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Similar or the Same? Why Biosimilars are not the Solution

Published online by Cambridge University Press:  01 January 2021

Lisa Diependaele ,
Julian Cockbain  and
Sigrid Sterckx
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Abstract

Advancements in the field of biotechnology have accelerated the development of drugs that are manufactured from cultures of living cells, commonly referred to as “biologics.” Due to the complexity of the production process, generic biologics are unlikely to be chemically identical to the reference product, and accordingly are referred to as “biosimilars.”

Encouraging the development of biosimilars has been presented as the key solution to decrease prices and increase access to biologics, but the development and use of biosimilars continues to raise problems, none of which can easily be addressed. Developing a biosimilar requires considerable time and financial resources, and legitimate safety concerns necessitate elaborate clinical testing of biosimilars. As a consequence, the introduction of biosimilars onto the market has not resulted in significant price reductions, and concerns regarding the substitution and interchangeability of original biologics with biosimilars persist.

This article will explain how the biologics production process distorts the trade-offs that traditionally guided both patent protection and regulatory exclusivities: disclosure as a key condition for benefiting from the corresponding monopoly position. Hence, we propose establishing a mechanism of mandatory deposit of the original biologic's cell line at the stage of the regulatory approval as the most effective remedy.

Type
Independent Articles
Information
Journal of Law, Medicine & Ethics , Volume 46 , Issue 3: The Medicalization of Poverty; Perspectives of Alzheimer's Disease: Ethical, Legal, and Social Issues , Fall 2018 , pp. 776 - 790
Copyright
Copyright © American Society of Law, Medicine and Ethics 2018

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References

Biologics encompass a broad range of different therapeutic classes, such as erythropoietin, growth hormones, interferons, stimulating factors, low molecular weight heparins, insulins, and monoclonal antibodies.Google Scholar
See Evaluate Pharma, “World Preview 2017, Outlook to 2022 (10th Edition),” June 2017, available at <www.evaluate.com/PharmaWorldPreview2017> (last visited August 2, 2018); Iqvia Institute for Human Data Science, “Medicine Use and Spending in the US: A Review of 2017 and Outlook to 2022,” April 2018, available at <www.iqvia.com/-/media/iqvia/pdfs/institute-reports/medicine-use-and-spending-in-the-us-a-review-of-2017-and-outlook-to-2022.pdf?_=1525781125780> (last visited August 2, 2018).+(last+visited+August+2,+2018);+Iqvia+Institute+for+Human+Data+Science,+“Medicine+Use+and+Spending+in+the+US:+A+Review+of+2017+and+Outlook+to+2022,”+April+2018,+available+at++(last+visited+August+2,+2018).>Google Scholar
Kesselheim, A.S., Avorn, J., and Sarpatwari, A., “The High Cost of Prescription Drugs in the United States: Origins and Prospects for Reform,” JAMA 316, no. 8 (2016): 858–871, at 859.CrossRefGoogle Scholar
For example, Humira (adalimumab) — one of the top revenue generating drugs — has generated a net revenue of US$14,012 million for 2015, US$16,078 million for 2016, and US$18,427 million for 2017. See AbbVie, “2017 Annual Report on Form 10-K and 2018 Proxy Statement” January 26, 2018, available at <https://investors.abbvie.com/static-files/8f8ea49f-4735-404c-be08-2f963441b74d> (last visited September 18, 2018); Other biologics that have generated among the highest global revenues are Avastin (bevacizumab) and Remicade (infliximab). See EvaluatePharma, “World Preview 2014, Outlook to 2020,” June 2014, available at <http://info.evaluategroup.com/rs/evaluatepharmaltd/images/EP240614.pdf> (last visited September 18, 2018); EvaluatePharma, “World Preview 2017, Outlook to 2022,” June 2017, available at <http://info.evaluategroup.com/rs/607-YGS-364/images/WP17.pdf> (last visited September 18, 2018); EvaluatePharma, “World Preview 2018, Outlook to 2024,” June 2018, available at <http://info.evaluategroup.com/rs/607-YGS-364/images/WP2018.pdf> (last visited September 18, 2018).+(last+visited+September+18,+2018);+Other+biologics+that+have+generated+among+the+highest+global+revenues+are+Avastin+(bevacizumab)+and+Remicade+(infliximab).+See+EvaluatePharma,+“World+Preview+2014,+Outlook+to+2020,”+June+2014,+available+at++(last+visited+September+18,+2018);+EvaluatePharma,+“World+Preview+2017,+Outlook+to+2022,”+June+2017,+available+at++(last+visited+September+18,+2018);+EvaluatePharma,+“World+Preview+2018,+Outlook+to+2024,”+June+2018,+available+at++(last+visited+September+18,+2018).>Google Scholar
The claim that costs of research and development have significantly increased has also been questioned. See Light, D.W. and Lexchin, J.R., “Pharmaceutical Research and Development: What Do We Get for All That Money?” BMJ 345 (2012): 1-5 and Morgan, S. et al., “The Cost of Drug Development: A Systematic Review,” Health Policy 100, no. 1 (2011): 4–17.Google Scholar
In order for a drug to be sold legally, the vendor (or her supplier) must have regulatory approval for it from the regulator of the state or region in which it is sold. In the U.S. this is the Food and Drug Administration (FDA), for the E.U. the European Medicines Agency (EMA) and the national regulatory bodies of the E.U. member states. Such regulatory approval must be applied for with the application being supported by clinical data showing that the drug is (sufficiently) safe and (sufficiently) effective for the purpose for which the drug is to be sold, e.g. to lower the patient's blood pressure.Google Scholar
Biologics typically are proteins (such as antibodies) or carbohydrates. Proteins are long, chain-like molecules with the links of the chain being amino acid residues. The biological activity of such compounds results from the way in which the chains fold presenting functional regions capable of interacting with human cells or other targets and provoking or suppressing a desired or undesired activity in the patient's body. As imaginatively described by Price and Rai, “In terms of size and rough complexity, if an aspirin were a bicycle, a small biologic would be a Toyota Prius, and a large biologic would be an F-16 fighter jet.” (Price, W.N. and Rai, A.K., “Manufacturing Barriers to Biologics Competition and Innovation,” Iowa Law Review 101, no. 3 (2016): 1023-1063, at 1026).Google Scholar
While, to obtain a patent, the originator may have had to deposit a sample of a cell line capable of producing a biological with the desired functionality, this may not be the cell line it subsequently uses to produce the biological that is put onto the market.Google Scholar
Declerck, P., Farouk-Rezk, M., and Rudd, P.M., “Biosimilarity Versus Manufacturing Change: Two Distinct Concepts,” Pharmaceutical Research 33, no. 2 (2016): 261-268, at 267.Google Scholar
We have limited our discussion to the U.S. and the E.U., as those are still the biggest pharmaceutical markets and the regulatory standards in other countries are often comparable to E.U. and U.S. frameworks.Google Scholar
“Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine,” Oviedo, April 4, 1997). ETS No. 164, available at <https://rm.coe.int/168007cf98> (last visited September 27, 2018).+(last+visited+September+27,+2018).>Google Scholar
de Mora, F., “Biosimilar: What It Is Not,” British Journal of Clinical Pharmacology 80, no. 5 (2015): 949-956, at 951.Google Scholar
Naizi, S.K., Biosimilars and Interchangeable Biologics: Strategic Elements (Boca Raton, FL: CRC Press, 2015): at 86.Google Scholar
Independent of the national regulatory authorities, the EMA is responsible for handling all centralized marketing-authorization applications. Once granted, the centralized marketing authorization is valid in all E.U. Member States as well as in Iceland, Liechtenstein and Norway.Google Scholar
Directive 2001/83/EC (consolidated version), Annex 1, Part II.4.Google Scholar
See EMA (European Medicines Agency), “Guideline on Similar Biologic Medicinal Products,” CHMP/437/04 Rev 1, October 23, 2014, available at <www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf> (last visited August 2, 2018); Argawal, A.B. and McBride, A., “Understanding The Biosimilar Approval And Extrapolation Process—A Case Study Of An Epoetin Biosimilar,” Critical Reviews in Oncology/Hematology 104 (2016): 98–107, at 99.Google Scholar
See Beck, A. and Reichert, J.M., “Approval Of The First Bio-similar Antibodies In Europe,” mAbs 5, no. 5 (2013): 621-623, at 622.Google Scholar
Naizi, supra note 13, at 81-87.Google Scholar
Id., at 81-91, 96-97.Google Scholar
Id., at 90-92.Google Scholar
For an overview of the debate in the U.S. and the legislative history of the Biologics Price Competition and Innovation Act (BPCIA), see Lietzan, E., Carver, K. Hessler, and Elikan, J., “An Unofficial Legislative History of the Biologics Price Competition and Innovation Act of 2009,” Food & Drug Law Journal 65, no. 4 (2010): 671-818 and Tam, J. Wing Yan, “Biologics Revolution: The Intersection of Bio-technology, Patent Law, and Pharmaceutical Regulation,” The Georgetown Law Journal 98, no. 2 (2010): 535-565, at 550-552.Google Scholar
Amending Section 351 of the Public Health Services Act (PHSA).Google Scholar
Naizi, supra note 13, at 157.Google Scholar
See Olech, E., “Biosimilars: Rationale and Current Regulatory Landscape,” Seminars in Arthritis and Rheumatism 45 (2016): S1-S10, at S7.Google Scholar
Naizi, supra note 13, at 340.Google Scholar
Olech, supra note 24, at S7.Google Scholar
See Kogan, L.A., “The U.S. Biologics Price Competition and Innovation Act of 2009 Triggers Public Debates, Regulatory/Policy Risks, and International Trade Concerns,” Global Trade and Customs Journal 6, no. 11/12 (2011): 513–538, at 514-515; Wing Yan Tam, supra note 21, at 541.Google Scholar
Kogan, supra note 27, at 519.Google Scholar
21 C.F.R. §314.108 (2017).Google Scholar
Feldman, R., “Regulatory Property: The New IP,” Columbia Journal of Law & The Arts 40, no. 1 (2016): 53-104, at 67-72.Google Scholar
See Woodage, T., “Blinded by (a Lack of) Science: Limitations in Determining Therapeutic Equivalence of Follow-On Biologics and Barriers to Their Approval and Commercialization,” Stanford Law Review (2012): 1-20, at 3; Lu, U., “Biologics Price Competition and Innovation Act: Striking a Delicate Balance Between Innovation and Accessibility,” Minnesota Journal of Law, Science & Technology 15, no. 1 (2014): 613-651, at 623-624; Feldman, supra note 30, at 57-62.Google Scholar
42 U.S.C. §262 (k) (7) (2011); see Lu, supra note 31, at 635-636; Feldman, supra note 30, at 82-84.Google Scholar
Directive 2001/83/EC (consolidated version), article 10(1).Google Scholar
EMA, “European Public Assessment Reports,” available at <www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124> (last visited August 2, 2018).+(last+visited+August+2,+2018).>Google Scholar
Beck and Reichert, supra note 17; Krishnan, A., Mody, R., and Malhotra, H., “Global Regulatory Landscape Of Biosimilars: Emerging And Established Market Perspectives,” Biosimilars 5 (2015): 19-32, at 21.Google Scholar
CDER (Center for Drug Evaluation and Research), “List of Licensed Biological Products with (1) Reference Product Exclusivity and (2) Biosimilarity or Interchangeability Evaluations to Date,” available at <www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM560162.pdf> (last visited July 2, 2018).+(last+visited+July+2,+2018).>Google Scholar
See Casey, D., “Key Strategic Factors For Stakeholders In The Current Global Biosimilar Market,” Drug Discovery Today 21, no. 2 (2016): 208-211, at 209; Remuzat, C. et al., “Key Drivers for Market Penetration of Biosimilars in Europe,” Journal of Market Access & Health Policy 5, no. 1 (2017): 1-15; Gupta, S.K., Chaudhari, P.S., and Nath, R., “Opportunities and Challenges in Biosimilar Development,” BioProcess International 15, no. 5 (2017), 24-33.Google Scholar
Gupta et al., supra note 37, at 32.Google Scholar
These countries have mainly based their regulatory requirements on the EMA or World Health Organization (WHO) guidelines. For a comprehensive overview of the global regulatory landscape for biosimilars see Krishnan et al., supra note 35; Olech, supra note 24.Google Scholar
Declerck et al., supra note 9, at 265.Google Scholar
The EMA reports that the E.U. monitoring system has not yet identified any relevant difference in the nature, severity or frequency of adverse effects between biosimilars and their reference medicines. See EMA, “Biosimilars in the EU: Information Guide for Healthcare Professionals,” April 27, 2017, available at <www.ema.europa.eu/docs/en_GB/document_library/Leaflet/2017/05/WC500226648.pdf>: at 4.:+at+4.>Google Scholar
Studies have indicated that biosimilar uptake differs greatly between therapeutic classes and can be influenced by various factors such as the national pricing system and reimbursement and procurement policies (See Remuzat et al., supra note 37, at 3, 7). For example, biosimilar uptake has risen significantly in Norway since the general public reimbursement system was reformed and biologics are now purchased through hospital tenders. See Welch, A., “The Norwegian Biosimilar Phenomenon: From Biosimilar To ‘Biogeneric,’” Biosimilar Development, July 26, 2016, available at <https://www.biosimilardevelopment.com/doc/the-norwegian-biosimilar-phenomenon-from-biosimilar-to-biogeneric-0001> (last visited August 2, 2018).+(last+visited+August+2,+2018).>Google Scholar
See van de Vooren, K., Curto, A. and Garattini, L., “Biosimilar Versus Generic Drugs: Same But Different?” Applied Health Economics and Health Policy 13, no. 2 (2015): 125-127, at 126; Moorkens, E. et al., “Overcoming Barriers to the Market Access of Biosimilars in the European Union: The Case of Biosimilar Monoclonal Antibodies,” Frontiers in Pharmacology 7 (2016): Article 193, at 4.Google Scholar
Weise, M. et al., “Biosimilars: the Science of Extrapolation,” Blood 124, no. 22 (2014): 3191-3196, at 3191-3192.Google Scholar
“Interchangeability” usually refers to the possibility of a physician changing a patient's prescription from the original biologic to the biosimilar. “Substitution,” on the other hand, generally refers to dispensing the biosimilars instead of the original biologic at the pharmacy level. In the latter case, the prescribing physician is unaware of the substitution. See Olech, supra note 24, at S6.Google Scholar
Brinks, V. et al., “Quality of Original and Biosimilar Epoetin Products,” Pharmaceutical Research 28 (2011): 386-393; Halim, L.A. et al., “Quality and Batch-to-Batch Consistency of Original and Biosimilar Epoetin Products,” Journal of Pharmaceutical Sciences 105, no. 2 (2016): 542-550; Jin, B. et al., “Interchangeability Between Biosimilar And Innovator Drug Products,” in Barker, K.B. et al., eds., Biosimilar Clinical Development: Scientific Considerations and New Methodologies (Boca Raton, FL: CRC Press, 2016): 65-95.Google Scholar
Krishnan et al., supra note 35, at 30.Google Scholar
See Moorkens, E. et al., “Policies for Biosimilar Uptake in Europe: An Overview,” PLoS ONE 12, no. 12 (2017): e0190147, Table 1.Google Scholar
Olech, supra note 24, at S6.Google Scholar
Naizi, supra note 13, at 178.Google Scholar
42 U.S.C. §262 (k) (4) (2011).Google Scholar
See FDA, “Considerations in Demonstrating Interchangeability With a Reference Product (Guidance for Industry),” Draft Guidance, January 17, 2017; CDER, supra note 36; There seems to be the expectation that establishing interchangeability will be a costly process, as the BPCIA introduces a period of 12 to 42 months of market exclusivity for the first biosimilar to be approved as “interchangeable.” See Heled, Y., “Regulatory Competitive Shelters,” Ohio State Law Journal 76, no. 2 (2015): 299-356, at 350.Google Scholar
See Emanuel, E.J., Wendler, D. and Grady, C., “What Makes Clinical Research Ethical?” JAMA 283, no. 20 (2000): 2701–2711, at 2703.Google Scholar
Article 16 states that research on a person may only be undertaken if there is no alternative of comparable effectiveness and the risks which may be incurred by that person are not disproportionate to the potential benefits of the research.Google Scholar
For the same reason, the entire absence of an abbreviated pathway for (traditional) generic drugs is said to be problematic. See Olech, supra note 24, at S5; 't Hoen, E., Boulet, P., and Baker, B.K., “Data Exclusivity Exceptions and Compulsory Licensing to Promote Generic Medicines in the European Union: A Proposal for Greater coherence in European Pharmaceutical Legislation,’ Journal of Pharmaceutical Policy and Practice 10, no. 19 (2017): 1-9, at 3.Google Scholar
Goel, N. and Chance, K., “Biosimilars in Rheumatology: Understanding the Rigor of their Development,” Rheumatology 56, no. 2 (2017): 187-197, at 192.CrossRefGoogle Scholar
QuintilesIMS, “The Impact of Biosimilar Competition in Europe,” May 5, 2017, available at <www.ec.europa.eu/Docs-Room/documents/23102> (last visted August 2, 2018).+(last+visted+August+2,+2018).>Google Scholar
See RAND Corporation, The Cost Savings Potential of Biosimilar Drugs in the United States (Santa Monica, CA: RAND Corporation, 2014); Bennett, C.L. et al., Comment, “Biosimilar and Generic Cancer Drugs Unlikely To Bend Cost Curve In The USA,” The Lancet Oncology 18, no. 1 (2017): 22-23. A2.5. These are preliminary estimates and it is difficult to predict how biosimilars will influence prices of biologics and how prices will evolve over time, as various factors can affect the uptake of biosimilars, and the price setting and buying policies of originators and payers. See Mehr, S.R. and Brook, R.A., “Factors Influencing the Economics of Biosimilars in the U.S.,” Journal of Medical Economics 20, no. 12 (2017): 1268–1271.Google Scholar
Sarpatwari, A., Avorn, J., and Kesselheim, A.S., “Progress and Hurdles for Follow-on Biologics,” New England Journal of Medicine 372, no. 25 (2015): 2380-2382, at 2381; Moorkens et al., supra note 43, at 4.Google Scholar
Kesselheim et al., supra note 3, at 864.Google Scholar
See, for example, OECD (Organization for Economic Cooperation and Development), Executive Summary of the Discussion on Competition and Generic Pharmaceuticals, Annex to The Summary Record Of The 121st Meeting Of The Competition Committee Held On June 18-19 2014, DAF/COMP/M(2014)2/ANN6/FINAL, February 10, 2015; Council of the EU, “Council Conclusions On Strengthening The Balance In The Pharmaceutical Systems In The EU And Its Member States,” Press Release 350/16, June 17, 2016; European Commission, “Joint Report on Health Case and Long-Term Care Systems & Fiscal Sustainability (Volume 1),” Institutional Paper 037, October 1, 2016.Google Scholar
Casey, supra note 37, at 209.Google Scholar
Kesselheim, A.S., Sinha, M.S., and Avorn, J., “Determinants of Market Exclusivity for Prescription Drugs in the United States,” JAMA Internal Medicine 177, no. 11 (2017):1658–1664.Google Scholar
Remuzat et al., supra note 37, at 3; Chandra, A. and Vanderpuye-Orgle, J., “Viewpoint: Competition in the Age of Biosimilars,” JAMA 314, no. 3 (2015): 225-226.Google Scholar
Sarpatwari et al., supra note 59, at 2382.Google Scholar
See Remuzat et al., supra note 37, at 11.Google Scholar
See Blackstone, E.A. and Fuhr, J.P., “The Economics of Biosimilars,” American Health & Drug Benefits 6, no.8 (2013): 469–478, at 471; Gosling, H., “Same Difference,” Pharma-Times.com, July 2016, available at <www.pharmatimes.com/magazine/2016/july_2016/same_difference> (last visited August 2, 2018), at 31.Google Scholar
See Rader, R.A., “An Analysis of the US Biosimilars Development Pipeline and Likely Market Evolution,” BioProcess International 11, no. 6 (2013): 16-23, at 18; Grabowski, H.G., Guha, R., and Salgado, M., “Regulatory And Cost Barriers Are Likely To Limit Biosimilar Development And Expected Savings In The Near Future,” Health Affairs 33, no. 6 (2014): 1048-1057, at 1050; de Gavre, T., “Key Issues in the Development of Biosimilars: Research, Intellectual Property And Competition,” presented at The Westminster Health Forum Keynote Seminar: The Future of Biosimilars in the UK: Regulation, Access And Medicines Optimization, London, June 15, 2017.Google Scholar
Notably, the purchase of the reference product for carrying out comparative clinical studies can account for a significant part of the total cost, and while some are optimistic about the evolution of biosimilar development costs, others expect the costs to rise as more complex monoclonal antibodies become the most important targets of biosimilar development. See Rader, supra note 68, at 18; Blackstone and Fuhr, supra note 67, at 471.Google Scholar
There are already several examples of biosimilar applications that have been withdrawn or refused by the regulatory authorities. See EMA, supra note 34.Google Scholar
Many originator companies have also entered the biosimilars market with biosimilar versions of their competitors' biologics. See Casey, supra note 37, at 208; Gupta et al., supra note 37, at 24; Some commentators have even described biosimilars as “me-too” drugs instead of generics, as market behavior and marketing strategies for biosimilars generally come closer to the former category than the latter. See McKinsey & Company, “Insights into Pharmaceuticals and Medical Products: Biosimilars seven years on: Where are we and what's next?” available at <https://www.mckinsey.com/~/media/mckinsey/dotcom/client_service/Pharma%20and%20Medical%20Products/PMP%20NEW/PDFs/Biosimilars%20Seven%20years%20on_White%20Paper.ashx> (last visited August 2, 2018); Williams, D.E., “Biosimilars Are ‘Me-Too’ Drugs, Not Generics,” Health Business Blog, May 11, 2016, available at <healthbusinessblog.com/2016/05/11/biosimi-lars-are-me-too-drugs-not-generics/> (last visited August 2, 2018). (last visited August 2, 2018); Williams, D.E., “Biosimilars Are ‘Me-Too’ Drugs, Not Generics,” Health Business Blog, May 11, 2016, available at (last visited August 2, 2018).' href=https://scholar.google.com/scholar?q=Many+originator+companies+have+also+entered+the+biosimilars+market+with+biosimilar+versions+of+their+competitors'+biologics.+See+Casey,+supra+note+37,+at+208;+Gupta+et+al.,+supra+note+37,+at+24;+Some+commentators+have+even+described+biosimilars+as+“me-too”+drugs+instead+of+generics,+as+market+behavior+and+marketing+strategies+for+biosimilars+generally+come+closer+to+the+former+category+than+the+latter.+See+McKinsey+&+Company,+“Insights+into+Pharmaceuticals+and+Medical+Products:+Biosimilars+seven+years+on:+Where+are+we+and+what's+next?”+available+at++(last+visited+August+2,+2018);+Williams,+D.E.,+“Biosimilars+Are+‘Me-Too’+Drugs,+Not+Generics,”+Health+Business+Blog,+May+11,+2016,+available+at++(last+visited+August+2,+2018).>Google Scholar
QuintilesIMS reports that biosimilar market share correlates negatively with the price reductions offered by the originator after biosimilar entry, which can, on the longer term, result in biosimilars not entering the market at all. See QuintilesIMS, supra note 57, at 5; Notably, the anti-trust authorities in the U.K. have recently issued a provisional decision indicting Merck & Co. for restricting competition by biosimilar versions of infliximab by using a discount scheme. See Gov.uk, “CMA issues provisional decision in relation to drug firm's pricing,” May 23, 2017, available at <https://www.gov.uk/government/news/cma-issues-provisional-decision-in-relation-to-drug-firms-pricing> (last visited August 2, 2018). Another interesting example of how the pricing-policy of originators can result in making biosimilars less attractive is the “rebate trap,” which occurs when originators revoke price discounts for the original biologic when a certain percentage of patients switches to a biosimilar, resulting in a total spending increase. See Hakim, A. and Ross, J.S., “Viewpoint: Obstacles to the Adoption of Biosimilars for Chronic Diseases,” JAMA 317, no. 21 (2017): 2163-2164.Google Scholar
See Hou, J.J.C. et al., “New Frontiers In Cell Line Development: Challenges For Biosimilars,” Journal of Chemical Technology and Biotechnology 86, no. 7 (2011): 895–904; Moorkens et al., supra note 43, at 5-8.Google Scholar
Waiting until after the expiry of all relevant patents and regulatory exclusivities, might come too late to ensure the timely introduction of generic competitors on the market. See Price and Rai, supra note 7, at 1050.Google Scholar
Proteins are long, linear molecules which can fold up in different ways. The same protein, produced by cells of different species, can be folded in a species-specific manner causing differences in activity.Google Scholar
Goel and Chance, supra note 56.Google Scholar
Several types of post-translational modifications may affect protein activity.Google Scholar
See Declerck et al., supra note 9, at 265-266; Moorkens et al., supra note 43, at 3; FDA, supra note 52.Google Scholar
The lack of recognition of biosimilars as fully equivalent “interchangeable” therapeutics makes it more difficult for physicians, patients, and payers, to allow switching. Hence, the possibility to establish such a status is critical to enable competition.Google Scholar
See Kim, Y.S. et al., “Biosimilars: Challenges and path forward,” Biotechnology and Bioprocess Engineering 19, no. 5 (2014): 755–765.Google Scholar
This can be illustrated by the fact that for major changes to an original biologic's manufacturing process — such as cell line change — comparative clinical studies to confirm the safety and therapeutic equivalence of the modified product are often required. See Declerck et al., supra note 9, at 261. On the other hand, when only minor changes are made to the original biologic's manufacturing and purification process limited quality and analytical studies will often suffice to ensure that the quality, safety and efficacy of the product are not affected. See Weise et al., supra note 48, at 3191; Declerck et al., supra note 9, at 265.Google Scholar
See Azevedo, V. et al., “Differentiating Biosimilarity and Comparability in Biotherapeutics,” Clinical Rheumatology 35, no. 12 (2016): 2877–2886; Bridges, S. L. Jr. et al., “The Science Behind Biosimilars: Entering a New Era of Biologic Therapy,” Arthritis & Rheumatology 70, no. 3 (2018): 334–344.Google Scholar
See Perez, I.A. et al., “Ensuring the Consistency of Biosimi-lars,” Current Pharmaceutical Design 23, no. 44 (2017): 6733–6738.Google Scholar
See Yang, J., “Cell Line and Cell Culture Development for Biosimilar Antibody-Drug Manufacturing,” in Biosimi-lars of Monoclonal Antibodies, Liu, C. and Morrow, K. J., Eds. (Hoboken, NJ, USA: John Wiley & Sons, Inc., 2016): 397–425.Google ScholarPubMed
See Price and Rai, supra note 7, and Price, W.N., “Regulating Secrecy,” Washington Law Review 91, no. 4 (2016): 1769-1812, for a parallel discussion of their proposal.Google Scholar
Id., at 1053.Google Scholar
Another preliminary suggestion has been made in a blog article. See DrugBaron, “Biosimilars Are Not Similar Enough: A Proposal For True ‘Biogenerics,’” DrugBaron Blog, March 19, 2013, available at <www.drugbaron.com/biosimilars-are-not-similar-enough-a-proposal-for-true-biogenerics/> (last visited August 2, 2018); This proposal, however, is incomplete as it is suggested that the originator should license others to make identical biologics. This would allow the originator companies to retain a relatively powerful position as this implies some control over how many competitors there will be, and thus prevent sufficient price competition.+(last+visited+August+2,+2018);+This+proposal,+however,+is+incomplete+as+it+is+suggested+that+the+originator+should+license+others+to+make+identical+biologics.+This+would+allow+the+originator+companies+to+retain+a+relatively+powerful+position+as+this+implies+some+control+over+how+many+competitors+there+will+be,+and+thus+prevent+sufficient+price+competition.>Google Scholar
If the entire CMC section is disclosed, also the knowledge on how the biologic can most effectively be produced will also be disclosed. If generic competitors can only access the cell line, the originator can retain the advantages that come with the prior knowledge and experience with the purification and manufacturing process.Google Scholar
For example, by making available the cell line of biologics for which similarity and interchangeability might more easily be established — allowing them to benefit from additional exclusivity periods they would have otherwise not enjoyed — and keeping the cell lines of biologics for which the biosimilar market entry would be more challenging (e.g. for very complex molecules or for very rare conditions) undisclosed.Google Scholar
This is one of the reasons Price and Rai see a mandatory disclosure mechanism as unfeasible. See Price and Rai, supra note 7, at 1054.Google Scholar
On the qualification of a physical asset as trade secret see Holman, C.M., “Trade Secret Law: An Increasingly Important Form of IP for Biotechnology,” Biotechnology Law Report 35, no. 2 (2016): 45-54.CrossRefGoogle Scholar
21 U.S. § 331(j).Google Scholar
See Lietzan, E., “A New Framework for Assessing Clinical Data Transparency Initiatives,” Marquette Intellectual Property Law Review 18, no 1 (2014): 33–85, at note 51. The EMA, on the other hand, has always had more discretion in deciding which information can be disclosed, although “commercially confidential information” is mostly redacted before disclosure. See Regulation (EEC) No 2309/93; Schneider, G., “A Transparency Challenge: Can Commercial Confidentiality in Clinical Trials Data Be Overcome?” European Pharmaceutical Law Review 2, no. 1 (2018): 3-18.Google Scholar
See Lietzan, supra note 93, at 56.Google Scholar
Id., at 57-59.Google Scholar
Ruckelhaus v. Monsanto Co., 467 U.S. 986 (1984).Google Scholar
See Epstein, R., “The Constitutional Protection of Trade Secrets and Patents under the Biologics Price Competition and Innovation Act of 2009,” Food and Drug Law Journal 66, no. 3 (2011): 285-328, at 304. Were cell line deposits to be required for already approved biologics, it would seem that any “taking” would be of the regulatory approval.Google Scholar
See Stone, G.R., Seidman, L.M., Sunstein, C.R., Tushnet, M.V., and Karlan, P.S., Constitutional Law (New York: Wolters Kluwer Law & Business; 2017): 1760 p., at 1583.Google Scholar
See Epstein, supra note 97, at 313.Google Scholar
Id., at 313.Google Scholar
Price, supra note 85, at 1804.Google Scholar
See Blackstone and Fuhr, supra note 67, at 474.Google Scholar
See Hirsch, D., “The Riddle of the Mysterious Patent Dance Wrapped in an Enigma: Is the Patent Dance of the BPCIA Optional or Mandatory?” Fordham Intellectual Property, Media and Entertainment Law Journal 27, no. 3 (2017): 645–690, at 677-678, explaining how the “patent dance” is necessary to ensure that originators can effectively enforce process patents protecting the original biologics, which would be much more difficult without such a disclosure obligation for biosimilar applicants. Interestingly, the mandatory nature of the patent dance has been challenged by Sandoz Inc. (the generic and biosimilar division of Novartis) when seeking approval for the first biosimilar version of filgrastim. In June 2017, the USSC did not answer the question whether the patent dance is mandatory or not, but instead ruled that a mere failure of a biosimilar applicant to disclose manufacturing information to the originator is not an act of artificial infringement and hence the exclusive remedies — injunctive relief and damages — do not apply. See Sandoz Inc. v. Amgen Inc., 582 U. S. ____ (2017), at 15.Google Scholar
As an essential component of this exchange, the disclosure of the invention requires “enablement,” meaning that a “person skilled in the art” can, based on the information disclosed in the patent, make and use the patented invention.Google Scholar
It has been argued that, absent a cell line to allow the enablement of a patented biologic, a biologics patent cannot be valid. See Mandel, G.N., “The Generic Biologics Debate: Industry's Unintended Admission that Biotech Patents Fail Enablement,” Virginia Journal of Law & Technology 11, no. 8 (2006): 1-25, at 21-24; Ouellette, L.L., “Access to Bio-Knowledge: From Gene Patents to Biomedical Materials,” Stanford Technology Law Review, N1 (2010): at para 100-103; However, in this context the problem of patent invalidity is also redundant, as the biologic that is actually put onto the market will rarely be identical to the biologic that would be produced by the cell line deposited at the time of the patent application. The patent deposit is required in order to enable the skilled reader to produce a biologic with the required properties, not necessarily the biologic that the patentee subsequently markets.Google Scholar
Price and Rai, supra note 7, at 1052.Google Scholar
21 U.S.C. §360; 21 U.S.C. §355 (j) (5)(B)(iv)).Google Scholar
SPCs can be applied for, to lengthen patent rights for a maximum of five years after patent expiry, as a compensation for the time needed to obtain regulatory approval for medicinal products.Google Scholar
Regulation (EC) No 469/2009, article 4.Google Scholar
Pharmaq v. Intervet, Case E-16/14, Judgement of the Court, 9 April 2015, available at <www.eftacourt.int/uploads/tx_nvcases/16_14_Judgment_EN.pdf> (last visited August 2, 2018).+(last+visited+August+2,+2018).>Google Scholar
For inventive new uses of a cell line or new indications an originator can apply for secondary patents, and in some cases enjoy an extension of the data exclusivity term. However, even when a secondary patent prevents the approval of a biosimilar for a new indication, “off-label” use is still possible, although cautiousness is generally advocated in absence of sufficient proof there are no clinically meaningful differences for that particular indication. See Li, E. and Lobaina, E., “Application of the FDA Biosimilar Extrapolation Framework to Make Off-Label Determinations,” Journal of Managed Care & Specialty Pharmacy 23, no. 12 (2017): 1227–1232; Zhao, S., Nair, J.R., and Moots, R.J., “Biosimilars: From Extrapolation into Off Label Use,” Current Pharmaceutical Design 23, no. 44 (2018): 6746–6751; For biogenerics, greater levels of certainty regarding functional equivalence with the original product may result in increased off label use, thereby placing originators in a situation similar to the situation for most small molecule drugs today. Without denying that the difficulty to enforce second use patents can be a legitimate concern for originators, the need to address this does not trump the potential benefits of our proposal. Other measures, such as adapting prescription and substitution policies and statutory and contractually limiting the purposes for which the deposited cell line (and resulting biologic product) may be used, can address some concerns in this regard. See infra Section 4.5.Google Scholar
See Yeh, B.T., “Protection of Trade Secrets: Overview of Current Law and Legislation,” Congressional Research Service (CRS) Report Prepared for Members and Committees of Congress, April 22, 2016.Google Scholar
In the paradigm case, trade secrecy ends the moment a secret is disclosed, for example in a patent application.Google Scholar
Holman, supra note 91.Google Scholar
One of the most prominent cases in the context of biotechnology is the United States Supreme Court ruling on Mayo Collaborative Services v. Prometheus Laboratories in 2012, reaffirming the law-of-nature exception to patentability. See Almeling, D.S., “Seven Reasons Why Trade Secrets Are Increasingly Important,” Berkeley Technology Law Journal 27, no. 2 (2012): 1091-1117, at 1114.Google Scholar
See Pooley, J., “Choosing Between Patents and Trade Secrets, A Discussion Worth Revisiting,” IP WatchDog, 2017, <www.ipwatchdog.com/2017/11/01/patents-and-trade-secrets-revisited/id=89641/> (last visited August 2, 2018).+(last+visited+August+2,+2018).>Google Scholar
See Almeling, supra note 115, at 1114.Google Scholar
See Linton, K., “The Importance of Trade Secrets: New Directions in International Trade Policy Making and Empirical Research,” Journal of International Commerce and Economics 7 (2016): 1-17.Google Scholar
Price and Rai, supra note 7.Google Scholar
In addition, originator companies can apply for patent protection in all the relevant global markets.Google Scholar
Price, supra note 85, at 1811.Google Scholar