Prospects and Challenges for the Commercialization of Biosimilars: Perspectives from the EU, Japan, and the US
Requires Subscription or Fee PDF

Keywords

Biosimilars Act
biosimilars
Biologics
Biologics Price Competition and Innovation Act

Abstract

With many blockbuster biologic drugs coming off patent in the next couple of years, biosimilars are making significant breakthroughs in cost-effective biologic therapies. The global market for biosimilars is expected to increase nearly 30 fold from $1.3 billion in 2013 to $35 billion by 2020. To promote biosimilar development and commercialization in the U.S., the Biosimilars Act was signed into law in 2010 to establish an abbreviated pathway by which the FDA could approve biosimilar versions of previously licensed biological products. Since its enactment, two biosimilars have been approved in the U.S. This Article will discuss key aspects of the U.S., the EU and Japanese approval pathways and will explore their likely impact on the commercialization of biosimilar medicines.  

https://doi.org/10.5912/jcb751
Requires Subscription or Fee PDF

References

“Global Biosimilars/Follow-on-Biologics Market (Technology, Types, Applications, Services and Geography) – Research Report, 2013-2020, July 2014. Accessed at www.researchandmarkets.com.

Andrew F. Bourgoin and Beth Nuskey, “An Outlook on US Biosimilar Competition,†April 2013. Accessed http://thomsonreuters.com/products/ip-science/04_013/anoutlookonusbiosimilarcompetition-cwp-en.pdf

Generics and Biosimilars Initiative, Biosimilars Approved in Europe. Accessed http://www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe

National Institute of Health Science, Biosimilars approved in Japan. Accessed at http://www.nihs.go.jp/dbcb/biosimilar.html [Japanese]

Patient Protection and Affordable Care Act, Pub. L. No. 111-148, 124 Stat. 119 (2010). The Patient Protection and Affordable Care Act was previously H.R. 3590, 111th Cong. (2009).

Biologics Price Competition and Innovation Act of 2009, Pub. L. No. 111-148, §§ S 7001-7003, 124 Stat. 119, 804-821 (2010).

Id.

http://www.financierworldwide.com/competitive-strategies-in-life-sciences-biobetters-versus-biosimilars/

PHSA § 351 (i), 42 U.S.C. § 262(i) (2006).

David M. Dudzinski, Reflections on Historical, Scientific, and Legal Issues Relevant to Designing Approval Pathways for Generic Versions of Recombinant Protein-Based Therapeutics and Monoclonal Antibodies, 60 Food & Drug L.J. 143, 143 (2005).

Edward L. Korwek, What Are Biologics? A Comparative Legislative, Regulatory and Scientific Analysis, 62 FOOD & DRUG L.J. 257 (2007). FOR A CHRONOLOGY OF PRODUCT CLASS DEVELOPMENTS, SEE BIO’S TIMELINE, HTTP://BIO.ORG/SPEECHES/PUBS/ER/TIMELINE.ASP (LAST VISITED APR. 22, 2008).

Increasingly popular therapeutic biological products even more complex than single proteins are monoclonal antibodies. Antibodies, which consist of multiple chains of individual proteins, are made by cells of the immune system and are designed to recognize and tightly bind to a specific target. Recombinant monoclonal antibodies are biological products made by the fusion of a beta cell of the immune system to an immortal cell such as a tumor cell. Dianne M. Dinnis & David C. James, Engineering Mammalian Cell Factories for Improved Recombinant Monoclonal Antibody Production: Lessons from Nature?, 91 Biotechnology & Bioengineering 180, 180 (2005).

Lehninger, David L. Nelson and Michael M. Cox, Biochemistry (5ed. 2008).

Vernon M. Ingram, Sickle-Cell Anemia Hemoglobin: The Molecular Biology of the First “Molecular Diseaseâ€- The Crucial Importance of Serendipity, 167 Genetics 1, 3 (2004).

Zuñiga L, Calvo B. Biosimilars: pharmacovigilance and risk management. Pharmacoepidem Dr S 2010;19:661-9; Nowicki M. Basic facts about biosimilars. Kidney Blood Pres Res 2007;30:267-72; and Roger SD, Mikhail A. Biosimilars: opportunity or cause for concern? J Pharm Pharmaceut Sci 2007; 10:405-10.

Safe and Affordable Biotech Drugs: The Need for a Generic Pathway, Hearing Before the House Comm. on Oversight and Gov’t. Reform, 110th Cong. (2007) (statement of Janet Woodcock, Deputy Comm’r, Chief Medical Officer, Food and Drug Administration) available at http://oversight.house.gov/documents/20070326104056-22106.pdf [hereinafter Woodcock Statement].

Michele Kessler et al., Immunogenicity of Biopharmaceuticals, 21 Nephrology Dialysis Transplantation (Supp.) v9, v10 (2006).

See Charles L. Bennett et al., Long-term Outcome of Individuals with Pure Red Cell Aplasia and Antierythropoietin Antibodies in Patients Treated with Recombinant Epoetin: A Follow-up Report from the Research on Adverse Drug Events and Reports (RADAR) Project, 106 BLOOD 3343 (2005).

See Huub Schellekens & Wim Jiskoot, Letter to the Editor, Eprex-Associated Pure Red Cell Aplasia and Leachates, 24 NATURE BIOTECHNOLOGY 613, 613-14 (2006). EACH PRODUCT WAS MANUFACTURED BY DIVISIONS OF THE SAME PHARMACEUTICAL COMPANY, BUT CHANGES WERE MADE TO EPREX® AT THE REQUEST OF EUROPEAN REGULATORY AGENCIES. ID.

Charles L. Bennett et al., Long-term Outcome of Individuals with Pure Red Cell Aplasia and Antierythropoietin Antibodies in Patients Treated with Recombinant Epoetin: A Follow-up Report from the Research on Adverse Drug Events and Reports (RADAR) Project, 106 BLOOD 3343 (2005).

Sahr, Robert,N., THE BIOLOGICS PRICE COMPETITION AND INNOVATION ACT: INNOVATION MUST COME BEFORE PRICE COMPETITION Boston College Intellectual Property & Technology Forum. Accessed at http://www.bciptf.org

Biologics Revolution: The Intersection of Biotechnology Patent Law and Pharmaceutical Regulation. Georgetown Law Journal. Tam,J.W.Y. 2010 , volume 98, page 535; Tam, Joyce,W.Y., BIOLOGICS REVOLUTION THE INTERSECTION OF BIOTECHNOLOGY PATENT LAW AND PHARMACEUTICAL REGULATION_The Georgetown Law Journal_2010_vol98 p535.

Id.

Katheleen R. Kelleher, FDA Approval of Generic Biologics: Finding a Regulatory Pathway, 14 Mich. Telecom. & Tech. L. Rev. 245, 252 (2007).

Natasha Singer, In Pursuit of a Pipeline of Biological Treatments, N.Y. Times, January 27, 2009.

Biotechnology Industry Organization, How Do Drugs and Biologics Differ?, http://bio.org/healthcare/followonbkg/DrugsVBiologics.asp (last visited Nov. 1, 2010).

Anthony D. so & Samuel L. Katz, Biologics Boondoggle, Op-Ed, N.Y. Times, March 7, 2010.

Jessica Dye, “Obama Wants To Limit Biologic Protection In Health Bill,†Law 360, January 15, 2010. http://www.law360.com/topnews/articles/143763/obama-wants-to-limit-biologic-protection-in-health-bill

Directive 2001/83/EC, as amended by Directive 2003/63/EC and Directive 2004/27/EC.

Biosimilars approved in Europe, Generics and Biosimilars Initiative http://www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe (last updated Nov. 14, 2014). Although 23 biosimilars have been approved since the European biosimilars pathway was created, two biosimilar approvals have been withdrawn. As a result, only 20 biosimilar drugs are currently approved for use in Europe.

Biological Guidelines, European Medicines Agency, http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000082.jsp (last visited Nov. 14, 2014).

EMA Procedural advice for users of Centralised Procedure for Similar Biological Medicinal Products applications, European Medicines Agency (Oct. 2014) at 5, http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/04/WC500125166.pdf

Id.

Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues, European Medicines Agency (May 30, 2012), http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500128686.pdf

GUIDANCE ON SIMILAR MEDICINAL PRODUCTS CONTAINING

SOMATROPIN, European Medicines Agency (Feb. 26, 2006),

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003956.pdf

GUIDELINE ON NON-CLINICAL AND CLINICAL DEVELOPMENT OF SIMILAR BIOLOGICAL MEDICINAL PRODUCTS CONTAINING LOW-MOLECULAR-WEIGHT-HEPARINS, European Medicines Agency (Mar. 19, 2009), http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003927.pdf

EMA Procedural advice for users of Centralised Procedure for Similar Biological Medicinal Products applications, European Medicines Agency (Oct. 2014) at 34, http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/04/WC500125166.pdf

Directive 2001/83/EC, as amended by Directive 2003/63/EC and Directive 2004/27/EC, Article 10(1).

Id.

Id.

Ministry of Health Labor and Welfare, Pharmaceutical and Food Safety Bureau, Guideline for Ensuring Quality, Safety, and Efficacy of follow-on biologics, Notification No. 0304007 (March 4, 2009) [Japanese]

National Institute of Health Science, Biosimilars approved in Japan. Accessed at http://www.nihs.go.jp/dbcb/biosimilar.html [Japanese]

Ministry of Health Labor and Welfare, Pharmaceutical and Food Safety Bureau, Application for follow-on biologics, Notification No. 0304004 (March 4, 2009) [Japanese]

Ministry of Health Labor and Welfare, Pharmaceutical and Food Safety Bureau, Guideline for Ensuring Quality, Safety, and Efficacy of follow-on biologics, Notification No. 0304007 (March 4, 2009) [Japanese]

Id. No. 0304004.

Ministry of Health Labor and Welfare, Pharmaceutical and Food Safety Bureau, Q&A for the Guideline for Ensuring Quality, Safety, and Efficacy of follow-on biologics No. 1 (July 21, 2009) [Japanese]

Id. No. 2 (March 31, 2010) [Japanese]

Id. No. 3 (December 15, 2015) [Japanese]

Article 14-4 of the Pharmaceutical and Medical Device Act (Law No.145 in 1960)

Public Health Service Act § 351(k)(2)(A)(i)(I), 42 U.S.C.A. § 262(k)(2)(A)(i)(I) (West 2010).

Section 7002(b) of the Biosimilars Act amends PHSA § 351 (i) to define "biosimilar" to mean "(A) that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and (B) there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product." Biologics Price Competition and Innovation Act of 2009, Pub. L. No. 111-148, § 7002(b), 124 Stat. 119, 814-15 (2010).

Id. § 351(k)(2)(A)(i)(II)-(IV).

Id. § 351(k)(2)(A)(i)(V).

Id. § 351(k)(4)(A).

Id. § 351(k)(4)(B).

Id. § 351(k)(2)(A)(i)(I).

Id. § 351(k)(2)(A)(ii).

Follow-On Biologics, Data Exclusivity, and the FDA. Berkeley Technology Law Journal. Tzeng,L. Jan 2010, volume 25, Issue 1, Article 6, Page 135; Tzeng, Linfong, FOLLOW-ON BIOLOGICS, DATA EXCLUSIVITY, AND THE FDA Berkeley Technology Law Journal_2010_vol25 p135.

FDA Guidance for Industry, “Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product†May 2014.

PHSA § 351(k)(7)(A).

PHSA § 351(k)(7)(B).

PHSA § 351(k)(6)(A).

PHSA § 351(k)(6)(B).

Id. § 351(k)(6)(C)(i).

Id. § 351(k)(6)(C)(ii).

Biologic medicines have been marketed to treat a number of diseases including multiple sclerosis, diabetes, rheumatoid arthritis, anemia, sepsis, and various cancers. For a catalog of currently approved biologics and their therapeutic indications, see FDA’s Therapeutic Biological Products, http://www.fda.gov/cder/biologics/default.htm (last visited Apr. 22, 2008).

Biologics Still on Top in Best Selling Drugs of 2013, http://cellculturedish.com/2014/03/top-ten-biologics-2013-us-pharmaceutical-sales-2/ (last visited Nov. 5, 2014).

Id.

Andrew F. Bourgoin, What You Need To About The Follow-On Biologic Market in the U.S.: Implications, Strategies, and Impact at 1, Thomson Reuters (January 2011), http://thomsonreuters.com/products/ip-science/04_013/newport-biologics.pdf.

Paula Trioni, “Pharmaceutical Pricing: A Review of Proposals to Improve Access and Affordability of Prescription Drugs,†19 Annals of Health Law (2010), 311.

Anna Edney, Sanofi Wins U.S. Approval for New Gaucher Disease Pill, Bloomberg, (Aug. 19, 2014, 4:45 PM ET), http://www.bloomberg.com/news/2014-08-19/sanoif-wins-u-s-approval-for-new-gaucher-disease-pill.html.

The Generic Pharmaceutical Association. Generic Drug Savings in the U.S. Fourth Annual Edition: 2012.

Schacht, Wendy H., and Thomas, John r. “Follow-On Biologics: The Law and Intellectual Property Issues.†Congressional Research Services, December 6, 2012.

Biosimilars/Follow-on-Biologics Market is Expected to Reach $35 Billion, Globally, by 2020, PR Newswire, (July 21, 2014), http://www.prnewswire.com/news-releases/biosimilarsfollow-on-biologics-market-is-expected-to-reach-35-billion-globally-by-2020-267947471.html.

Id.

Id.

Id.

Id.

Celltrion files for US FDA approval of Remsima®, Celltrion, (Aug. 11, 2014), http://www.celltrion.com/en/COMPANY/notice_view.asp?idx=456&code=ennews&intNowPage=1&menu_num=&align_year=all

Id.

Id.

Id.

Joanna T. Brougher and David A. Fazzolare, “Will the Biosimilars Act Encourage Manufacturers to Bring Biosimilars to Market?†Food and Drug Policy Forum, Vol.1, No. 5, March 8, 2011.

Will the Biosimilars act encourage manufacturer to bring Biosimilars to Marker? FDLI’s. Brougher,J. March 2011 Volume 1, Issue 5 .

FDA Guidance for Industry, “Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product†May 2014.

PHSA § 351(k)(6)(A).- (C).

Fazzolare, David A. “Gaming the Biosimilars Act: Loopholes Allow Authorized Interchangeable Settlement Agreements to Delay Authentic Generic Competition up to 18 Months,†FDA Update, July/August 2010.

Biosimilars Act, § 351(l)(4)(A).

Brougher, J. “Intellectual Property and Health Technologies: Balancing Innovation and the Public’s Health†Springer Publishing, 2014 ed.

Manheim BS, et al. ‘Follow-On Biologics’: Ensuring Continued Innovation In The Biotechnology Industry. Biotech Industry. March/April 2006, 394-403.

Biosimilars Act, § 351(k)(7)(C).

Unless specified by prior arrangement, the author agrees to the following terms and assurances:

  1. For myself and on behalf of the other authors listed on this work, I assign to thinkBiotech LLC the copyright* in the contribution for the full term throughout the world.
  2. I/we further give to the following assurances
    1. I am the sole author of the contribution, or, if not, I have the written authority of the other authors to transfer the copyright* to thinkBiotech LLC and give these warranties;
    2. I and (where appropriate) the other authors are entitled to transfer the copyright to thinkBiotech LLC and no one else would be entitled to prevent us from publishing the contribution;
    3. To the best of my/our knowledge, all the facts in the contribution are true and accurate;
    4. The content of the contribution is entirely original to me (and where appropriate to the other authors) or, if not, the written permission of the owner of the copyright in any material copied from elsewhere has been obtained for all media (all such permissions to be attached to the contribution as supplementary files);
    5. Nothing in the contribution is obscene or libellous;
    6. Nothing in the contribution infringes any duty of confidentiality which I/or the other authors may owe to anyone else.
    7. I and/or the other authors have obtained the appropriate clearances from my/our employer(s) or other concerned institution(s).
* Works by US government employees prepared as part of official duties are in the public domain and the authors are therefore exempt from copyright assignment.