Biosimilars
H Grabowski,Duke University,Durham,NC,USA
G Long and R Mortimer,Analysis Group,Inc.,Boston,MA,USA r2014Elsevier Inc.All rights reserved.
Introduction
Although the biotech industry is a relatively new source of medical therapies–itsfirst new drug approvals came in the early1980s–it has recently become a major source of drug industry growth and innovation.New biological entities (NBEs)have a significantly higher likelihood of being afirst-in-class or novel introduction compared with other new drug entities(Grabowski and Wang,2006).For example,the on-cology class has experienced the introduction of breakthrough monoclonal antibodies and targeted biological agents re-sulting from increased knowledge of the molecular mech-anisms for cancer(DiMasi and Grabowski,2007a).Substantial improvements in survival,morbidity,and patients’quality of life have been documented in diseases previously resistant to successful treatment,such as aggressive HER-2positive breast cancer(Smith et al.,2007)and disability associated with rheumatoid arthritis(Weaver,2004).
Although NBEs have been an important source of bio-pharmaceutical innovation,they have also accounted for a rising share of overall drug expenditures in the US and worldwide.They now account for approximately one-quarter of all the US expenditures on pharmaceuticals and represent approximately half of all products in clinical testing(Trusheim et al.,2010).NBEs for oncology patients and other indications also can cost tens of thousands of dollars per course of treat-ment.They are also frequently targeted to life-threatening and disabling diseases.These facts and trends have made bio-logical entities an increasing focus of attention for policy-makers and payers grappling with rising healthcare costs and budgets.
A recent development in Europe and the US is the estab-lishment of an abbreviated pathway for the so-called biosi-milars–biological products that are similar to,but not identical with,a reference biological product in terms of quality,safety,and efficacy.Biologics are typically more com-plex molecules than small-molecule chemical drugs.Biologics are manufactured not through chemical synthesis but through biological processes involving manipulation of genetic ma-terial and large-scale cultures of living cells,where even small changes to the manufacturing process may lead to clinically significant and unintended changes in safety and efficacy.As a result,establishing that a biosimilar is‘similar enough’to achieve comparable therapeutic effects in patients is a much more challenging task for companies and
regulators than es-tablishing bioequivalence for generic chemical drugs.Biosi-milars generally require analytical studies,animal testing data, and some clinical trial evidence on safety and efficacy to gain approval.Biosimilars can provide an important new source of competition to established biological entities.A key issue at the present time is how this competition is likely to develop and how it will influence expenditures for biopharmaceuticals by payers and consumers,investment in innovation,and the research,development,and marketing processes for manufacturers.
The EU has had a framework in place for approving biosimilars since2005.The European Medicines Agency (EMA)has issued general and class-specific guidelines in six classes and has approved biosimilars in three product classes–somatropins,erythropoietins,and granulocyte colony-stimulating factors(G-CSFs).The experience of bio-similars in various European countries is considered later in this article.
In March2010,as part of the overall Patient Protection and Affordable Care Act,the US Congress created an abbreviated pathway to approve biosimilars.The Food and Drug Administration(FDA)is in the process of implementing the law,including consulting with potential entrants and de-veloping and releasing for public comment draft guidelines. The US situation is of particular interest as it has been the center of biotech innovation and the country with the largest expenditures on biological products.Al
though the US has a strong history of generic drug utilization,until the2010Act, there was no corresponding pathway for biosimilar entry.
In this article,the authorsfirst discuss regulatory,re-imbursement,and economic factors that will affect how competition between branded biologics and biosimilars may evolve.These factors are based on current market dynamics including initial European biosimilar experiences,the pro-visions of the new US law enacted in2010,and the US ex-periences under the Hatch-Waxman Act.Taking into account the scientific,manufacturing,and other differences between biologics and chemically synthesized drugs,and between the regulatory frameworks governing each,expected biosimilar competition is then compared and contrasted with generic competition.Finally,the likely impact of biosimilars on cost savings is briefly assessed and potential impacts on innovation incentives in the biopharmaceutical industry is discussed. Biosimilar Experience in the European Union
The EU has had in place a well-defined regulatory pathway for biosimilars for several years.In October2005,the European Commission adopted an EMA framework for the approval of biosimilars.The framework includes an overarching set of principles;general guidelines on quality,safety,and efficacy; and guidelines specific to product classes.To date,the EMA has issued guidelines in six therapeutic classes.Guidance is under development for three other major types of biol
ogics: monoclonal antibodies,recombinant follicle-stimulating hormone,and recombinant interferon beta.Other countries have used a European-like approach,including Canada (where biosimilars are termed‘subsequent entry biologics’(SEBs))and Japan.Australia adopted the EU guidelines in August2008.
Encyclopedia of Health Economics,Volume1doi:10.1016/B978-0-12-375678-7.01208-6 86
The EMA has required at least one Phase II or III clinical trial for biosimilars to demonstrate similar safety and efficacy to their reference molecules.As opposed to the legislative biosimilar framework in the US,in which the FDA approves applications as biosimilars or interchangeable biosimilars,the EMA framework does not result in anyfindings of inter-changeability,and questions of substitution are left to the member states to regulate.Local substitution laws differ across the EU member states,with some including explicit prohib-itions on automatic substitution for biologics(such as Spain and France).
Since2006,14biosimilar products in three therapeutic classes–erythropoietins,somatropin,and granulocyte colony-stimulating factors(G-CSFs)–have been approved, referencing four innovative products,and13are currently marketed in Europe.Three applications for biosimilar human insulin(with different formulations)were withdrawn in December2007,based on failure to demonstrate compar-ability,and one approved product was later withdrawn (Table1).
Empirical Evidence from Biosimilars in the European Union Germany has exhibited the highest level of aggregate demand and market share for any biosimilar product(erythropoietin). To date,Germany’s Federal Healthcare Committee,which decides which products and services are reimbursed,has em-braced biosimilars wholeheartedly.In addition to a reference pricing system in place for biosimilars,Germany has specific targets or quotas for physician and sickness funds for biosi-milars that vary by region.Furthermore,Germany is a main source of biosimilar manufacturing in Europe,and biosimilar companies generally enjoy strong reputations with healthcare providers.
Uptake in other European countries has been slower.In some cases,this reflects later biosimilar entry dates and the timing of reimbursement approval by government payers. Although evidence from experiences in Germany or other European countries with biosimilar substitution are not dir-ectly applicable to other markets,given differences in the markets and pricing,access,and reimbursement systems,they nevertheless suggest that over time,payers,physicians,and patients will accept biosimilars.
Table2summarizes biosimilar shares infive large Euro-pean countries:France,Germany,Italy,Spain,and the UK,for the therapies somatropin,erythropoietin alpha,and G-CSF from2007to2009.The extent of biosimilar penetration var-ied substantially both across therapies within a country and across countries
for the same therapy.In Germany,the biosi-milar erythropoietin alpha accounted for62%of total biosi-milar and innovator product units sold in2009,within2years of its launch;by contrast,in France,Italy,Spain,and the UK, biosimilar erythropoietin alpha had less than a5%share in 2009.Biosimilar market shares for G-CSF in2009ranged from 21%(UK)to7%(Spain).However,there is evidence that biosimilar G-CSF shares have grown rapidly in several Euro-pean countries since2009(Grabowski et al.,2012).In par-ticular,a study undertaken by IMS Health found that biosimilars in the G-CSF class had shares more than50%in Germany,France,and the UK by the third year after launch, and characterized the market for this class in these counties as being commodity-like and mainly controlled by payers(IMS, 2011a).In contrast,the shares for somatropin are lower than the other two classes in most European countries,reflecting conservative physician prescribing and a differentiated market with competition based on price,promotion,and delivery device-based patient convenience.
Biosimilar market development(and share uptake)may differ between European countries and the US,given the dif-ferences between their healthcare systems.For example,the US is more litigious than Europe;thus,the FDA may decide to proceed more cautiously and require more clinical data than the EMA has in the past.This broad generalization may not always hold true;however,in the US,the FDA ap
proved Sandoz’s enoxaparin sodium abbreviated new drug appli-cation(ANDA)as a fully substitutable generic(referencing Lovenox s)requiring no clinical evidence.In contrast,the EMA requires clinical data to approve a biosimilar application for a low molecular weight heparin.Future research com-paring biosimilar market attitudes and experience in European countries,countries with a European-like , Australia,Japan,and Canada),the US,and other , the so-called‘BRIC’nations of Brazil,Russia,India,and China)is needed.Given the significant differences in the regulatory,medical delivery,and reimbursement systems be-tween less-developed and more-developed nations,the pattern of biosimilar competition may also be very different.
The United States Biologics Price Competition and Innovation Act
The Biologics Price Competition and Innovation Act of2009 (BPCIA),enacted as part of the Patient Protection and Affordable Care Act of2010(PPACA),created an abbreviated pathway for the FDA to approve biosimilars.This legislation complements the28-year-old Drug Price Competition and Patent Term Restoration Act of1984(generally referred to as the Hatch-Waxman Act),which provides a clear path for generic drug entry in the case of new chemical entities(NCEs) approved under the Food,Drug,and Cosmetic Act(FD&C Act)through the ANDA process.Through that process,generic drugs demonstrated to be bioequivalent to off-patent refer-ence drugs may be approved without the su
bmission of clin-ical trial data on efficacy and safety.ANDA approval requires a finding that the generic drug is bioequivalent to its reference drug and has the same active ingredient(s),route of ad-ministration,dosage form and strength,previously approved conditions of use,and labeling(with some exceptions).Some initially marketed biologic products were approved under the FD&C Act,such as human growth hormones.However,most large molecule biologic medicines were approved under the Public Health Service Act and have not been subject to generic competition under the ANDA process of the Hatch-Waxman Act.Biologic medicines approved under the Public Health Service Act will now be subject to competition from products coming to market through an expedited biosimilar approval process–relying at least in part on the innovator’s package of
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data or a prior FDA approval–for thefirst time as a result of the BPCIA.
The key provisions of the new legislation establishing an abbreviated pathway for the FDA to approve a biosimilar are:•Biosimilarity:A biosimilar does not have to be chemically
identical to its reference product but must be‘‘highly similar to the reference product notwithstanding minor differences in clinically inactive components’’and there must be‘‘no clinically meaningful differences,in terms of safety,purity,and potency.’’(PPACA,Section7002(b)(3))•Interchangeability:The FDA may deem a biosimilar inter-changeable with its reference product if it can be shown that it‘‘can be expected to produce the same clinical result as the reference product in any given patient’’and that‘‘the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.’’(PPACA,Section7002(k)(4))Thefirst biosimilar shown to be interchangeable is entitled to a1-year exclusivity period during which no other product may be deemed inter-changeable with the same reference product.•Regulatory review:The FDA will determine whether a product is biosimilar to a reference product based on step-wise consideration of analytical,animal-based,and clinical studies(including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics).In February 2012,the FDA released thefirst three documents in a set of guidance
documents for the development of biosimilars under BPCIA.
•Regulatory Exclusivity for the innovative biologic:Bio-similar applications may be submitted beginning4years after FDA approval of the reference innovative product.
Before the FDA can approve a biosimilar using the
abbreviated pathway,there is a12-year period of ex-
clusivity following FDA approval of the innovative bio-
logic.An additional6months of exclusivity is available
for the reference innovative biologic if pediatric-study
requirements are met,which applies to both the4-and
12-year exclusivity periods.The most important(and
contentious)of these exclusivity provisions is the12years
of exclusivity for an innovative biologic before a biosi-
milar can enter using an abbreviated application.This12-
year exclusivity term is referred to as regulatory exclusivity
in distinction from the exclusivity afforded through pa-
tents granted by the US Patent and Trademark Office.•Limitations on12-year exclusivity:Several types of licen-sures or approvals are not eligible for12-year exclusivity,
including:(1)a supplemental biologics license appli-
cation(sBLA)for the reference biologic;(2)a subsequent
BLAfiled by the same sponsor,manufacturer,or other
related entity as the reference biologic product that does
not include structural changes in a biologic’s formulation
(e.g.,a new indication,route of administration,dosing
schedule,dosage form,delivery system,delivery device,or
strength);or(3)a subsequent BLAfiled by the same
sponsor,manufacturer,or other related entity as the ref-
erence biologic product and that includes structural
changes in a biologic’s formulation but does not result in
improved safety,purity,or potency.•Reimbursement:A potential disincentive for biosimilar adoption is mitigated by setting the reimbursement for a biosimilar under Medicare Part B at the sum of its Average Selling Price(ASP)and6%of the ASP of the reference biologic.
•Patent provisions:The BPCIA requires a series of poten-tially complex private information exchanges between the biosimilar applicant and reference product sponsor,fol-lowed by negotiations and litigation,if necessary.In contrast to the patent provisions for NCEs under the Hatch-Waxman Act,there is no public patent listing akin to the Orange Book,no30-month stay when a patent infringement suit is brought,and no180-day exclusivity awarded to thefirstfirm tofile an abbreviated application and achieve a successful Paragraph IV patent challenge.
documented evidenceFood and Drug Administration Regulations and the Costs of Developing a Biosimilar
The new law authorizing biosimilars gives broad latitude to the FDA to define the process and standards for approval.FDA decisions will affect both the demand for and the supply of biosimilars:
•The level of evidence required will affect the costs of market entry,the number of biosimilar entrants,and the assets and capabilities required to compete successfully.
•The level of clinical trials and other evidence required to establish interchangeability or similarity will also poten-tially affect the level of market adoption,as greater levels of evidence may increase physicians’,payers’,and patients’confidence in a biosimilar medicine.
Table2Initial biosimilar competition in selected EU countries:
Market share evidence
Biosimilar unit share of the molecular entity
France Germany Italy Spain UK
Somatropin
20072%3%6%1%0%
200810%6%17%1%0%
200916%8%27%5%1%
Erythropoietin alpha
20070%0%0%0%0%
20080%35%0%0%0%
20094%62%0%4%1%
GCSF
2007–––––
20080%1%0%0%2%
20097%17%N/A9%21%
Note:Biosimilar share of unit sales are measured based on Defined Daily Dose.
Biosimilar G-CSF was not launched until2008,so biosimilar shares for2007are not
reported in Table3.For G-CSF in Italy in2009,the biosimilar share is recorded as N/A
to reflect insufficient data for calculating a biosimilar share–fewer than5000DDDs
were reported in the data for combined innovator and biosimilar unit sales in Italy that
year.
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•Naming conventions and pharmacovigilance requirements for biosimilars will affect market entry and perceptions of substitutability by physicians,payers,and patients,as well as safety monitoring after launch.
•Whether data on one indication can be extrapolated to others–absent additional clinical trials in that patient population will have an impact on entry decisions,per-ceptions of substitutability,and biosimilar market uptake.•Definitions of what constitutes changes in‘safety,purity, or potency,’as they are applied to determine whether a 12-year exclusivity is to be authorized for next-generation products will affect biotech investor incentives.
Criteria for Establishing Biosimilarity
The initial draft guidance documents released by the FDA in February2012state that‘‘FDA intends to consider the totality of the evidence provided by a sponsor to support a demonstration of biosimilarity’’(emphasis added).For a given biosimilar ap-plication,the FDA draft guidance notes that‘‘(t)he scope and magnitude of clinical studies will depend on the extent of re-sidual uncertainty about the biosimilarity of the two products after conducting structural and functional characterizations and possible animal studies.’’(Food and Drug Administration (FDA),2012a,pp.2,12).Theoretically,this could encompass,at one extreme,only a bioequivalence study(similar to what is required for generic approval under Hatch-Waxman)or,at the other extreme,when science and experience require more data,a full program of clinical studies equivalent to that included in a biologic’s license application.
FDA officials,in a New England Journal of Medicine publication,had previously stated that‘‘[a]lthough additional animal and clinical studies will generally be needed for pro-tein biosimilars for the foreseeable future,the scope and extent of such studies may be reduced further if more extensivefin-gerprint-like characterization is used.’’(Kozlowski et al.,2011, p.386)In the future,the agency hypothesizes,the current state-of-the-art for analytic characterizations may advance to allow highly sensitive evaluations of relevant product attri-butes and permit a‘fingerprint-like’identification of very si
milar patterns in two different products(such strategies were cited in the FDA’s approval of the Sandoz ANDA for enox-aparin sodium,a complex mixture,mentioned later in this article.)
The costs of an FDA submission for the US approval could be lower for biosimilars already on the market in Europe if the biosimilar can rely on previously undertaken European clinical trials,at least for some products.In its draft guidance documents released in February2012,the FDA noted it will accept clinical studies undertaken for approval in other jurisdictions under certain circumstances,when justified scientifically and when accompanied by‘bridging’data.However,it also noted,‘‘[a]t this time,as a scientific matter,it is unlikely that clinical com-parisons with a non-US-licensed product would be an adequate basis to support the additional criteria required for a de-termination of interchangeability with the US-licensed reference product,’’and the specific data requirements for products will be determined by the FDA on a case-by-case basis.(Food and Drug Administration(FDA),2012b,p.8.)
If the FDA requires significant clinical trial evidence,ap-provals for biosimilars,as compared with generics,will require a much bigger investment.The cost for biosimilar approval will depend on the number and size of the necessary clinical trials,the number of indications involved,and other specific FDA requirements.The current requirement for a BLA is typically two large-scale Phase III pivotal trials.If the FDA requires at least one Phase II/III type study comparable to those undertaken by innova
tors,then the out-of-pocket costs will likely be in the range of US$20million to US$40million for the studies alone.In addition,the preclinical costs asso-ciated with biosimilars may in some cases be higher for bio-similars than for innovative products,as they entail modifying the production process to achieve a specific profile that very closely approximates the reference product without the benefit of the innovator’s experience.Others have estimated that for very complex biologics such as some monoclonal antibodies, biosimilar development costs could total US$100million to US$200million and take8or more years to bring a product to market(Kambhammettu,2008).In contrast,the cost of completing bioequivalence studies for generic drugs is esti-mated to be only US$1million to US$2million. Regulatory Requirements for an Interchangeability Designation
Another key regulatory issue will be the analytical and clinical evidence required to deem a biosimilar interchangeable with its reference product,thus enabling automatic substitution without physician approval,subject to relevant state laws. Under the BPCIA,for products used more than once by pa-tients(the majority of biologics),the biosimilar sponsor will need to demonstrate that switching between the biosimilar and reference product poses no additional risk of reduced safety or efficacy beyond that posed by the reference product alone.Postapproval interchangeability assessments may require a strong postmarketing system and evaluation of postmarketing data.
Achieving an FDAfinding of interchangeability may be as-sociated with far greater development costs than achieving a determination of biosimilarity,so it may be limited initially to a select few examples where molecules meet certain tests for es-tablishing‘sameness’through differentiated characterization or other available technology.For instance,the availability of dif-ferentiated analytical characterization technology supported the FDA’s approval of Sandoz’s ANDA for generic enoxaparin so-dium(referencing Lovenox s).Although not a biosimilar (Lovenox s,a chemically synthesized product derived from natural sources,has been described as a complex mixture),the factors that the FDA cited in its approval may give some insight into the Agency’s current approach and how continued tech-nological change could influence the evidence necessary to es-tablish interchangeability in the future.
For classes of more complex biologics,applications for biosimilarity will likely require some clinical trial data in order to be approved and costly switching trial data in order to be deemed interchangeable.Manyfirms may elect not to make the investments necessary to pursue interchangeability ini-tially,given the current state of scientific knowledge regarding
90Biosimilars
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