2 Introduction 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 possible Like biological medicines, biosimilars are complex protein molecules that are produced by living organisms During the past 15 years, biological medicines have had a profound impact on healthcare >primarily in the areas of rheumatology and oncology >as well as endocrinology, cardiology, dermatology, gastroenterology, and neurology Many of the world’s top-selling medicines are now biological medicines However, biological medicines are expensive (sometimes by several orders of magnitude more than small-molecule chemical drugs), limiting patient access As many biological medicines come off patent globally, there is great interest in the development of biosimilars, which are likely to be more affordable
3 The increasing rate of development of biosimilars Patent expiries expected: 99 Patent expiries expected: 91 Patent expiries expected: 46 Biological medicines due to come off patent 2,3 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. 1 1.Barkalow F, Biosimilar monoclonal antibodies. In the pipeline: major players and strategies. Citeline. 2.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, http://articles.chicagotribune.com/ /news/sns-rt-elan-spinofftysabril6e8jd71t _1_tysabri- elan-patent-protection 2010– –2020 Post–2020
4 As of Sept 2013, 16 biosimilars have been approved in the EU* BiosimilarSponsorReference productDate of approval Abseamed (epoetin alfa) Medice Arzneimittel Pütter (Germany) Eprex (Janssen) August 2007 Biograstim (filgrastim; G-CSF) CT ArzneimittelNeupogen (Amgen)September 2008 Binocrit (epoetin alfa) Sandoz (unit of Novartis)Eprex (Janssen)August 2007 Epoetin alfa Hexal (epoetin alfa) Hexal Biotech (owned by Novartis) Eprex/Erypo (Janssen)August 2007 Filgrastim Hexal (filgrastim; G-CSF) Hexal BiotechNeupogen (Amgen)February 2009 Nivestim (filgrastim; G-CSF) Hospira EnterprisesNeupogen (Amgen)June 2010 Omnitrope (somatropin; human growth hormone) SandozGenotropin (Pfizer)April 2006 Ratiograstim (filgrastim; G-CSF) Ratiopharm (acquired by Teva) Neupogen (Amgen)September 2008 Filgrastim Ratiopharm (filgrastim; G-CSF) Ratiopharm (acquired by Teva) Neupogen (Amgen) September 2008 (withdrawn April 2011**) Retacrit (epoetin zeta)HospiraEprex (Janssen)December 2007 Silapo (epoetin zeta)StadaEprex (Janssen)December 2007 Tevagrastim (filgrastim; G-CSF)Teva Pharma IndustriesNeupogen (Amgen)September 2008 Valtropin (somatropin; HGH)BioPartners GmbhHumatrope (Eli Lilly)April 2006 Zarzio (filgrastim; G-CSF) Sandoz (unit of Novartis)Neupogen (Amgen)February 2009 Inflectra (infliximab)HospiraRemicade (Janssen)10 September 2013 Remsima (infliximab)CelltrionRemicade (Janssen)10 September 2013 *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.EMA biosimilar EPAR listing: Accessed October 2013
5 Even if a biosimilar uses the same human gene as its originator It will differ in other parts of the process Human gene DNA vector Cloning into DNA vector Transfer into host cell Bacterial or mammalian cell produces protein Fermentation Formulation Different process = different product Small-molecule genericBiosimilar Low molecular weight and complexityHigh molecular weight and complex 3-D structure Chemical synthesisProduced by living organisms Manufacturing process easy to reverse-engineerManufacturing process cannot be replicated Identical copy of active ingredient Although required to contain the same primary amino acid sequence, the biosimilar is not identical to the originator, but rather highly similar Biosimilars differ from small-molecule generic drugs – manufacture Adapted from The Biosimilars Handbook, Barclays Capital, 11 Feb 2011
6 Biosimilars are subjected to a more rigorous clinical development process than generics Biosimilars Generics Proof of quality and bioequivalence No substantial clinical data required Reference to originator’s data Different manufacturing processes can and often do yield differences in the end product After the quality of a biological medicine is demonstrated, some non-clinical and clinical studies are necessary Immunogenic response cannot be predicted and therefore must be tested Source: J. Mascaro: Regulatory evaluation of therapeutic biological medicines, Aug 15, 2007 Small molecule Biological medicine
7 The potential impact of biosimilars A 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 level >Values range from a 5% discount for filgrastim in the UK to a 53% discount for the same medicine in Denmark in 2009 >The 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 products Expected cost savings Mean discount in 24 EU member states Somatropin25.4%25.9%14.1% Epoetin32.1%17.3%17.0% Filgrastim ‐‐‐ 10.8%35.0% *Rovira J, Espín J, García L, and Olry de Labry A. The impact of biosimilars’ entry in the EU market
10 Examples of copies of biological medicines from largely unregulated markets may not meet today’s rigorous standards In the past, copies of biological medicines have been produced in some countries where a rigorous regulatory pathway had not been established for biosimilars These are known as copy-biologics, alternative biologics or intended copies of biological products They 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 testing As guidelines are established worldwide to standardize the testing of biosimilars for comparability against an originator product, the development of such products becomes less widespread* *Barkalow F, Biosimilar monoclonal antibodies. In the pipeline: major players and strategies. Citeline.
11 Why 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 studies For a somatropin biosimilar, non-neutralizing antibodies were triggered by increased levels of HCPs For an epoetin biosimilar, neutralizing antibodies were triggered leading to premature termination of the clinical trial Changes in manufacturing process, however, have been associated with problems with immunogenicity even in novel biological medicines Immunogenicity testing is therefore an essential part of the biosimilar testing process 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 Increased incidence of pure red cell aplasia with EPREX ® (epoetin) SC Related to leachables from changes in primary packaging Immunogenicity of GM-CSF Non-immunogenic in immunosuppressed patients Antibodies in non-immunosuppressed patients Thrombopoietin immunogenicity Pegylated rHuMGDF: highly immunogenic persistent thrombocytopenia meant development program was stopped Tryptophan-eosinophilamyalgia syndrome Production strain changed: purification modified. Unrecognized impurity caused EMS (>1300 cases, 38 deaths)
12 Highly 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 process To 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 originator In Europe, no unusual or unexpected clinical events have been observed with biosimilars of somatropin, epoetin, or filgrastim In 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 ® McCamish M and Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther 2012;91(3):405–417.
13 The BPCI Act appears in Title VII, subtitle A of the Patient Protection and Affordable Care Act, March US Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a reference product. Draft Guidance. Feb Draft revisions to Overarching Guideline; Quality Guideline; Non-clinical and Clinical Guideline EMEA Legislative Pathway EMEA Regulatory Guidance [Overarching Guideline] under revision Product Class Specific Guidelines: Low molecular weight heparin, recombinant Interferon-alpha Product Class Monoclonal antibodies – non-clinical and clinical issues Product Class Specific Guideline: Erythropoietin (revised) Quality Guideline; Non-Clinical and Clinical Guideline (under revision ) Product Class Specific Guidelines: Insulin, G-CSF, Somatropin Product Class Immunogenicity assessment of monoclonal antibodies Public Health Service Act amended to allow the approval of biosimilars Overarching Draft Guidelines on biosimilars EuropeUS Biosimilar regulations in EU and USA: different stages of development The EU pioneered the development of biosimilar regulations US overarching guidelines issued Draft revisions to Product Class Specific Guideline: Insulin, low molecular weight heparin Product Class Follicle stimulating hormone, Interferon- beta
14 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 efficacy The definition of ‘biosimilarity’ in the USA vs EU 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.
15 Requirements 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 initiated Phase 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 differences If 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 labeling Uses 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 studies 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.
16 Requirements 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 studies Both 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 medicine Chance K. US Biosimilar Guidelines: Summary and Insights Regulatory Focus April 2012Regulatory Focus April 2012 Datamonitor; Pharmaceutical key trends 2011—Biosimilar market overview.
17 The biosimilar approval pathways across highly regulated markets are similar CriteriaEU and AustraliaUSAJapan Biosimilar pathway status Pathway established Clinical trialsMandatory, but extent negotiable Phase I studies mandatory, Phase III studies may be abbreviated in some situations Reference 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 acceptable Both 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 acceptable Reference must be approved and marketed in Japan FormulationSame strength and route of administration, otherwise further studies required Same strength and route of administration Post-marketing safety surveillance Mandatory along with risk management plan Tailored to the particular safety and effectiveness concerns associated with the reference medicine, its drug class, clinical use elsewhere, and the biosimilar candidate itself Plan must be created to trace adverse events and a drug safety report submitted Datamonitor; 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.
18 The biosimilar approval pathways across highly regulated markets are similar CriteriaEUUSA Equivalence margins Not 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 trials Extrapolation to other indications Will be permitted providing the mechanism of action is the same as the reference; scientific justifications for extrapolation are required Scientific justification for extrapolation required, even if the biosimilar and reference have the same mechanism of action: Relevant target receptors for each indication Pattern of molecular signaling upon receptor binding Expression and location of target receptors Relevance of pharmacodynamic measures to mechanism of action Relevance of pharmacokinetic values in different patient populations Differences 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 level US Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a reference product. Draft Guidance. Feb 2012.
19 Comparative biosimilar approval pathways across the world CriteriaCanadaSouth KoreaIndiaChina Biosimilar pathway status Pathway established Pathway established (2012)No pathway; copy biological medicines approved as new drugs Clinical trialsMandatory, but extent negotiable Phase I studies mandatory, Phase III studies may be abbreviated in some situations Phase I and Phase III trials mandatory Mandatory: Phase I–III studies for copy biological medicines with a reference not marketed in China. Phase III studies for copy biological medicines marketed in China Reference medicine Reference should be approved and marketed in Canada, unless a waiver is approved Reference should be approved and marketed in South Korea Reference should be approved and marketed in India, although some flexibility is allowed if reference is not marketed in India Not defined Interchange- ability Decision at province and territory level Not defined FormulationSame dosage, form, and route of administration Dosage, form, and strength must be the same Same strength and route of administration Not defined Post- marketing surveillance Mandatory along with risk management plan and period safety updates Pharmacovigilance plan must be submitted Not defined Datamonitor; Biosimilars global regulatory update, May2012. Regulatory agency websites. Department of Biotechnology. Guidelines on similar biologics: Regulatory requirements for marketing authorization in India, 2012.
20 EMA and FDA have rigorous standards for biosimilar applications Generic/Reference/ Biosimilar Significant biophysical differences Significant clinical variation from reference PK Efficacy Tolerability Interferon-alfa-2a/Roferon-A/AlpheonYes Human insulin/Humulin/Insulin Human Rapid Marvel, Insulin Human 30/70 Mix Marvel, and Insulin Human Long Marvel Insufficient dataNoYesNo *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 experience on 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 Pharmacol Ther 2012;91(3):405–417. 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 FDA Following 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 observed Examples of EMA-rejected or withdrawn biosimilar applications:
21 CountryInceptionApproval pathway ArgentinaSept 2009 Administracion Nacional de Medicamentos, Alimentos y Tecnologia (ANMAT) published biologics and biosimilar approval guidance AustraliaJune 2006 Agrees to follow CHMP/437/04 Guideline on Similar Biological Medicinal Products BrazilDec 2010Resolution 55/2010 regulates all biologic products CanadaMar 2010Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics ChinaAll biologics, original or copy-biologics undergo the same pathway ColombiaLicense for Manufacturing Facilities of Biological Products EUOct 2005CHMP/437/04 Guideline on Similar Biological Medicinal Products EUNov 2010Guideline on similar biological medicinal products containing monoclonal antibodies IndiaFeb Department of Biotechnology finalizes guidelines for nonclinical evaluation of similar biologics (biosimilars) JapanMar 2009Guidance issued by Japan’s Ministry of Health, Labour and Welfare MalaysiaJuly 2008Guidance Document for Registration of Biosimilars in Malaysia MexicoJune 2009Article 222 of the General Health Law RussiaBiosimilars are subject to the same regulations as generics Saudi ArabiaDec 2010Guidelines on Biosimilars version 1.1 SingaporeApril 2010Appendix 17 of the Guidance on Medicinal Product Registration in Singapore South KoreaSept 2010Guidelines on the Evaluation of Biosimilar Products TaiwanNov 2008 Review Criteria for Registration and Market Approval of Pharmaceuticals-Registration and Market Approval of Biological Products TurkeyAugust 2008Instruction Manual on Biosimilar Medical Products. Adopted EMA guidance into law 2011 USAMarch 2010Law. No. 111–148, The Approval Pathway For Biosimilar Biologic Products VenezuelaAugust 2000 SRPB-R Guidelines: application for Health registry of DNA recombinant products, monoclonal and therapeutic antibodies Regulatory guidelines for biosimilar approvals are developing at different paces Datamonitor. Biosimilars global regulatory update, May2012. European Generic Medicines Association, 2010.