oUn

Updatethese conditions must be provided [3].The EMEAhas laid down the following requirements for

the Marketing Authorisation Applications of a biosimilarproduct: Comparability studies are required between the biosi-

milar and the chosen reference medicinal product. Nonclinical studies, although usually less extensive

than those for innovatory applications, will be requiredfor the biosimilar.

Clinical studies will be needed to support the safety andeffectiveness of a biosimilar. In particular, the studiesmust address immunogenicity concerns.

Post-market pharmacovigilance plans will be expectedas part of approval commitments.

city of a biosimilar and to post-marketing testing andsurveillance to detect any potential safety issues. Unfortu-nately, the immunogenicity of biosimilars often cannot befully predicted using preclinical studies, and clinicalimmunogenicity studies are thus required before approval.Therefore, safety data will be needed before MarketingAuthorisation and will also be required post marketing

It is also worthmentioning that the granting of approvaldoes not mean that the biosimilar product can be automati-cally substituted for the reference product and vice versa.This decision should only be taken after obtaining theopinion of a qualified health professional. Several countries,suchasFrance, Spain, Italy,Germany, theNetherlands, theUK and Sweden, have established legislative measures toprohibit the automatic substitution of these products.

Another issue regarding biosimilars is the use of theInternational Non-proprietary Name (INN) [4,8]. In theCorresponding author: Calvo, B. (b.calvo@ehu.es).FORUM: Policy & Regulation

Regulatory aspectsEuropeLeyre Zuniga and Begona Calvo

Pharmaceutical Technology Department. Faculty of Pharmacy,

In early 2004, the patent protection for several first-generation biopharmaceuticals began to expire, open-ing the door to the so-called biosimilars. The knowl-edge on biosimilars is steadily growing, and keepingup with state-of-the-art technologies and methods forprotein characterization is compelling not only formanufacturers but also for the authorities. The chal-lenges now are to review current marketing approvalprocedures and to develop standardised methods forevaluating the quality, safety and efficacy of theseproducts.

Biosimilar productsA biosimilar drug is a medicine that is similar but notidentical to a biological medicine that has already beenauthorised (the biological reference medicine) [1,2]. Thisconcept of a similar biological medicinal product has beenclarified by different regulatory bodies such as the EMEA(European Agency for the Evaluation of Medicinal Pro-ducts) and FDA (Food and Drug Administration), amongothers.

These products do not meet the conditions for beingdefined as generic medicinal products, mostly because ofdifferences between the similar biological medicinal pro-duct and the reference biological medicinal product interms of rawmaterials or manufacturing processes. There-fore, for a biosimilar product to be approved, the results ofappropriate pre-clinical tests or clinical trials relating to0167-7799/$ see front matter 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tibtech.20f biosimilars in

iversity of the Basque Country, Vitoria-Gasteiz, Spain

Marketing Authorisations for products derived frombiotechnologyA wide range of licenced biosimilars are available in sev-eral countries, including China, India and South Korea.Examples of such marketed products include interleukins,interferons, erythropoietins, growth factors, hormones,enzymes and monoclonal antibodies [4]. By contrast, thereare considerably fewer biosimilars on the European mar-ket; these are mainly somatropin, epoetin and filgrastimproducts. Nevertheless, Europe has already established anadvanced regulatory framework to enable the approval ofthese medicines. Comparable regulatory oversight is cur-rently under discussion in the United States, Canada andJapan [4].

The European Directive 2001/83/EC [5], as amended byDirective 2003/63/EC [6] and Directive 2004/27/EC [3],defines the regulatory process for biosimilars and laysdown specific guidelines. These guidelines comprise anoverarching guideline as well as more general guidelinesconcerning the product quality and other clinical and non-clinical issues. Product-specific guidelines are also avail-able, and the EMEA is in the process of developingadditional product-specific guidelines and is planning toupdate these guidelines as new information comes to light(Table 1). In Europe, pharmaceutical products derivedfrom biotechnology can only be registered using the Cen-tralised Procedure, resulting in a European Union (EU)licence that is valid in all Member States [7].

The European system for biosimilar approval devotesspecial attention to concerns over potential immunogeni-09.03.005 Available online 19 May 2009 385

ilar

rodu

Co

danoceCoTable 1. European biological guidelines of relevance for biosim

Guideline reference number Guideline title

Overarching guideline

CHMP/437/04 Similar Biological Medicinal Product

Quality issues guidelines

CPMP/BWP/3207/00 (Rev.1) Comparability of Medicinal PActive Substance: Quality Issues

CHMP/49348/05 Similar Biological Medicinal ProductsSubstance: Quality Issues

Non-clinical and clinical issues guidelines

CPMP/ICH/5721/03 (ICH Topic Q5E) Step 4. Note for Guito Changes in their Manufacturing Pr

CHMP/42832/05 Similar Biological Medicinal Products

Updatecontext of global pharmacovigilance, the INN is a usefultool but should not be the sole means of product identifi-cation for biosimilars. All available tools should beemployed, such as lot number, manufacturer and otherrelevant information (Box 1).

EMEA guidelinesThe EMEA guidelines on biosimilar products consider bio-similars as similar but non-identical entities to the innova-tor product (chosen reference medicinal product) and stressthe importance of the manufacturing process, which con-ditions the characteristics of the biological medicine pro-duct. Small differences can arise in the biosimilar product

Substance: Non-Clinical and Clinical Issu

CHMP/BMWP/101695/06 Comparability of Biotechnology-DerivedManufacturing Process: Non-Clinical and

CHMP/BMWP/14327/06 Immunogenicity Assessment of Biotechn

Product-specific guidelines

CHMP/31329/05 Annex to Guideline on Similar BiologicaDerived Proteins as Active Substance: NBiosimilar Medicinal Products ContaininFactor

CHMP/94528/05 Annex to Guideline on Similar BiologicaDerived Proteins as Active Substance: NSimilar Medicinal Products Containing S

CHMP/32775/05 Annex to Guideline on Similar BiologicaDerived Proteins as Active Substance: NSimilar Medicinal Products Containing R

CHMP/94526/05 Annex to Guideline on Similar BiologicaDerived Proteins as Active Substance: NSimilar Medicinal Products Containing R

CHMP/BMWP/118264/07 Similar Biological Medicinal Products Co

Draft guidelines

CHMP/BMWP/102046/06 Similar Medicinal Products Containing R

Concept papers

CPMP/BWP/1113/98 Development of a CPMP Guideline on Co

CHMP/BMWP/7241/2006 Similar Biological Medicinal Products Cothe Guideline on Similar Biological MedProteins as Active Substance (Non) Cli

CHMP/BMWP/496286/06 Similar Biological Medicinal Products CoNon-Clinical Issues

EMEA/CHMP/BMWP/170734/08 Revision of the Guidance on Similar MedErythropoietins

EMEA/CHMP/114720/2009 Immunogenicity Assessment of Monoclo

ahttp://www.emea.europa.eu/htms/human/humanguidelines/multidiscipline.htm.bPD = publication date; ED = effective date.

386sa

Dateb

PD: Sep 2005ED: Oct 2005

cts Containing Biotechnology-Derived Proteins as PD: Dec 2003ED: Dec 2003

ntaining Biotechnology-Derived Proteins as Active PD: Feb 2006ED: Jun 2006

ce on Biotechnological/Biological Products Subjectss

PD: Dec 2004ED: Jun 2005

ntaining Biotechnology-Derived Proteins as Active PD: Feb 2006

Trends in Biotechnology Vol.27 No.7owing to changes in themanufacturing process. Such differ-ences are verydifficult to analyseandmighthave significantimpact on safety and efficacy. This is illustrated by the caseof the epoetin-a molecule Eprex1, which is used for thetreatment of pure red cell aplasia (PRCA). A small andseemingly inconsequential change in the Eprex1manufac-turing process, namely the switch from human serum albu-min in the product formulation to polysorbate 80, had acritical impact onPRCApatients [9,10]. Thus, the safetyandefficacy profile of biosimilar products is highly dependent onthe robustness and control of quality aspects.

In Europe, for any biosimilar, the chosen referencemedicinal product must be a medicinal product authorised

es ED: Jun 2006Medicinal Products after a Change in theClinical Issues

PD: Jul 2007ED: Nov 2007

ology-Derived Therapeutic Proteins PD: Jan 2008ED: Apr 2008

l Medicinal Products Containing Biotechnology-on-Clinical and Clinical Issues Guidance ong Recombinant Granulocyte-Colony Stimulating

PD: Feb 2006ED: Jun 2006

l Medicinal Products Containing Biotechnology-on-Clinical and Clinical Issues Guidance onomatropin

PD: Feb 2006ED: Jun 2006

l Medicinal Products Containing Biotechnology-on-Clinical and Clinical Issues Guidance onecombinant Human Insulin

PD: Feb 2006ED: Jun 2006

l Medicinal Products Containing Biotechnology-on-Clinical and Clinical Issues Guidance onecombinant Erythropoietins

PD: Mar 2006ED: Jul 2006

ntaining Low-Molecular-Weight Heparins PD: Apr 2009ED: Oct 2009

ecombinant Interferon a PD: Release forconsultation Oct2007

mparability of Biotechnology-Derived Products PD: Jun 1998

ntaining Recombinant a-Interferon Annex toicinal Products Containing Biotechnology-Derivednical Issues

PD: Release forconsultation Apr2006

ntaining Low-Molecular-Weight Heparins: PD: Release forconsultation Jan2007

icinal Products Containing Recombinant PD: Release forconsultation Jul2008

nal Antibodies Intended for In Vivo Clinical Use PD: Release forconsultation Mar2009

to a certain extent on the applicants ability to convince theAgency that suitablepharmacovigilanceplanswill be imple-

Box 1. Important issues related to biosimilars

Update Trends in Biotechnology Vol.27 No.7in the EU, on the basis that a complete dossier is availablein accordance with the provisions of Article 8 of Directive2001/83/EC [5], as amended. This reference product will beused throughout the comparability program for quality,safety and efficacy studies during the development andapproval process of a biosimilar to generate coherent dataand conclusions.

Approval will result in the publication of a EuropeanPublic Assessment Report (EPAR; http://www.emea.europa.eu/htms/human/epar/eparintro.htm), a public sum-mary written in collaboration with the applicant. TheEPARs objective is to improve the transparency of theregulatory process, describing the regulatory history of theapplication in detail [11].

In practice, the guidelines required before approval willbe granted will translate into increased development costs,which aremainly associatedwith Phase III testing require-ments, and will likely affect the pricing of the final pro-ducts, potentially resulting in savings in the cost of a

Biosimilar medicines cannot be considered biogenerics owing to,in particular, differences relating to raw materials or differences inmanufacturing processes of the similar biological medicinalproduct and the reference biological medicinal product.

Approval of biosimilars requires the planning of comparabilitystudies covering quality and pre-clinical and clinical aspectsbetween the biosimilar and the chosen reference medicinalproduct.

Biosimilars cannot be assumed to have the same immunogenicityprofile as the original product. Because immunogenicity is largelyunpredictable, the assessment of a biosimilar must be based on (i)a thorough riskbenefit assessment and (ii) a robust post-market-ing risk management program.

Biosimilars should not be substituted without the oversight of aprescribing physician. Unauthorised or unrecorded substitutionmust be avoided.

The EMEAs decision to approve a biosimilar product can depend toa certain extent on the applicants ability to convince the Agencythat suitable pharmacovigilance plans will be implemented.biosimilar that might be less than expected compared tothat of a synthetic generic drug [1214].

ConclusionAlthough the EU currently has the most advanced regulat-ory pathways for biosimilars, there is no harmonised world-wide regulatory system for these products. A well-definedregulatory framework will need to be developed that can befurther expanded in response to increasing experiencewith,and scientific knowledge of, biosimilars. It is important thatsuch a regulatory framework will not only guarantee thatbiosimilars are safe, efficacious and of consistent quality butalso ensure traceability, pharmacovigilance and coherentdata collection for this new class of product.

There is still a lack of clear definition in many aspects ofbiosimilar development guidelines. For example, theEMEAsdecision toapproveabiosimilarproduct candependmented. However, the criteria of what constitutes an accep-table pharmacovigilance plan remain to be determined.

Another crucial step in the regulatory procedures forbiosimilars is to set up the requirements for non-clinicaland clinical data that are necessary and sufficient todemonstrate biosimilarity.

For these reasons, it is recommended that any applicantseeks scientific advice from the Agency as early as possibleduring the development stages to ensure that the companyis following the right strategy, which will save time andmoney.

References1 European Medicines Agency (2007) Questions and answers onbiosimilar medicines (similar biological medicinal products). Doc.Ref. EMEA/74562/2006 (http://www.emea.europa.eu/pdfs/human/pcwp/7456206en.pdf)

2 Mellstedt, H. et al. (2008) The challenge of biosimilars. Ann. Oncol. 19,411419

3 TheEuropeanParliament and theCouncil of theEuropeanUnion (2004)Directive 2004/27/EC of the European Parliament and of the Council of31 March 2004 amending Directive 2001/83/EC on the Community coderelating to medicinal products for human use. In Official Journal of theEuropean Union, L136, pp. 3457 (http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2004:136:0034:0057:EN:PDF)

4 Joung, J. et al. (2008) WHO informal consultation on regulatoryevaluation of therapeutic biological medicinal products held at WHOHeadquarters, Geneva, April 2007. Biologicals 36, 269276

5 The European Parliament and the Council of the European Union(2001) Directive 2001/83/EC of the European Parliament and of theCouncil of 6 November 2001 on the Community code relating tomedicinal products for human use. In Official Journal of theEuropean Union, L311, pp. 67128 (http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2001:311:0067:0128:EN:PDF)

6 The Commission of the European Communities (2003) CommissionDirective 2003/63/EC of 25 June 2003 amending Directive 2001/83/ECof the European Parliament and of the Council on the Community coderelating to medicinal products for human use. InOfficial Journal of theEuropean Union, L159, pp. 4694 (http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2003:159:0046:0094:EN:PDF)

7 EuropeanCommission (2006)Chapter 4.Centralisedprocedure. Volume2A Procedures for Marketing Authorization. In The RulesGoverning Medicinal Products in the European Union, EuropeanCommission (http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/a/chap4rev200604%20.pdf)

8 Boring, D. (1997) The development and adoption of non-proprietary,established, and proprietary names for pharmaceuticals. Drug Inf. J.31, 621634

9 Rossert, J. (2005) Erythropoietin-induced, antibody-mediated pure redcell aplasia. Eur. J. Clin. Invest. 35 (Suppl. 3), 9599

10 Boven, K. et al. (2005) Epoetin-associated pure red cell aplasia inpatients with chronic kidney disease: solving the mystery. Nephrol.Dial. Transplant. 20 (Suppl. 3), iii33iii40

11 Fruijtier, A. (2006) Registration procedures for medicinal products:past, present and future. Update of chapter 11. In Fundamentals of EURegulatory Affairs (Michor, S. and Rowland, K., eds), pp. 125136,Regulatory Affairs Professionals Society

12 Covic, A. and Kuhlmann, M.K. (2007) Biosimilars: recentdevelopments. Int. Urol. Nephrol. 39, 261266

13 Gottlieb, S. (2008) Biosimilars: policy, clinical, and regulatoryconsiderations. Am. J. Health Syst. Pharm. 65, S2S8

14 Moran, N. (2008) Fractured European market undermines biosimilarlaunches. Nat. Biotechnol. 26, 56387

Regulatory aspects of biosimilars in EuropeBiosimilar productsMarketing Authorisations for products derived from biotechnologyEMEA guidelinesConclusionReferences