Presentation on theme: "Biosimilars Knowledge Connect Slide Resource This slide deck has been designed to be used as a central resource from which pertinent slides can be extracted."— Presentation transcript:
1Biosimilars Knowledge Connect Slide Resource This slide deck has been designed to be used as a central resource from which pertinent slides can be extracted as needed and is not intended for use in its entirety
2Introduction to biological medicines and biosimilars A biosimilar is an approved version of a biological medicine with an identical primary amino acid sequence to the originator and developed with the intention to be as close to the originator as possibleLike biological medicines, biosimilars are complex protein molecules that are produced by living organismsDuring the past 15 years, biological medicines have had a profound impact on healthcareprimarily in the areas of rheumatology and oncologyas well as endocrinology, cardiology, dermatology, gastroenterology, and neurologyMany of the world’s top-selling medicines are now biological medicinesHowever, biological medicines are expensive (sometimes by several orders of magnitude more than small-molecule chemical drugs), limiting patient accessAs many biological medicines come off patent globally, there is great interest in the development of biosimilars, which are likely to be more affordableBiological medicines have added new treatment options for various diseases, including some for which no effective therapies were previously available or were clearly inadequate. For example they have provided lifesaving replacement proteins for patients with rare diseases who cannot produce the proteins themselves (e.g. resistant forms of Gaucher disease).
3The increasing rate of development of biosimilars It has been estimated that 31 different companies were developing biosimilar monoclonal antibodies (as of March 2012), compared with 18 companies as of Sept 2011 – an increase of 67% in a 6-month period.1Biological medicines due to come off patent2,3Patent expiries expected: 99Patent expiries expected: 91Patent expiries expected: 462010–20152016–2020Post–2020The sales of biosimilars increased from €3.3 million to €65.5 million between 2007 and 2009.Barkalow F, Biosimilar monoclonal antibodies. In the pipeline: major players and strategies. Citeline.Haag T (Lonza) and Krattiger C (GfK). The emergence of biosimilars—How are they different from generics and what are the implications from marketing? EphMRA presentation. June 29, 2011.
4As of Sept 2013, 16 biosimilars have been approved in the EU* SponsorReference productDate of approvalAbseamed (epoetin alfa)Medice Arzneimittel Pütter (Germany)Eprex (Janssen)August 2007Biograstim (filgrastim; G-CSF)CT ArzneimittelNeupogen (Amgen)September 2008Binocrit (epoetin alfa)Sandoz (unit of Novartis)Epoetin alfa Hexal (epoetin alfa)Hexal Biotech (owned by Novartis)Eprex/Erypo (Janssen)Filgrastim Hexal (filgrastim; G-CSF)Hexal BiotechFebruary 2009Nivestim (filgrastim; G-CSF)Hospira EnterprisesJune 2010Omnitrope (somatropin; human growth hormone)SandozGenotropin (Pfizer)April 2006Ratiograstim (filgrastim; G-CSF)Ratiopharm (acquired by Teva)Filgrastim Ratiopharm (filgrastim; G-CSF)(withdrawn April 2011**)Retacrit (epoetin zeta)HospiraDecember 2007Silapo (epoetin zeta)StadaTevagrastim (filgrastim; G-CSF)Teva Pharma IndustriesValtropin (somatropin; HGH)BioPartners GmbhHumatrope (Eli Lilly)Zarzio (filgrastim; G-CSF)Inflectra (infliximab)Remicade (Janssen)10 September 2013Remsima (infliximab)CelltrionApprovals include: 5 epoetin biosimilars, 7 filgratim biosimilars, 2 somatropin biosimilars and 2 infliximab biosimilarsPlease note: there are 15 current approvals. Filgrastim ratiopharm (Ratiopharm GmbH) was approved Sept 15, 2008, but was then voluntarily withdrawn April 20, (source:Full EMA approvals listing can be found here:*Out of a total of 20 marketing authorization applications. **The marketing authorization for Filgrastim Ratiopharm was voluntarily withdrawn in 2011 at the request of the marketing authorization holder.Source:EMA biosimilar EPAR listing: Accessed October 2013.
5Biosimilars differ from small-molecule generic drugs – manufacture Low molecular weight and complexityHigh molecular weight and complex 3-D structureChemical synthesisProduced by living organismsManufacturing process easy to reverse-engineerManufacturing process cannot be replicatedIdentical copy of active ingredientAlthough required to contain the sameprimary amino acid sequence, the biosimilaris not identical to the originator, but ratherhighly similarEven if a biosimilar uses the same human gene as its originatorIt will differ in other parts of the processHumangeneDNAvectorCloning into DNA vectorTransfer intohost cellBacterial or mammalian cell produces proteinFermentationFormulationDifferent process = different productAdapted from The Biosimilars Handbook, Barclays Capital, 11 Feb 2011
7The potential impact of biosimilars Expected cost savingsA survey conducted in the European Union in 2010 found cost savings in 24 member states where biosimilars were marketed alongside their originators*There was sustained price discounting in all countries, although this did vary at the country levelValues range from a 5% discount for filgrastim in the UK to a 53% discount for the same medicine in Denmark in 2009The availability of biosimilars of somatropin, epoetin alfa, and filgrastim in Europe has led to price discounts relative to their respective originators ranging from 5–82%The table below describes the mean price discount of biosimilar versions of the medicines listed relative to their originator productsMean discount in 24 EU member states200720082009Somatropin25.4%25.9%14.1%Epoetin32.1%17.3%17.0%Filgrastim‐‐‐10.8%35.0%Biosimilars can bring the benefits of biological medicines to more patients.Particularly, biosimilars can benefit those who lack private insurance coverage or who live in areas where biological therapies are not covered by state-funded insurance.Other observers have noted that price discounts in Europe for biosimilar medicines typically range from 25-30%.Jelkmann W. Biosimilar epoetins and other “follow-on” biologics: update on the European experiences. Am J Hematol 2010;85:771–780.*Rovira J, Espín J, García L, and Olry de Labry A. The impact of biosimilars’ entry in the EU market
10Examples of copies of biological medicines from largely unregulated markets may not meet today’s rigorous standardsIn the past, copies of biological medicines have been produced in some countries where a rigorous regulatory pathway had not been established for biosimilarsThese are known as copy-biologics, alternative biologics or intended copies of biological productsThey may not meet the current criteria defined by the FDA or EMA for biosimilarity and would not be approved in most regulated markets at the present time without additional testingAs guidelines are established worldwide to standardize the testing of biosimilars for comparability against an originator product, the development of such products becomes less widespread*However, the manufacturers of copy biologics may choose to carry out the required testing in order to access regulated markets in the future.*Barkalow F, Biosimilar monoclonal antibodies. In the pipeline: major players and strategies. Citeline.
11Why immunogenicity testing is essential To date, there have been no reports of an approved biosimilar being associated with any unusual or unexpected adverse events, although at least two biosimilars that are currently approved in the EU encountered unwanted antibody development during pre-approval clinical studiesFor a somatropin biosimilar, non-neutralizing antibodies were triggered by increased levels of HCPsFor an epoetin biosimilar, neutralizing antibodies were triggered leading to premature termination of the clinical trialChanges in manufacturing process, however, have been associated with problems with immunogenicity even in novel biological medicinesImmunogenicity testing is therefore an essential part of the biosimilar testing processIncreased incidence of pure red cell aplasia with EPREX® (epoetin) SCRelated to leachables from changes in primary packagingImmunogenicity of GM-CSFNon-immunogenic in immunosuppressed patientsAntibodies in non-immunosuppressed patientsThrombopoietin immunogenicityPegylated rHuMGDF: highly immunogenic persistent thrombocytopenia meant development program was stoppedTryptophan-eosinophilamyalgia syndromeProduction strain changed: purification modified. Unrecognized impurity caused EMS (>1300 cases, 38 deaths)Saenger, P. Current status of biosimilar growth hormone. Int J Pediatr Endocroinol 2009;Bennett, CL et al. Pure red-cell aplasia and epoetin therapy. NEJM 2004;351:1403–8.Mascaro J, presentation . Mexico, August 15, 2007
12Highly regulated markets ensure safe biosimilar medicines Biosimilar quality is assured by rigorous testing requirements, which include head-to-head analytical/non-clinical/clinical testing against the reference originator. In addition, the regulatory authorities, such as the European Medicines Agency (EMA) and US FDA, require robustness in manufacturing processTo date, there have been no reports of a biosimilar medicine in highly regulated markets being associated with any unusual or unexpected adverse events as compared to its originatorIn Europe, no unusual or unexpected clinical events have been observed with biosimilars of somatropin, epoetin, or filgrastimIn the USA, no unusual or unexpected adverse events have been seen with products approved as follow-on biologics on the basis of abbreviated data packages, including Omnitrope®Following 20 marketing applications, the EMA has approved 15 based on comparability to respective reference originators. Thus far, in the absence of differences in biophysical properties between biosimilars and their reference, no significant clinical variation has been observed. Currently 14 biosimilars are available.McCamish M and Woollett G. The state of the art in the development of biosimilars Clin Pharmacol Ther 2012;91(3):405–417.
13Biosimilar regulations in EU and USA: different stages of development The EU pioneered the development of biosimilar regulationsUS overarching guidelines issuedDraft revisions to Product Class Specific Guideline: Insulin, low molecular weight heparinDraft revisions to Overarching Guideline; Quality Guideline; Non-clinical and Clinical Guideline2004200920112006200720082012201020132005EMEA Legislative PathwayEMEA Regulatory Guidance [Overarching Guideline] under revisionProduct Class Specific Guidelines: Low molecular weight heparin, recombinant Interferon-alphaProduct Class Monoclonal antibodies – non-clinical and clinical issuesProduct Class Specific Guideline: Erythropoietin (revised)Quality Guideline;Non-Clinical and Clinical Guideline (under revision )Product Class Specific Guidelines: Insulin, G-CSF, SomatropinProduct Class Immunogenicity assessment of monoclonal antibodiesPublic Health Service Act amended to allow the approval of biosimilarsOverarching Draft Guidelines on biosimilarsProduct ClassFollicle stimulating hormone, Interferon-betaEuropeUSThe BPCI Act appears in Title VII, subtitle A of the Patient Protection and Affordable Care Act, March 2010.US Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a referenceproduct. Draft Guidance. Feb 2012.
14The definition of ‘biosimilarity’ in the USA vs EU USA: a biosimilar is “highly similar to the reference product notwithstanding minor differences in clinically inactive components” and “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency”EU: a similar biological or 'biosimilar' medicine is a biological medicine that is similar to another biological medicine that has already been authorized for use and it does not have any meaningful differences from the reference medicine in terms of quality, safety, or efficacyThe US definition of biosimilarity was established in the Biologics Price Competition and Innovation Act (BPCI Act, drafted 2009 and passed into law 2010).McCamish M and Woollett G. The state of the art in the development of biosimilars Clin Pharmacol Ther 2012;91(3):405–417.Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a reference product. Draft Guidance. Feb Article 8 of Directive 2001/83, as amended.
15Requirements of clinical studies in the USA and EU Once a Phase I study establishes that a biosimilar possesses comparable pharmacokinetic and pharmacodynamic attributes in human subjects to the reference biological medicine, a Phase III study of safety, efficacy, and immunogenicity is usually initiatedPhase III studies use the most sensitive, homogeneous patient population and clinical endpoint to establish the similarity of the biosimilar to the reference and to be able to detect product-related differencesIf the mechanism of action (MoA) for the reference medicine is known, the biosimilar medicine is expected to have the same MoA for the prescribed conditions based on labelingUses for the biosimilar medicine in its labeling must “have been previously approved for the reference product”The extent, duration and timing of studies for evaluation of immunogenicity vary depending on a variety of factors including:the expected duration of product use, nature of product, known incidence and clinical consequences of immune response for the reference product, results of analytical comparability studiesRegulatory authorities generally accept that the basic concepts needed for patient treatment, such as dose response, have already been established by the originator product. Therefore, Phase II studies are not usually required for biosimilar candidates. Also, the number of patients in the Phase III trials can be reduced. Consequently, the duration and cost of biosimilars development can be less in than developing original biological medicines.Phase III clinical trials are initiated following satisfactory conclusion of pharmacodynamic and pharmacokinetic studies, and the focus of the Phase III program is predominately on the safety of the biosimilar medicine. These studies are statistically powered to prove the clinical comparability of the biosimilar to the originator. The duration of biosimilar trials is tailored to adequately explore the potential for development of immunogenic responses, as this is one of the main risks of biological medicines.Gravel P, Naik A, Le Cotonnec J-Y. Biosimilar rhG-CSFs: how similar are they? Targ Oncol 2012; 7(Suppl 1):S3–S16.US Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a reference product. Draft Guidance. Feb 2012.
16Requirements of clinical studies in the USA and EU US FDA requires a comparative repeat dose toxicity study in a relevant species (if available) that includes toxicokinetic measurements, systemic exposure, local tolerance, and immunogenicity assessments. EMA suggests a risk-based approach to animal studies, taking into consideration factors such as residual uncertainty at the end of in vitro studies and availability of sensitive species/models for in vivo animal studiesBoth EMA and FDA require a sufficient number of product batches to be tested during physiochemical and functional comparative studies to capture the inherent batch-to-batch variability in product characteristics. The biosimilar is expected to exhibit variability similar to the reference medicineEvaluation of residual risk/uncertainty at each step determines the need for further studies.Some comparative assessments between a biosimilar and its reference product can be tested in vitro, for example the binding of an antibody to its specific target. However, safety and efficacy assessments require in vivo testing in human clinical trials.Regulatory authorities generally accept that the basic concepts needed for patient treatment, such as dose response, have already been established by the originator product. Therefore, Phase II studies are not usually required for biosimilar candidates. Also, the number of patients in the Phase III trials can be reduced. Consequently, the duration and cost of biosimilars development can be less in than developing original biological medicines.Chance K. US Biosimilar Guidelines: Summary and Insights Regulatory Focus April 2012Datamonitor; Pharmaceutical key trends 2011—Biosimilar market overview.
17The biosimilar approval pathways across highly regulated markets are similar CriteriaEU and AustraliaUSAJapanBiosimilar pathway statusPathway establishedClinical trialsMandatory, but extent negotiablePhase I studies mandatory, Phase III studies may be abbreviated in some situationsReference medicineBoth biosimilar and originator must have the same MOA. Reference must be marketed in the EU/Australia although EU guidelines indicate that studies utilizing a foreign reference could be acceptableBoth biosimilar and originator must have the same MOA. Reference must be marketed in the USA although US guidelines indicate that studies utilizing a foreign reference could be acceptableReference must be approved and marketed in JapanFormulationSame strength and route of administration, otherwise further studies requiredSame strength and route of administrationPost-marketing safety surveillanceMandatory along with risk management planTailored to the particular safety and effectiveness concerns associated with the reference medicine, its drug class, clinical use elsewhere, and the biosimilar candidate itselfPlan must be created to trace adverse events and a drug safety report submittedDatamonitor; Biosimilars global regulatory update, May Regulatory agency websites.US Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a reference product. Draft Guidance. Feb 2012.
18The biosimilar approval pathways across highly regulated markets are similar CriteriaEUUSAEquivalence marginsNot currently defined, but it is expected that equivalence margins will be pre-defined by the sponsor along with a strong scientific justification prior to conduct of clinical trialsNot currently defined, but it is expected that equivalence margins will be pre-defined by the sponsor along with a strong scientific justification prior to conduct of clinical trialsExtrapolation to other indicationsWill be permitted providing the mechanism of action is the same as the reference; scientific justifications for extrapolation are requiredScientific justification for extrapolation required, even if the biosimilar and reference have the same mechanism of action:Relevant target receptors for each indicationPattern of molecular signaling upon receptor bindingExpression and location of target receptorsRelevance of pharmacodynamic measures to mechanism of actionRelevance of pharmacokinetic values in different patient populationsDifferences seen in toxicities for the various conditions of use in the various patient populations (non-comparative data)InterchangeabilityDecision at country levelYes, if assessed by FDA based on adequate clinical data. Substitution decisions made at the state levelBioequivalence parameters for biosimilar products have not been specifically established, but as with small-molecule generic products, a range of 80–125% similarity is normally accepted as adequate.US Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a reference product. Draft Guidance. Feb 2012.
19Comparative biosimilar approval pathways across the world CriteriaCanadaSouth KoreaIndiaChinaBiosimilar pathway statusPathway establishedPathway established (2012)No pathway; copy biological medicines approved as new drugsClinical trialsMandatory, but extent negotiablePhase I studies mandatory, Phase III studies may be abbreviated in some situationsPhase I and Phase III trials mandatoryMandatory: Phase I–III studies for copy biological medicines with a reference not marketed in China. Phase III studies for copy biological medicines marketed in ChinaReference medicineReference should be approved and marketed in Canada, unless a waiver is approvedReference should be approved and marketed in South KoreaReference should be approved and marketed in India, although some flexibility is allowed if reference is not marketed in IndiaNot definedInterchange-abilityDecision at province and territory levelFormulationSame dosage, form, and route of administrationDosage, form, and strength must be the sameSame strength and route of administrationPost-marketing surveillanceMandatory along with risk management plan and period safety updatesPharmacovigilance plan must be submittedDatamonitor; Biosimilars global regulatory update, May2012. Regulatory agency websites.Department of Biotechnology. Guidelines on similar biologics: Regulatory requirements for marketing authorization in India, 2012.
20EMA and FDA have rigorous standards for biosimilar applications Biosimilar quality is assured by the rigorous testing that is integral to the development and manufacturing process required by regulatory authorities such as the European Medicines Agency and US FDAFollowing 20 marketing applications, the EMA has approved 16 biosimilar medicines*Thus far, in the absence of differences in biophysical properties between biosimilars and their originators, no significant clinical variation has been observedExamples of EMA-rejected or withdrawn biosimilar applications:Generic/Reference/BiosimilarSignificant biophysical differencesSignificant clinical variation from referencePK Efficacy TolerabilityInterferon-alfa-2a/Roferon-A/AlpheonYesHuman insulin/Humulin/Insulin Human Rapid Marvel, Insulin Human 30/70 Mix Marvel, and Insulin Human Long MarvelInsufficient dataNo*Post-approval, the marketing authorization for Filgrastim Ratiopharm was voluntarily withdrawn in 2011 at the request of the marketing authorization holder (Ratiopharm), so 15 biosimilars are currently available.Ahmed I, Kaspar B, and Sharma, U. Biosimilars: Impact of biologic product life cycle and European experienceon the regulatory trajectory in the United States. Clin Ther 2012; 34(2):400–419.McCamish M and Woollett G. The state of the art in the development of biosimilars. Clin PharmacolTher 2012;91(3):405–417.
21Regulatory guidelines for biosimilar approvals are developing at different pacesCountryInceptionApproval pathwayArgentinaSept 2009Administracion Nacional de Medicamentos, Alimentos y Tecnologia (ANMAT) published biologics and biosimilar approval guidanceAustraliaJune 2006Agrees to follow CHMP/437/04 Guideline on Similar Biological Medicinal ProductsBrazilDec 2010Resolution 55/2010 regulates all biologic productsCanadaMar 2010Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry BiologicsChinaAll biologics, original or copy-biologics undergo the same pathwayColombiaLicense for Manufacturing Facilities of Biological ProductsEUOct 2005CHMP/437/04 Guideline on Similar Biological Medicinal ProductsNov 2010Guideline on similar biological medicinal products containing monoclonal antibodiesIndiaFeb 2012201 Department of Biotechnology finalizes guidelines for nonclinical evaluation of similar biologics (biosimilars)JapanMar 2009Guidance issued by Japan’s Ministry of Health, Labour and WelfareMalaysiaJuly 2008Guidance Document for Registration of Biosimilars in MalaysiaMexicoJune 2009Article 222 of the General Health LawRussiaBiosimilars are subject to the same regulations as genericsSaudi ArabiaGuidelines on Biosimilars version 1.1SingaporeApril 2010Appendix 17 of the Guidance on Medicinal Product Registration in SingaporeSouth KoreaSept 2010Guidelines on the Evaluation of Biosimilar ProductsTaiwanNov 2008Review Criteria for Registration and Market Approval of Pharmaceuticals-Registration and Market Approval of Biological ProductsTurkeyAugust 2008Instruction Manual on Biosimilar Medical Products. Adopted EMA guidance into law 2011USAMarch 2010Law. No. 111–148, The Approval Pathway For Biosimilar Biologic ProductsVenezuelaAugust 2000SRPB-R Guidelines: application for Health registry of DNA recombinant products, monoclonal and therapeutic antibodiesDatamonitor. Biosimilars global regulatory update, May2012. European Generic Medicines Association, 2010.
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