Regulatory Approval of Biosimilars: a Global Perspective

The increasing demand from government agencies, insurers and patients to reduce the steep cost of blockbuster biopharmaceutical products has created considerable opportunities in the global biosimilar market. By the end of this decade, a significant number of blockbuster drugs will go off patent, allowing a large number of biosimilar products to enter the market. Regulatory developments favoring the biosimilar market in countries such as the US are expected to boost the profits and market share of the companies involved.

In the US, the Biologics Price Competition and Innovation Act (BPCIA), included in the Patient Protection and Affordable Care Act (ACA), created an abbreviated licensure pathway for products demonstrated to be interchangeable with a US Food and Drug Administration (FDA)-licensed biological product.¹ The EU developed guidelines for the approval of biosimilars in 2005, established an abbreviated registration process for biosimilars in 2006, and has since published a guideline for the approval of similar biological medicinal products containing monoclonal antibodies.^2-6 In Asia, regional differences are common. In Japan, guidelines based on the EU processes were published in 2009.⁷ In China, there is no explicit process for biosimilar approval; all pharmaceuticals go through basically the same drug registration process with the China Food and Drug Administration.⁸ In India, specific guidelines for approval of biosimilars are largely absent.⁸ Therefore, there has been a virtually unrestrained flood of biosimilars into the Indian market.

A new research report states that, regionally, the US stands first in line to be the most lucrative market for biosimilars, followed by the EU and Japan.⁹ Regardless of the region of manufacture, the end result must be the production of a safe and efficacious product by market players. Clearly navigable regulatory pathways are essential for this outcome. This article reviews the various regional regulatory processes in effect to date and highlights the need for harmonization.

The Patent Cliff

As defined by the World Health Organization (WHO) in its guideline, a similar biotherapeutic product is "similar in terms of quality, safety and efficacy to an already licensed reference biotherapeutic product."^{10, 11} Reference biotherapeutic products are approved for sale by regulatory agencies such as FDA only after pharmaceutical companies submit extensive data establishing the products' safety and efficacy. These data result from years of research and clinical trials and are very expensive for the drug developer to produce. A variety of statutes protect the interests of the originators of reference biotherapeutic products, including data exclusivity and patent laws.

The term "patent cliff" refers to the phenomenon of the brisk drop in sales following patent expiration of products that previously captured large shares of the market. AstraZeneca is a good example of a company facing a patent cliff. In 2014, the patent for Nexium expires. Nexium was responsible for $5 billion in revenue in 2010. Additionally, in 2016, the patent on Crestor expires. This product generated almost $6 billion in revenue in 2010. Alone, these two drugs accounted for almost 30% of AstraZeneca's total profits. The company already saw its revenue for Arimidex, which came off patent in 2011, decline by half the following year.¹² AstraZeneca's revenue will experience another sharp decrease if this pattern is replicated by the Nexium and Crestor patent expirations. This phenomenon also occurred following patent expiration for Pfizer's Genotropin, where sales of biosimilar somatropin led to a rapid decline in branded drug sales.¹³

Following the expiration of patents on approved reference biotherapeutic products, similar biologic products may be introduced to the market. EU regulators have named these products biosimilars or similar biological medicinal products.¹⁴ US regulators refer to them as biosimilars or follow-on biologics.¹⁵ Subsequent entry biologic (SEB) is the term used by Health Canada's Biologics and Genetic Therapies Directorate (BGTD).¹⁶ Other terms include generic biologics and biogenerics (see Table 1). Regardless of the name, the value of the global biosimilar market is expected to grow from $243 million in 2010 to more than $17.9 billion in 2017.¹⁷

Regulatory Landscape: Guidance

North America

Numerous regional regulatory guidelines have been established for the development of biosimilar products (see Table 2). In North America, Health Canada has provided a single guidance for sponsors to instruct them about the information and regulatory requirements under the Food and Drugs Act and Regulations for the authorization of SEBs in Canada.¹⁸ In Canada, the concept of an SEB applies to all biologic drug submissions where the sponsor seeks "authorization for sale based on demonstrated similarity to a previously approved biologic drug and relies, in part, on prior information regarding that biologic drug in order to present a reduced clinical and non-clinical package as part of the submission."¹⁹ Products employing different approaches to manufacture than the reference biologic drug may not be suitable for authorization as SEBs.

Similarly, FDA has issued four guidances outlining its recommendations for developing and approving biosimilar therapies.^20-23 Initially, three separate draft guidances that mapped out the scientific issues, quality analytical factors and other regulatory considerations for bringing follow-on biologics to market were released in February 2012. These documents describe a step-wise approval pathway. This process starts with extensive data characterization to demonstrate similarity. FDA then evaluates the data and gives advice to the sponsor on the amount and scope of animal and human testing needed to show biosimilarity. Once FDA determines a product is biosimilar, the sponsor can choose to demonstrate interchangeability, which requires further switching studies to show that changing to the new product does not affect safety and efficacy. In February 2013, Draft Guidance for Industry-Biosimilars: Questions and Answers Regarding Implementation of the BPCIA of 2009 was published for comment.²⁴ The BPCIA, enacted as part of the Biologics Price Competition and Innovation Act (Pub. L. 111-148) on 23 March 2010, created an abbreviated licensure pathway under Section 351(k) of the Public Health Service Act (42 U.S.C. 262(k)) for biological products demonstrated to be biosimilar to, or interchangeable with, an FDA-licensed biological reference product.

Unlike European regulators, FDA decided not to issue separate guidances for developing biosimilars in different drug product classes. To avoid unnecessary and redundant animal and clinical testing, sponsors are permitted to use a non-US licensed comparator in certain studies, with appropriate associating data.

EU

The biosimilar process in the EU is the most advanced of any region. In 2003, the European Commission added provisions for "similar biological medicinal products" to the legislation governing marketing applications to establish requirements for approval of these products (see Table 2).

Following the amendment to the legislation, three general guidances were issued; the first in 2005 followed by two in 2006 outlining quality, clinical and nonclinical requirements. Three additional guidances are in draft.

Additional guidances apply to six categories of products including therapeutic proteins, vaccines, blood-derived products, monoclonal antibodies and gene and cell therapies. Further, in 2011 a concept paper was issued on revision of the guidance, suggesting the process should focus on similarity rather than clinical benefit.

Japan

Japan's approach to biosimilars regulation generally follows the EU approach of showing similarity based on quality, safety and efficacy of biosimilar products. A guideline was published in 2009 by the Ministry of Health, Labour and Welfare (MHLW) on the quality, safety and efficacy of biosimilar products, although with a slightly less inclusive scope than the EU guidance (see Table 2).²⁵ The guideline covers specific product categories (i.e., recombinant vaccines, PEGylated recombinant proteins and non-recombinant proteins that are highly purified and characterized) while excluding others (e.g., polyglycans and synthetic peptides).

Regulatory Landscape: Submission Types

North America

A marketing application for a new drug in Canada is called a New Drug Submission (NDS). Health Canada's BGTD is responsible for regulating biologics, including blood and blood products, viral and bacterial vaccines, cells, tissues, organs and xenografts. To date, BGTD has approved one NDS for an SEB: Omnitrope (see Table 3). Approval for this drug was based on a comparability assessment with the reference biologic drug, Genotropin.

Biologics generally are approved by FDA via a Biologic License Application (BLA), rather than an NDA (described under Section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act). The 505(b)(2) regulatory pathway is defined in the act as an NDA containing investigations of safety and effectiveness that are being relied upon for approval and were not conducted by or for the applicant, and for which the applicant has not obtained a right of reference.²⁶ These applications allow a sponsor to rely, in part, on FDA's findings of safety and/or effectiveness for a previously approved reference drug. Under section 505(b)(2) of the FD&C Act, a "generic" need not be an exact duplicate of the brand-name original in order to be approved.²⁷

An Abbreviated New Drug Application (ANDA, described under Section 505(j) of the act) for a generic drug generally does not require all the clinical trials customarily required for a new drug under an NDA. Rather, the basis for approval is a demonstration of bioequivalence to the reference product, meaning the generic is absorbed at the same rate and extent as the reference product.

The majority of biological drugs, including most recombinant proteins, do not qualify for an ANDA submission under existing US law.²⁸ However, a few biologic medicines, including biosynthetic insulin, calcitonin, growth hormone, glucagon and hyaluronidase, are grandfathered under governance of the FD&C Act [21 USC 321(p)(1)].²⁹Only menotropins and enoxaparin have been approved in the US via the simplified 505(j) procedures allowed for small molecule generics. Follow-on biological products approved through these abbreviated pathways are listed in Table 3.

The current legal pathway in the US for the approval of biosimilars is the BPCIA. To date, FDA has not approved a biological product as biosimilar or interchangeable through the abbreviated licensure pathway created by the ACA.³⁰

EU

Sixteen similar biological medicinal product applications have been approved in the EU (see Table 3). One of the requirements for biosimilar approval is a reference product authorized for sale in the EU. The biosimilar should have the same active ingredient, route of administration and dosage form.

Japan

Two new drug applications for follow-on biologics have been approved to date in Japan (see Table 3). Requirements in Japan also include a reference product authorized in that country. The dosage form and route of administration of biosimilar products should be the same as that of the reference product. Yet, it is not essential for the biosimilar product to have the same formulation as the reference product.³¹

Regulatory Landscape: Submission Requirements

US

FDA determines animal and/or clinical testing requirements on a per-product basis following assessment of the comparative analytical data. An application may need to include a chemistry and manufacturing package, information on the innovator biologic's safety and efficacy, data to demonstrate chemical and biological comparability to the innovator product, comparative animal toxicity and toxicological data, pharmacokinetic/pharmacodynamic (PK/PD) data, an immunogenic profile and a clinical package demonstrating the follow-on biologic's safety and efficacy.^32-34

EU

A biosimilar should have the same active ingredient, route of administration and dosage form as its EU-authorized reference product. The comparability exercise for quality includes consideration of analytical methods, physicochemical characterization, biological activity, purity and specifications of the similar biological medicinal product. Comparative PK studies are an essential part of the comparability exercise. PD markers should be selected on the basis of their relevance to demonstrate therapeutic efficacy.³⁵ Comparative clinical trials are required to demonstrate clinical comparability. In some cases, PK/PD studies may suffice for this. Immunogenicity should always be considered and investigated.³⁶

Japan

Regarding quality, the manufacturing package must be sufficient to demonstrate a robust manufacturing process. Accelerated and stress stability studies are recommended to obtain useful data for evaluating the properties of the biosimilar product. A comparison of stability with the reference product or a nonclinical evaluation of impurities is not necessarily required. Expiration dating of biosimilar products is determined based on data from real-time/real-temperature studies.

For nonclinical studies, comparability of the pharmacological action should be evaluated directly. Repeated dose-toxicity studies may be valuable to evaluate both single-dose and repeated-dose toxicity. Local tolerance could be evaluated in repeated-dose toxicity studies. A direct comparative study of the toxicity profile and other general nonclinical safety studies may not always be necessary.

To evaluate efficacy, the comparability of biosimilar product should be demonstrated through clinical studies. PK/PD studies may be sufficient to ensure comparability. To address immunogenicity, clinical safety studies should be considered to evaluate antibody formation and other immunogenicity factors.^{37, 38}

Harmonization

The global harmonization of regulatory requirements for follow-on biologics/biosimilars/SEBs is severely lacking. This may be the result of several factors. Although entities such as the International Conference on Harmonisation aid in the establishment of standards, worldwide regulatory authorities and pharmaceutical industries did not convene to discuss the issues concerning biosimilar product development prior to the establishment of local guidance and regulations. In the US, this lack of consultation may have been driven by the fact that it was believed new legislation would need to be created as a result. However, in the EU, ICH guidance is adopted as law while in the US, ICH guidance is not codified. Although different terminology and guidances exist, common themes do emerge. With the exception of allowing formulation differences as discussed earlier, CMC data requirements are similar in all regions; apart from Japan, which does not require new impurity qualification studies, the need for nonclinical data is driven by science in all geographies and requirements for clinical data are driven by product complexity and clinical risk. Although the global harmonization of regulatory requirements for biosimilar development currently is absent, sound science should drive similarities.

About the Authors

Gretchen E. Parker, PhD, RAC, is a regulatory advisor for Pearl Pathways (www.pearlpathways.com), and serves as Institutional Review Board co-chair for Pearl IRB (www.pearlirb.com). She has published dozens of scientific articles in major peer-reviewed journals and holds a patent for a diagnostic assay. Parker holds a PhD from Purdue University, and completed a post-doctoral fellowship in biochemistry and molecular biology at the Indiana University School of Medicine Center for Diabetes Research. She earned Regulatory Affairs (RAC) Certification in 2007. Parker can be reached at [email protected].

Sarah Witwer, JD, RAC, is a regulatory advisor for Pearl Pathways and has more than 30 years of experience in drug development with particular skills in CMC (chemistry, manufacturing and controls). She is a microbiologist and lawyer and holds degrees from Miami University and Indiana University. Witwer can be reached at [email protected].

Gretchen Miller Bowker, MS, RAC, FRAPS, serves as chief operating officer for Pearl Pathways and has more than 25 years of experience in the development of drugs, biologics and devices. She has experience working in academic research settings, large pharmaceutical companies, small biotechs and large device companies. At Pearl Pathways, Bowker oversees the company's commercial IRB Board, oversees all client consulting engagements, and serves as the company's quality director. She holds an MS in biology from Purdue University, earned the RAC in 2002, and has been a RAPS Fellow since 2011. She can be reached at [email protected].

Cite as: Parker G, Witwer S, Bowker G. "Regulatory Approval of Biosimilars: A Global Perspective." Regulatory Focus. January 2014. Regulatory Affairs Professionals Society.

Charts and Tables

Table 2. Biosimilar Regulatory Guidance

Table 3. Approved "similar" protein products

References

1. Guidance for Industry: Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants. US FDA website. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM345649.pdf. Published March 2013. Accessed 15 July 2013.
2. Guideline on Similar Biological Medicinal Products. EMA website. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003517.pdf. Published 30 October 2005. Accessed 15 July 2013.
3. Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies-Non-Clinical and Clinical Issues. EMA website. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500128686.pdf. Published 30 May 2012. Accessed  15 July 2013.
4. Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues, revision 1. 2013. EMA website. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003953.pdf. Published 22 February 2006. Accessed 15 July 2013.
5. Multidisciplinary: Biosimilar. EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c. Accessed 8 October 2013.
6. Guideline on Immunogenicity Assessment of Monoclonal Antibodies Intended for In Vivo Clinical Use. EMA website. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500128688.pdf. Published 24 May 2012. Accessed 15 July 2013.
7. Guideline for the quality, safety and effectiveness of biosimilar products (in Japanese). Generics and Biosimilars Initiative website. http://www.gabionline.net/Guidelines/Japanese-guidelines-for-biosimilars. Accessed 15 July 2013.
8. Hurdles to biosimilars in Asia. Generics and Biosimilars Initiative website. http://www.gabionline.net/Biosimilars/General/Hurdles-to-biosimilars-in-Asia. Posted 10 December 2010. Accessed 15 July 2013.
9. Biosimilars - Global Strategic Business Report. Research and Markets website. http://www.researchandmarkets.com/reports/1227769/biosimilars_global_strategic_business_report. Published April 2012. Accessed 15 July 2013.
10. Kresse GB. Biosimilars -science, status, and strategic perspective. Eur J Pharm Biopharm. 2009;72(3):479-486.
11. Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs). WHO website. http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf. 19 to 23 October 2009. Accessed 15 July 2013.
12. Will The Big Pharmaceuticals Fall Off A Patent Cliff? Seeking Alpha website. http://seekingalpha.com/article/1367261-will-the-big-pharmaceuticals-fall-off-a-patent-cliff. Published 24 April 2013. Accessed 9 October 2013.
13. Global endocrinology market is set to show moderate growth in near future. TransWorldNews website. http://www.transworldnews.com/1071677/c1/global-endocrinology-market-is-set-to-show-moderate-growth-in-near-future. Published 8 May 2012. Accessed 8 October 2013.
14. Op cit 2.
15. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. US FDA website. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Published February 2012. Accessed 15 July 2013.
16. Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs). Health Canada website. http://www.biotech.ca/uploads/sebs/seb-pbu_e%202010.pdf. Published 5 March 2010. Accessed 15 July 2013.
17. Global Biosimilars Market to Reach US$17.9 Billion by 2017, According to a New Report by Global Industry Analysts, Inc. PRWeb website. http://www.prweb.com/releases/biosimilars/follow-on_biologics/prweb9386524.htm. Posted 10 April 2012. Accessed 12 August 2013.
18. Op cit 16.
19. Ibid.
20. Op cit 1.
21. Op cit 15.
22. Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product. FDA website. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291134.pdf. Published February 2012. Accessed 15 July 2013.
23. Guidance for Industry: Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009. FDA website. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM273001.pdf. Published February 2012. Accessed 15 July 2013.
24. Ibid.
25. Op cit 7.
26. Guidance for Industry: Applications Covered by Section 505(b)(2).http://www.fda.gov/downloads/Drugs/.../Guidances/ucm079345.pdf. 2013. Accessed 15 July 2013.
27. Ibid.
28. Rey R. New Drug Application (NDA) and Abbreviated New Drug Application (ANDA). Slide presentation. Universidad Interamericana de Puerto Rico. http://facultad.bayamon.inter.edu/rrey/CHEM%203350/NDA%20and%20ANDA.pdf. 2013. December 2012. Accessed 12 August 2013.
29. FDA. CPG Sec. 440.100 Marketed New Drugs Without Approved NDAs and ANDAs Guidance for FDA Staff and Industry Marketed Unapproved Drugs-Compliance Policy Guide Chapter 4 Subchapter 440. 2013. Accessed 12 July 2013.
30. Sherman RE. Biosimilar Biological Products. Slide presentation. FDA website. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM292463.pdf. Posted 15 February 2012. Accessed 12 August 2013.
31. Op cit 7.
32. Op cit 1.
33. Op cit 15.
34. Op cit 22.
35. Op cit 2.
36. Ibid.
37. Op cit 7.
38. Japanese Biosimilars Guideline. Biosimilar News website. http://www.biosimilarnews.com/japanese-biosimilars-guideline. Published 29 August 2011. Accessed 12 July 2013.

Table References

Table 1 References

• a.     Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs). WHO website. http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf. 19 to 23 October 2009. Accessed 15 July 2013.
• b.     Guidance for Industry: Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants. FDA website. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM345649.pdf. Published March 2013. Accessed 15 July 2013.
• c.     Op cit a.
• d.     Guideline on Similar Biological Medicinal Products. EMA website. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003517.pdf
• . Published 30 October 2005. Accessed 15 July 2013.
• e.     Japanese Biosimilars Guideline. Biosimilar News website. http://www.biosimilarnews.com/japanese-biosimilars-guideline. Published 29 August 2011. Accessed 12 July 2013.
• f.      Wang J, Chow S. "On the Regulatory Approval Pathway of Biosimilar Products." Pharmaceuticals. 2013;5:353-368.

Table 2 References

• a.     Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs). WHO website. http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf. 19 to 23 October 2009. Accessed 15 July 2013.
• b.     Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs). Health Canada website. http://www.biotech.ca/uploads/sebs/seb-pbu_e%202010.pdf. Published 5 March 2010. Accessed 15 July 2013.
• c.     Guidance for Industry: Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants. US FDA website. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM345649.pdf. Published March 2013. Accessed 15 July 2013.
• d.     Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. FDA website. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Published February 2012. Accessed 15 July 2013.
• e.     Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product. FDA website. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291134.pdf. Published February 2012. Accessed 15 July 2013.
• f.      Guidance for Industry:  Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009.  FDA website. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM273001.pdf. Published February 2012. Accessed 15 July 2013.
• g.     Guideline on similar biological medicinal products.  EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c. Published September 2005. Accessed 15 July 2013.
• h.     Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues, revision 1. 2013. EMA website. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003953.pdf. Published 22 February 2006. Accessed  15 July 2013.
• i.      Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues. EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c. Published February 2006. Accessed 15 July 2013.
• j.      Draft Annex Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Drug Substance - Non Clinical and Clinical Issues - Guidance on Biosimilar Medicinal Products containing Recombinant Human Insulin. EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c. Published February 2006. Accessed 15 July 2013.
• k.     Draft Annex Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Drug Substance - Non-Clinical and Clinical Issues - Guidance on Biosimilar Medicinal Products containing Somatropin. EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c. Published February 2006. Accessed 15 July 2013.
• l.      Draft Annex Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Drug Substance - Non Clinical and Clinical Issues - Guidance on Biosimilar Medicinal Products containing Recombinant Granulocyte-Colony Stimulating Factor. EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c. Published February 2006. Accessed 15 July 2013.
• m.    Draft Annex Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Drug Substance - Non Clinical and Clinical Issues - Guidance on Biosimilar Medicinal Products containing Recombinant Erythropoietins. EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c. Published March 2006. Accessed 15 July 2013.
• n.     Guideline on similar medicinal products containing recombinant interferon alpha. EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c. Published June 2009. Accessed 15 July 2013.
• o.     Similar biological medicinal products containing recombinant low molecular weight heparins - non-clinical issues. EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c. Published April 2009. Accessed 15 July 2013.
• p.     Comparability of biotechnology-derived medicinal products after a change in the manufacturing process - nonclinical and clinical issues. EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c. Published July 2007. Accessed 15 July 2013.
• q.     Immunogenicity assessment of biotechnology-derived therapeutic proteins. EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c. Published January 2008. Accessed 15 July 2013.
• r.      Similar biological medicinal products containing recombinant follicle-stimulating hormone. EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c. Published March 2013. Accessed 15 July 2013.
• s.     Similar biological medicinal products containing interferon beta. EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c. Published March 2013. Accessed 15 July 2013.
• t.      Similar biological medicinal products containing monoclonal antibodies: non-clinical and clinical issues. EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c. Published June 2012. Accessed 15 July 2013.
• u.     Similar biological medicinal products containing recombinant erythropoietins. EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c. Published April 2010. Accessed 15 July 2013.
• v.     Draft Annex Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Drug Substance - Non Clinical and Clinical Issues - Guidance on Biosimilar Medicinal Products containing Recombinant Erythropoietins. EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c. Published March 2006. Accessed 15 July 2013.
• w.    Guideline on Non-Clinical and Clinical Development of Similar Biological Medicinal Products Containing Low-Molecular-Weight-Heparins. EMA website. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c. Published April 2009. Accessed 15 July 2013.
• x.     Guideline on Immunogenicity Assessment of Monoclonal Antibodies Intended for In Vivo Clinical Use. EMA website. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500128688.pdf. Published 24 May 2012. Accessed 5 July 2013.
• y.     Guidance on registration of similar biological products in Singapore. Health Sciences Authority website. http://www.hsa.gov.sg/publish/etc/medialib/hsa_library/health_products_regulation/western_medicines/files_guidelines.Par.63688.File.dat/Appendix%2017_Guidance%20on%20Registration%20of%20Similar%20Biological%20Products%20in%20Singapore%202011.pdf. Published April 2011. Accessed 15 July 2013.
• z.     Guidelines on similar biologics: regulatory requirements for marketing authorization in India. Central Drugs Standard Control Organization website. http://cdsco.nic.in/Bio%20Similar%20Guideline.pdf. Published 2012. Accessed 15 July 2013.
• aa.   Guideline for the quality, safety and effectiveness of biosimilar products (in Japanese). Generics and Biosimilars Initiative website. http://www.gabionline.net/Guidelines/Japanese-guidelines-for-biosimilars. Accessed 15 July 2013.
• bb.   Korean Guidelines on the Evaluation of Similar Biotherapeutic Products (SBPs); Evaluation Guidelines for Biosimilars. Korea Food and Drug Administration website. http://www.biosimilars.ca/docs/Evalutation_Guidelines_for_Biosimilars.pdf.  Published July 2009. Accessed 15 July 2013. 
• cc.    Suh SK, Park Y. Regulatory guideline for biosimilar products in Korea. Biologicals. 2013;39:336-338.
• dd.  Guidance document and guidelines for registration of biosimilars in Malaysia. Ministry of Health Malaysia National Pharmaceutical Control Bureau website. portal.bpfk.gov.my/view_file.cfm?fileid=1048. Published 4 August 2008. Accessed 15 August 2013.

Table 3 References

a.     EMA Procedural advice for users of the Centralised Procedure for Similar Biological Medicinal Products applications. EMA/940451/2011 . EMA website. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/04/WC500125166.pdf. Published March 2013. Accessed 15 July 2013.