Biosimilars Initiative. What clinical trials will be required for biosimilar mAbs?http://www.gabionline.net/Biosimilars/Research/What-clinical-trials-will-be-required-for-biosimilar-mAbsOctober 2010 21 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  28. 28. Biosimilars: surveying the market landscapeprovisions analogous to, but different from, those for small molecules under the Hatch–Waxman Act.LegislationMade law in March 2010 by the Obama administration, the Patient Protection andAffordable Care Act (PPAC Act) amends the PHS Act to establish an abbreviated approvalpathway for biological products that are demonstrated to be highly similar (biosimilar) toor interchangeable with an FDA-approved biological product. These new provisions mayalso be referred to as the Biologics Price Competition and Innovation Act of 2009 (BPCIAct), which is included as a subtitle to the PPAC Act.According to the FDA 32, under the BPCI Act, a sponsor may seek approval of a biosimilarproduct under new section 351(k) of the PHS Act. A biological product may bedemonstrated to be biosimilar if data shows that the product is highly similar to thereference product, notwithstanding minor differences in clinically inactive components.There must also be no clinically meaningful differences between the biological product andthe reference product in terms of safety, purity and potency.In May 2010, the FDA instituted the role of Acting Associate Director for Biosimilars withinthe Office of New Drugs (OND), and established the Biosimilars Review Committee (BRC).The BRC will advise the OND as it considers sponsor requests for advice about how todevelop a biosimilar product and as it reviews biosimilar BLAs. The FDA also stated itsintention to hold public meetings in order to receive information and comments from abroad group of stakeholders, such as healthcare professionals, healthcare institutions,manufacturers of biomedical products, interested industry and professional associations,patients and patient associations, third-party payers and the public regardingimplementation of the BPCI Act. The first of these will be on November 2 and 3, 2010 andwill cover the issues of biosimilarity, interchangeability, patient safety andpharmacovigilance, exclusivity and user fees, among others 33.It is not mandatory for guidance to have been issued for the FDA to consider biosimilarsapplications. But how the FDA will interpret the legislation is a matter for conjecture.Key32 US Food and Drug Administration. Implementation of the Biologics Price Competition and Innovation Act of2009. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm215089.htm33 Department of Health and Human Services, Food and Drug Administration. Approval Pathway for Biosimilar andInterchangeable Biological Products; Public Hearing; Request for Comments.http://thehill.com/images/stories/blogs/biosimilars.pdf22 October 2010 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  29. 29. Biosimilars: surveying the market landscapequestions are how ‘highly similar’ the FDA will require a biosimilar to be, and what ‘minordifferences in clinically active components’ will taken to mean. Companies may thereforebe reluctant to make a biosimilar product application until the discussion period is over andguidance has been issued.Substitution/interchangeabilityOnce approved, standard generic drugs can be automatically substituted by a pharmacistfor the reference product without the intervention of the prescribing healthcare provider inmany states. This is a key plank in the business model of generics manufacturers in theUSA. However, biosimilars are not automatically interchangeable under the PPAC Act,which has effectively created a second category of biosimilars—those that areinterchangeable.In its commentary on the PPAC Act, the FDA states that “in order to meet the higherstandard of interchangeability, a sponsor must demonstrate that the biosimilar productcan be expected to produce the same clinical result as the reference product in any givenpatient and, for a biological product that is administered more than once, that the risk ofalternating or switching between use of the biosimilar product and the reference product isnot greater than the risk of maintaining the patient on the reference product.” This ismuch more difficult to prove. In the short term, it may be impossible as considerablepharmacovigilance data collection will be required before a biosimilars manufacturer maybe able to make a claim for interchangeability status.The first biosimilar to be granted interchangeability status will receive one year ofmarketing exclusivity. Other non-interchangeable products can still be approved.Data exclusivityThe PPAC Act provides four years of data exclusivity from the date on which the referenceproduct was first licensed During that period, a biosimilar application may not be made.There is also provision for a further eight years of marketing exclusivity when a biosimilarproduct may not be sold, and six months paediatric exclusivity. This exclusivity runsconcurrently with the patents.October 2010 23 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  30. 30. Biosimilars: surveying the market landscapeThe total 12-year market exclusivity period granted by the legislation, and which isadditional to any existing patent rights, is contentious. In June 2009, an FTC Report 34concluded that innovative products should not receive additional market exclusivity beyondthe term of their patents because the original products would keep 70 to 90 percent oftheir market share. Manufacturers have disagreed, arguing that 12 years of exclusivity areessential because it is easier to design around patents for biological drugs than those forsmall-molecule drugs. This claim has been refuted by the FTC (see ‘Patents’ under‘Biosimilars are not generics’).Perhaps good news for potential biosimilars manufacturers is that because the biosimilarapplication can be filed as soon as four years after approval of the reference product, anypatent litigation may be resolved well before the 12-year period of regulatory exclusivityhas expired 35. However, it has been suggested that manufacturers of potential biosimilarsmay prefer to ignore the new pathway and opt to file a standard Biologics LicenseApplication (BLA), which would not be subject to the 12-year delay. Any higher cost wouldbe offset by the greater profit opportunity available to early market entrants 36. Teva optedfor this route for its filgrastim (Neutroval) when they submitted a full BLA in December2009. In November 2009, they had sought to have declared invalid two of Amgen’sNeupogen patents that expire in 2013.Extrapolation to other indicationsThe PPAC Act does not give specific guidance on whether a biosimilar tested in one patientpopulation will receive approval for all the indications that the reference product isapproved for.Patent information exchangeThere is no equivalent of the ‘Orange Book’, created by Hatch–Waxman, for BLA holders.This requires each NDA holder to identify any patent, in existence at the time of filing orissued subsequently, that claims the drug or a method of using the drug and for which anaction of infringement can reasonably be asserted. The biosimilars legislation therefore34 Emerging Health Care Issues: Follow-on Biologic Drug Competition. Federal Trade Commission; June 2009.http://www.ftc.gov/os/2009/06/P083901biologicsreport.pdf35 Fairchild BA. Updated patent strategy for biosimilar era. Genetic Engineering and Biotechnology News.http://genengnews.com/gen-articles/updated-patent-strategy-for-biosimilar-era/3343/?page=136 Engelberg AB, Kesselheim AS, Avorn J. Balancing innovation, access, and profits—market exclusivity forbiologics. N Engl J Med 2009;361:1917–19.24 October 2010 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  31. 31. Biosimilars: surveying the market landscapecreated a unique scheme for the confidential exchange of information regarding patentrights relevant to the biosimilar, and the reference product so that issues of patent validityor infringement can be resolved before approval of the biosimilar. The scheme is complexand includes penalties for non-compliance. Yet it represents a default which originatorsand biosimilar companies can find alternatives to.Biological products approved as drugsAlthough a specific biosimilar approval pathway has only recently been approved, somebiological products have seen competition in the USA for some years. Some earlybiological drugs, such as somatropin and insulin, were approved as drugs under the FDCAct. ‘Biosimilar’ versions cannot be approved as generics under 505(j) (ANDA) regulations,as these require a drug to be identical in active ingredient, form, route of administrationetc. Instead, they have received approval for New Drug Applications (NDAs) under section505(b)(2) of the FDC Act.Examples of biopharmaceuticals approved under these provisions are Sandoz’ Omnitrope(somatropin), LG Life Sciences’ Valtropin (somatropin), several versions of hyaluronidase,Fortical (salmon calcitonin) and GlucaGen (glucagon). More recently, Sandoz /Momenta’sversion of enoxaparin was granted an ANDA. (See ‘Low-molecular-weight heparins’ under‘Target biopharmaceutical products’)October 2010 25 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  32. 32. Biosimilars: surveying the market landscapeOther marketsFollowing the EU’s lead, biosimilar approval guidelines have been implemented orproposed in several markets, including some emerging markets that have adopted the EUguidelines or used them as a basis for their own (Table 1).Table 1. Countries outside the EU and the USA in which guidelines for an abbreviatedregulatory pathway for biosimilars existCountry Regulatory body/Guideline title Date of implementationJapan Ministry of Health, Labor and Wealth Mar 2009 Based on similar scientific principles to the EMA approval pathwayS. Korea Jun 2009Malaysia Ministry of Health Malaysia July 2008 Guidance document and guidelines for registration of biosimilars in Malaysia Based on EMA guidelinesSingapore Health Sciences Authority Aug 2009 Guidance on registration of similar biological products in SingaporeAustralia Therapeutic Goods Administration Aug 2008 Adopted EMA guidelinesCanada Health Canada Mar 2010 Draft guideline on subsequent entry biologicalsTurkey General Directorate of Pharmaceuticals and Aug 2008 Pharmacy Instruction manual on biosimilar medical productsMiddle Expert panel recommended the implementation of Recommendation 2008East the EMA guidelines 37Saudi Drug master file requirements for the registration Draft Aug 2008Arabia of biosimilars37 Curr Med Res Opin 2008;24:2897–903.26 October 2010 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  33. 33. Biosimilars: surveying the market landscapeCountry Regulatory body/Guideline title Date of implementationWHO Guidelines on evaluation of similar biotherapeutic 2009 products (SBPs)Reproduced with permission from Ingrid Schwarzenberger, Head of Global RegulatoryAffairs Biopharmaceuticals, Sandoz GmbH.Japan published draft guidelines in September 2008. In November of that year, KisseiPharmaceutical filed Japan’s first biosimilar application, for its epoetin kappa, which waslaunched in May 2010. However, the first biosimilar to be approved in Japan was Sandoz’Omnitrope (somatropin) in June 2009, three months after the approval guideline wasadopted.‘Biosimilar’ versions of biological medicines have been available in both India and China forseveral years. However, their regulatory systems are less stringent and the productswould not be approvable as biosimilars in the major markets. Furthermore, these countrieshave underdeveloped pharmacovigilance systems and provide few adverse drug reactionreports to the WHO International Programme on Drug Monitoring database, managed bythe Uppsala Monitoring Centre 38.“Biosimilars are only those products which have been approved in Europe according to thevery stringent European guidelines for the approval of biosimilars,`explains Dr IngridSchwarzenberger, Head of Global Regulatory Affairs Biopharmaceuticals at Sandoz, toldFirstWord. Those approved in Canada or Japan could also be called biosimilars and soon,hopefully, also those approved in the USA. But all the other copy products of biologicswhich are approved and available in India, China, Korea, Latin America must not be calledbiosimilars. These products have been approved nationally with very little data and havenot been subject to a comprehensive comparability exercise as it is required for the EU,Japan, Canada or the USA.”According to the Generics and Biosimilars Initiative, India has the greatest acceptance of‘biosimilars’. Around 50 biopharmaceutical products have been approved for marketing inIndia in recent years, with more than half of them being ‘biosimilars’. Until 2005, Indianlaw allowed companies to manufacture generic versions of products including biologicals,as long as the process used was different from the originator’s. However, India joined the38 WHO Drug Information 2009;23:87–94.October 2010 27 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  34. 34. Biosimilars: surveying the market landscapeWorld Trade Organization (WTO) in 1995 and in 2005 started the process of becomingcompliant with the TRIPS agreement (WTO’s Trade-Related Intellectual Property Rights)and recognizing product patents. This may well lead to fewer biogenerics being sold.India has no specific approval pathway for biosimilars. Approval is on a case-by-casebasis. However, in 2010, the Indian government began the process of streamlining thebiosimilars approval process and it has been suggested that the WHO biosimilarsguidelines (see below) could help 39. Currently, responsibility for regulating thedevelopment and approval of all biological drugs is shared between the Review Committeeon Genetic Manipulation (RCGM; Department of Biotechnology) and the Drugs ControllerGeneral of India (DCGI). The RCGM gives permission to either develop a recombinantclone or, if a clone is imported, to perform toxicology studies. The preclinical protocol isalso submitted to the RCGM and once preclinical studies are completed, the sponsorapplies to the DCGI to conduct clinical trials; for a biosimilar, this typically includes a non-inferiority study but not extensive clinical trials. The DCGI also gives final marketingapproval 40.Jill Deviprasad of Biocon believes that a stringent regulatory framework in India coulddeny less well-off Indians access to biological drugs. There is no managed care programmein India, no health insurance and patients have to pay for drugs themselves. However, anIndian pharmaceutical industry commentator believes that the lack of a specific regulatoryframework for biological drugs might allow poor-quality products to be sold, which couldruin the reputation of the Indian industry.Global biosimilars strategyThe WHO seeks to promote improved access to biological drugs at a reduced price; in2007, the body formally recognised the need for additional global regulatory guidelines forthe evaluation and regulation of biosimilars. Since then, WHO has been working withregulators from many countries on a draft document to provide a base standard for thedevelopment and evaluation of biological products by abbreviated licensing pathways. Thedocument was finalised in 2010 41 and, according to WHO, “can be adopted as a whole, or39 Som N. Bionomics of biosimilars. Biospectrum Asia 2010, Feb 04.http://www.biospectrumasia.com/content/040210IND11983.asp40 Iyer H. MAbs 2009;1:411–16.41 WHO. Guidelines on evaluation of similar biotherapeutic products (SBPs). Geneva: World Health Organization;2009.http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf28 October 2010 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  35. 35. Biosimilars: surveying the market landscapepartially, by national regulatory authorities worldwide or used as a basis for establishingnational regulatory frameworks for licensure of these products.” At the 8th EGA BiosimilarsSymposium in September 2010, EGA Director General Greg Perry noted: “This is animportant step towards a global, harmonised, regulatory approach”.If worldwide development programmes are to become a reality, the generic andbiotechnology industries need to persuade the regulatory authorities to work together todevelop harmonised regulations. A key issue is the source of the reference product. TheEU regulations, the Japanese guideline and the US legislation require the use of areference product authorised in their jurisdiction. This means that new clinical trials mustbe conducted in each region, a situation described by Ingrid Schwarzenberger at the 7thEGA Symposium on Biosimilars in April 2009 as “unnecessary, unethical… anduneconomical” 42. Dr Schwarzenberger told FirstWord that it will take several more years topersuade the regulatory authorities to accept that duplication of preclinical/clinical studiesin each region is not necessary. She also commented that the resulting ‘global datapackage’ used for the successful approval in the EU, USA and Japan could then be used forapproval in all other countries in the world, without any further local study requirements.The recent passage of US biosimilars legislation may move the situation forward. “Oneimmediate consequence [of the legislation] is that the environment is now ripe for FDAand EMA to increase their dialogue on biosimilar medicines, which we fully support,” saysSuzette Kox of the EGA.42 Schwarzenberger I. Global development, the way forward: the EGA’s perspective. 7th EGA Annual Symposiumon Biosimilars; London, 23–24 April 2009.http://www.egagenerics.com/doc/ega_biosimilars_Schwarzenberger_090424.pdfOctober 2010 29 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  36. 36. Biosimilars: surveying the market landscapeTarget biopharmaceutical productsIn the market for traditional drugs, relatively few compounds account for adisproportionate share of sales and profits. It is these that will attract the most interestfrom biosimilars manufacturers, as in the market for traditional generic drugs. There,several studies have established that the number of entrants is strongly related to the sizeof the branded product’s sales before entry 43. Teva, the world’s largest generic drugmanufacturer and a leader in the biosimilars market, projected in 2010 that about$53 billion in sales of branded biological drugs will be exposed to biosimilar competition by2015 through patent expirations alone.Biopharmaceuticals fall into several categories depending on their complexity (Table 3).Some of the simpler ones have already been the subject of biosimilar competition inEurope, while the more complex promising products—the monoclonal antibodies andfusion proteins—remain remain are subjected to competition. This section of the report willlook at the biosimilar competition that exists and discuss the potential for the next wave ofproducts.43 Grabowski H, Cockburn I, Long G. Health Aff (Millwood) 2006;25:1291–1301.30 October 2010 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  37. 37. Biosimilars: surveying the market landscapeTable 3. The major classes of biological drugsProduct class DefinitionEU biosimilars guidelines exist Somatropin (growth Non-glycosylated protein of 191 amino acids hormone) Used for growth failure, growth hormone deficiency, short bowel syndrome and HIV-related weight loss or wasting Epoetin Heavily glycosylated protein hormone of 165 amino acids that stimulates red blood cell production Used for treating anaemia in patients with chronic kidney disease or patients with cancer who are receiving chemotherapy Filgrastim (G-CSF) Minimally glycosylated protein of 174 amino acids that stimulates the production of white blood cells Used to restore white blood cell levels and prevent infections in patients with cancer or who have had a bone marrow transplant Insulin Peptide of 51 amino acids Used in Type I and Type II diabetes Interferon alfa Protein of 165 amino acids secreted in response to infection Used for chronic hepatitis B or C virus infection and cancers Heparins Glycosaminoglycans (mucopolysaccharides) – long, unbranched polysaccharides used to prevent blood coagulationEU biosimilars guidelines in preparation Monoclonal antibodies and Based on the antibodies (immunoglobulins) the fusion proteins body uses to fight infection and cancer and which are involved in the development of immune conditions such as rheumatoid arthritis and psoriasis Interferon beta Glycoprotein of 166 amino acids secreted in response to infection Used in multiple sclerosisOctober 2010 31 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  38. 38. Biosimilars: surveying the market landscapeProduct class Definition Follitropin (follicle- Glycoprotein consisting of two polypeptide chains stimulating hormone; FSH) that regulates growth, development and reproduction Used in fertilization medicine for women, and for men to induce and maintain spermatogenesisBiosimilars guidelines not available or planned Vaccines Live, weakened or killed microorganisms, or recombinant subunits of the infecting organism Enzymes Replacement for enzymes deficient owing to a genetic disorder such as Gaucher’s disease ThrombolyticsImiglucerase Blood coagulation factors Naturally occurring or recombinant coagulation factors for the treatment of haemophilia Factor VIII Factor IXFourteen biological products have been approved in the EU under the biosimilars pathway:two somatropins, five epoetins and seven filgrastims. A further five products had beensubmitted for approval by December 2009, but the CHMP either declined to recommendapproval or the products were withdrawn from the authorisation process. These were oneinterferon alfa-2a, one interferon beta-1a and three insulin products (see relevant sectionsbelow).32 October 2010 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved
  39. 39. Biosimilars: surveying the market landscapeSomatropin (growth hormone)Several somatropin products are available that have been developed as new products (seeTable 5). There are no second-generation products. However superior branded versionsexist with improved delivery systems. Biopartners says it is on track to be the firstcompany to submit a sustained-release somatropin formulation that will cut the number ofself-administered injections from one per day to one per week.Table 5. Original somatropin productsBrand Distributor ManufacturerGenotropin Pfizer/Pharmacia GenentechNutropin/Nutropin AQ Genentech/Ipsen GenentechHumatrope Lilly LillyNorditropin Novo Nordisk Novo NordiskSaizen/Serostim/Zorbtive Merck Serono Merck SeronoZomacton Ferring FerringTwo biosimilar somatropins have been approved in the EU (Table 6), one of which isSandoz’ Omnitrope 44, the first biosimilar to be approved in a highly regulated market. Thishas been subject to relatively few competitors compared with epoetins and filgrastims, forseveral reasons. The somatropin market is low-value, saturated and device-driven;manufacturers engage in aggressive pricing tactics to maintain market share. Moreover,the patient population is predominantly paediatric, with treatment typically lasting sixyears, and biosimilars will almost certainly be restricted to new patients. There are alsosuperior formulations available that would out-compete basic lyophilized biosimilar growthhormone.44 Stanhope R, Sörgel F, Gravel P, Pannatier Schuetz YB, Zabransky M, Muenzberg M. Bioequivalence studies ofOmnitrope, the first biosimilar/rHGH follow-on protein: two comparative phase 1 randomized studies andpopulation pharmacokinetic analysis. J Clin Pharmacol 2010 Feb 19. [Epub ahead of print].October 2010 33 All Contents Copyright © 2010 Doctors Guide Publishing Limited. All Rights Reserved

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