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.
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References
1.
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.
A.S.Kesselheim, J.Avorn, and A.Sarpatwari, “The High Cost of Prescription Drugs in the United States: Origins and Prospects for Reform,”JAMA316, no. 8 (2016): 858–871, at 859.
The claim that costs of research and development have significantly increased has also been questioned. See D.W.Light and J.R.Lexchin, “Pharmaceutical Research and Development: What Do We Get for All That Money?”BMJ345 (2012): 1-5 and S.Morganet al., “The Cost of Drug Development: A Systematic Review,”Health Policy100, no. 1 (2011): 4–17.
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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.
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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.” (W.N.Price and A.K.Rai, “Manufacturing Barriers to Biologics Competition and Innovation,”Iowa Law Review101, no. 3 (2016): 1023-1063, at 1026).
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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.
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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.
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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.
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16.
See EMA (European Medicines Agency), “Guideline on Similar Biologic Medicinal Products,” CHMP/437/04 Rev 1, October23, 2014, available at <www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf> (last visited August 2, 2018); A.B.Argawal and A.McBride, “Understanding The Biosimilar Approval And Extrapolation Process—A Case Study Of An Epoetin Biosimilar,”Critical Reviews in Oncology/Hematology104 (2016): 98–107, at 99.
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For an overview of the debate in the U.S. and the legislative history of the Biologics Price Competition and Innovation Act (BPCIA), see E.Lietzan, K. HesslerCarver, and J.Elikan, “An Unofficial Legislative History of the Biologics Price Competition and Innovation Act of 2009,”Food & Drug Law Journal65, no. 4 (2010): 671-818 and J. Wing YanTam, “Biologics Revolution: The Intersection of Bio-technology, Patent Law, and Pharmaceutical Regulation,”The Georgetown Law Journal98, no. 2 (2010): 535-565, at 550-552.
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Amending Section 351 of the Public Health Services Act (PHSA).
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27.
See L.A.Kogan, “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 Journal6, no. 11/12 (2011): 513–538, at 514-515; Wing Yan Tam, supra note 21, at 541.
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29.
21 C.F.R. §314.108 (2017).
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R.Feldman, “Regulatory Property: The New IP,”Columbia Journal of Law & The Arts40, no. 1 (2016): 53-104, at 67-72.
31.
See T.Woodage, “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; U.Lu, “Biologics Price Competition and Innovation Act: Striking a Delicate Balance Between Innovation and Accessibility,”Minnesota Journal of Law, Science & Technology15, no. 1 (2014): 613-651, at 623-624; Feldman, supra note 30, at 57-62.
32.
42 U.S.C. §262 (k) (7) (2011); see Lu, supra note 31, at 635-636; Feldman, supra note 30, at 82-84.
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See D.Casey, “Key Strategic Factors For Stakeholders In The Current Global Biosimilar Market,”Drug Discovery Today21, no. 2 (2016): 208-211, at 209; C.Remuzatet al., “Key Drivers for Market Penetration of Biosimilars in Europe,”Journal of Market Access & Health Policy5, no. 1 (2017): 1-15; S.K.Gupta, P.S.Chaudhari, and R.Nath, “Opportunities and Challenges in Biosimilar Development,”BioProcess International15, no. 5 (2017), 24-33.
38.
Gupta et al., supra note 37, at 32.
39.
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.
40.
Declerck et al., supra note 9, at 265.
41.
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,”April27, 2017, available at <www.ema.europa.eu/docs/en_GB/document_library/Leaflet/2017/05/WC500226648.pdf>: at 4.
42.
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 A.Welch, “The Norwegian Biosimilar Phenomenon: From Biosimilar To ‘Biogeneric,’”Biosimilar Development, July26, 2016, available at <https://www.biosimilardevelopment.com/doc/the-norwegian-biosimilar-phenomenon-from-biosimilar-to-biogeneric-0001> (last visited August 2, 2018).
43.
See K.van de Vooren, A.Curto and L.Garattini, “Biosimilar Versus Generic Drugs: Same But Different?”Applied Health Economics and Health Policy13, no. 2 (2015): 125-127, at 126; E.Moorkenset al., “Overcoming Barriers to the Market Access of Biosimilars in the European Union: The Case of Biosimilar Monoclonal Antibodies,”Frontiers in Pharmacology7 (2016): Article 193, at 4.
44.
M.Weiseet al., “Biosimilars: the Science of Extrapolation,”Blood124, no. 22 (2014): 3191-3196, at 3191-3192.
45.
“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.
46.
V.Brinkset al., “Quality of Original and Biosimilar Epoetin Products,”Pharmaceutical Research28 (2011): 386-393; L.A.Halimet al., “Quality and Batch-to-Batch Consistency of Original and Biosimilar Epoetin Products,”Journal of Pharmaceutical Sciences105, no. 2 (2016): 542-550; B.Jinet al., “Interchangeability Between Biosimilar And Innovator Drug Products,” in K.B.Barkeret al., eds., Biosimilar Clinical Development: Scientific Considerations and New Methodologies (Boca Raton, FL: CRC Press, 2016): 65-95.
47.
Krishnan et al., supra note 35, at 30.
48.
See E.Moorkenset al., “Policies for Biosimilar Uptake in Europe: An Overview,”PLoS ONE12, no. 12 (2017): e0190147, Table 1.
49.
Olech, supra note 24, at S6.
50.
Naizi, supra note 13, at 178.
51.
42 U.S.C. §262 (k) (4) (2011).
52.
See FDA, “Considerations in Demonstrating Interchangeability With a Reference Product (Guidance for Industry),”Draft Guidance, January17, 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 Y.Heled, “Regulatory Competitive Shelters,”Ohio State Law Journal76, no. 2 (2015): 299-356, at 350.
53.
See E.J.Emanuel, D.Wendler and C.Grady, “What Makes Clinical Research Ethical?”JAMA283, no. 20 (2000): 2701–2711, at 2703.
54.
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.
55.
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; E.'t Hoen, P.Boulet, and B.K.Baker, “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 Practice10, no. 19 (2017): 1-9, at 3.
56.
N.Goel and K.Chance, “Biosimilars in Rheumatology: Understanding the Rigor of their Development,”Rheumatology56, no. 2 (2017): 187-197, at 192.
See RAND Corporation, The Cost Savings Potential of Biosimilar Drugs in the United States (Santa Monica, CA: RAND Corporation, 2014); C.L.Bennettet al., Comment, “Biosimilar and Generic Cancer Drugs Unlikely To Bend Cost Curve In The USA,”The Lancet Oncology18, 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 S.R.Mehr and R.A.Brook, “Factors Influencing the Economics of Biosimilars in the U.S.,”Journal of Medical Economics20, no. 12 (2017): 1268–1271.
59.
A.Sarpatwari, J.Avorn, and A.S.Kesselheim, “Progress and Hurdles for Follow-on Biologics,”New England Journal of Medicine372, no. 25 (2015): 2380-2382, at 2381; Moorkens et al., supra note 43, at 4.
60.
Kesselheim et al., supra note 3, at 864.
61.
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, June17, 2016; European Commission, “Joint Report on Health Case and Long-Term Care Systems & Fiscal Sustainability (Volume 1),”Institutional Paper 037, October1, 2016.
62.
Casey, supra note 37, at 209.
63.
A.S.Kesselheim, M.S.Sinha, and J.Avorn, “Determinants of Market Exclusivity for Prescription Drugs in the United States,”JAMA Internal Medicine177, no. 11 (2017):1658–1664.
64.
Remuzat et al., supra note 37, at 3; A.Chandra and J.Vanderpuye-Orgle, “Viewpoint: Competition in the Age of Biosimilars,”JAMA314, no. 3 (2015): 225-226.
65.
Sarpatwari et al., supra note 59, at 2382.
66.
See Remuzat et al., supra note 37, at 11.
67.
See E.A.Blackstone and J.P.Fuhr, “The Economics of Biosimilars,”American Health & Drug Benefits6, no.8 (2013): 469–478, at 471; H.Gosling, “Same Difference,”Pharma-Times.com, July2016, available at <www.pharmatimes.com/magazine/2016/july_2016/same_difference> (last visited August 2, 2018), at 31.
68.
See R.A.Rader, “An Analysis of the US Biosimilars Development Pipeline and Likely Market Evolution,”BioProcess International11, no. 6 (2013): 16-23, at 18; H.G.Grabowski, R.Guha, and M.Salgado, “Regulatory And Cost Barriers Are Likely To Limit Biosimilar Development And Expected Savings In The Near Future,”Health Affairs33, no. 6 (2014): 1048-1057, at 1050; T.de Gavre, “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.
69.
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.
70.
There are already several examples of biosimilar applications that have been withdrawn or refused by the regulatory authorities. See EMA, supra note 34.
71.
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); D.E.Williams, “Biosimilars Are ‘Me-Too’ Drugs, Not Generics,”Health Business Blog, May11, 2016, available at <healthbusinessblog.com/2016/05/11/biosimi-lars-are-me-too-drugs-not-generics/> (last visited August 2, 2018).
72.
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,”May23, 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 A.Hakim and J.S.Ross, “Viewpoint: Obstacles to the Adoption of Biosimilars for Chronic Diseases,”JAMA317, no. 21 (2017): 2163-2164.
73.
See J.J.C.Houet al., “New Frontiers In Cell Line Development: Challenges For Biosimilars,”Journal of Chemical Technology and Biotechnology86, no. 7 (2011): 895–904; Moorkens et al., supra note 43, at 5-8.
74.
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.
75.
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.
76.
Goel and Chance, supra note 56.
77.
Several types of post-translational modifications may affect protein activity.
78.
See Declerck et al., supra note 9, at 265-266; Moorkens et al., supra note 43, at 3; FDA, supra note 52.
79.
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.
80.
See Y.S.Kimet al., “Biosimilars: Challenges and path forward,”Biotechnology and Bioprocess Engineering19, no. 5 (2014): 755–765.
81.
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.
82.
See V.Azevedoet al., “Differentiating Biosimilarity and Comparability in Biotherapeutics,”Clinical Rheumatology35, no. 12 (2016): 2877–2886; S. L.Bridges, Jr. et al., “The Science Behind Biosimilars: Entering a New Era of Biologic Therapy,”Arthritis & Rheumatology70, no. 3 (2018): 334–344.
83.
See I.A.Perezet al., “Ensuring the Consistency of Biosimi-lars,”Current Pharmaceutical Design23, no. 44 (2017): 6733–6738.
84.
See J.Yang, “Cell Line and Cell Culture Development for Biosimilar Antibody-Drug Manufacturing,” in Biosimi-lars of Monoclonal Antibodies, C.Liu and K. J.Morrow, Eds. (Hoboken, NJ, USA: John Wiley & Sons, Inc., 2016): 397–425.
85.
See Price and Rai, supra note 7, and W.N.Price, “Regulating Secrecy,”Washington Law Review91, no. 4 (2016): 1769-1812, for a parallel discussion of their proposal.
86.
Id., at 1053.
87.
Another preliminary suggestion has been made in a blog article. See DrugBaron, “Biosimilars Are Not Similar Enough: A Proposal For True ‘Biogenerics,’”DrugBaron Blog, March19, 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.
88.
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.
89.
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.
90.
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.
91.
On the qualification of a physical asset as trade secret see C.M.Holman, “Trade Secret Law: An Increasingly Important Form of IP for Biotechnology,”Biotechnology Law Report35, no. 2 (2016): 45-54.
92.
21 U.S. § 331(j).
93.
See E.Lietzan, “A New Framework for Assessing Clinical Data Transparency Initiatives,”Marquette Intellectual Property Law Review18, 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; G.Schneider, “A Transparency Challenge: Can Commercial Confidentiality in Clinical Trials Data Be Overcome?”European Pharmaceutical Law Review2, no. 1 (2018): 3-18.
94.
See Lietzan, supra note 93, at 56.
95.
Id., at 57-59.
96.
Ruckelhaus v. Monsanto Co., 467 U.S. 986 (1984).
97.
See R.Epstein, “The Constitutional Protection of Trade Secrets and Patents under the Biologics Price Competition and Innovation Act of 2009,”Food and Drug Law Journal66, 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.
98.
See G.R.Stone, L.M.Seidman, C.R.Sunstein, M.V.Tushnet, and P.S.Karlan, Constitutional Law (New York: Wolters Kluwer Law & Business; 2017): 1760 p., at 1583.
99.
See Epstein, supra note 97, at 313.
100.
Id., at 313.
101.
Price, supra note 85, at 1804.
102.
See Blackstone and Fuhr, supra note 67, at 474.
103.
See D.Hirsch, “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 Journal27, 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.
104.
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.
105.
It has been argued that, absent a cell line to allow the enablement of a patented biologic, a biologics patent cannot be valid. See G.N.Mandel, “The Generic Biologics Debate: Industry's Unintended Admission that Biotech Patents Fail Enablement,”Virginia Journal of Law & Technology11, no. 8 (2006): 1-25, at 21-24; L.L.Ouellette, “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.
106.
Price and Rai, supra note 7, at 1052.
107.
21 U.S.C. §360; 21 U.S.C. §355 (j) (5)(B)(iv)).
108.
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.
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 E.Li and E.Lobaina, “Application of the FDA Biosimilar Extrapolation Framework to Make Off-Label Determinations,”Journal of Managed Care & Specialty Pharmacy23, no. 12 (2017): 1227–1232; S.Zhao, J.R.Nair, and R.J.Moots, “Biosimilars: From Extrapolation into Off Label Use,”Current Pharmaceutical Design23, 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.
112.
See B.T.Yeh, “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.
113.
In the paradigm case, trade secrecy ends the moment a secret is disclosed, for example in a patent application.
114.
Holman, supra note 91.
115.
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 D.S.Almeling, “Seven Reasons Why Trade Secrets Are Increasingly Important,”Berkeley Technology Law Journal27, no. 2 (2012): 1091-1117, at 1114.
See K.Linton, “The Importance of Trade Secrets: New Directions in International Trade Policy Making and Empirical Research,”Journal of International Commerce and Economics7 (2016): 1-17.
119.
Price and Rai, supra note 7.
120.
In addition, originator companies can apply for patent protection in all the relevant global markets.
