Abstract
The FDA has authority to license manufacture of biosimilar and interchangeable biologics that are expected to compete at lower prices with the most successful and important modern pharmaceuticals, and make those life-saving medicines more accessible. Based on scientific evidence, FDA can only license such biosimilars if it finds that they are “highly similar” to licensed reference products and that they are safe, pure, and potent treatments. FDA has received at least 22 investigational new drugs for biosimilar development programs, and it has held scores of meetings with biosimilar sponsors, relating to more than a dozen reference products. Patent and statutory exclusivities protecting those reference products from competition have begun to expire. Reference product manufacturers have adopted new strategies to eliminate or delay competition for their valuable product franchises. They have asked FDA to require biosimilars to bear non-proprietary (identical non-proprietary name) names different from those assigned to a reference product. These requests are unwarranted and will impede the legislative purpose to make biologic medicines more affordable and accessible. This article addresses the background of these new naming strategies and the several arguments made by reference product manufacturers. It contends that use of different identical non-proprietary names will create undesirable barriers to acceptance of biosimilar products, effectively deterring investment in safe, effective, and affordable biosimilar and interchangeable medicines. The article contends that no scientific reasons exist for use of different identical non-proprietary names to label the “highly similar” active drug substance in reference products and their corresponding biosimilars; that is, there is no evidence that medical and pharmaceutical professionals, in light of all of the available data, are likely to be confused; and that all of the needs of robust pharmacovigilance are already met, without use of differential identical non-proprietary names. It offers a naming solution that meets all these needs.
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References
1.42 U.S.C. §262(k)(2)(A)(i)(I–V) .
2.42 U.S.C. §262(i)(3) .
3.See FDA, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (2012), at 4, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf (last visited April 24, 2014) (hereinafter, parenthetical reference to a date, following a URL, will indicate the date of last visit)
4.Id ., at 5 (“Advances in analytical sciences enable some protein products to be extensively characterized with respect to their physico-chemical and biological properties, such as higher order structures and functional characteristics. … Despite such significant improvements in analytical techniques, however, current analytical methodology may not be able to detect all relevant structural and functional differences between two proteins.”) See also C.K. Schneider, Biosimilars in rheumatology: the wind of change , Ann Rheum Dis March 2013, Vol. 72, No. 3, at 315 (“The sentence ‘biosimilar and biological reference medicines are similar but not identical’ … is perhaps one of the most frequently misunderstood sentences in the history of biosimilars and has almost become a mantra when raising concerns around biosimilars.”), http://ard.bmj.com/content/72/3/315 (May 1, 2014)
5.See FDA, Scientific Considerations, supra , Note 4, at 8
6.See C.K. Schneider, supra , Note 5 (“The ‘art’ for a biosimilar is to demonstrate that the biosimilar is as close as possible to its reference product in all relevant functional and structural aspects, again within current technical and scientific possibilities and its inherent variability.”) See also M. McCamish & G. Woolett, The continuum of comparability extends to biosimilarity: how much is enough and what clinical data are necessary? , Nature Publishing, Clinical Pharmacology & Therapeutics, Vol. 93, No. 4 (April 2013), at 315, 317 (“the specificity of analytical and biological characterization technologies now available,” means that “originator biologics and biosimilars can be fully characterized so that functional integrity and performance can be assured before clinical trials.”), http://www.nature.com/clpt/journal/v93/n4/full/clpt201317a.html (May 1, 2014)
7.See C.K. Schneider, supra , Note 5, quoting ICH Guideline, Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process Q5E. 2004. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q5E/Step4/Q5E_Guideline.pdf (May 1, 2014) (emphasis added). See also FDA, Q5E Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process (2005), http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm128076.pdf (April 25, 2104)
8.C.K. Schneider, supra, Note 5, at 316 (Figure 1(A)). See, also, M. Schiestl, et al., Acceptable changes in quality attributes of glycosylated biopharmaceuticals , Nature Biotechnology, (Apr. 2011); 29, 4, 310-312, http://www.nature.com/nbt/journal/v29/n4/full/nbt.1839.html (April 25, 2014) .
9.Gregory N. Mandel, The generic biologics debate: industry's unintended admission that biotech patents fail enablement , 11 Va. J. L. & Tech. 1, 3 (2006). See also Pfizer, Comments , FDA Public Workshop, [69 Fed. Reg. 50386 (Aug. 16, 2004)], Docket No. 2004N-0355, http://www.fda.gov/ohrms/dockets/dailys/04/nov04/111604/04N-0355-emc00004-02.pdf .
10.See, e.g., Pfizer, Citizens Petition (Omnitrope) , Docket No. FDA-2001-P-0369 (formerly 2001P-0323) (July 27, 2001), and Docket No. 2004P-023 l/CP 1 (2004), at 2-3), http://www.fda.gov/ohrms/dockets/dockets/04p0231/04p-0231-sup0001-01-vol1.pdf (April 24, 2014); and K. Carver, et al., An unofficial legislative history of the biologics price competition and innovation act of 2009 , 65 Food & Drug L.J. 671, 698–99 (2010) .
11.Pub. L. No. 111-148, Title VII, Subtitle A, 124 Stat. 119, 804-821 (2010); 42 U.S.C. § 262 (k) and (l). See J. Johnson, Congressional Research Service, FDA Regulation of Follow-On Biologics (2010), https://primaryimmune.org/advocacy_center/pdfs/health_care_reform/Biosimilars_Congressional_Research_Service_Report.pdf (April 24, 2014) .
12.42 U.S.C. §§262(k)(2)(A)(i)(I–V) and 262(k)(2)(A)(iii) .
13.42 U.S.C. §262(k)(4). Compare EMA, Guideline on Similar Biological Medicinal Products (May 2013 Draft Rev.), http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/05/WC500142978.pdf (April 25, 2014); and Article 6 of Regulation (EC) No 726/2004 63 and Article 10(4) of Directive 2001/83/EC, as amended.In January 2014, FDA announced its intention to issue new draft guidance in 2014 concerning “Considerations in Demonstrating Interchangeability to a Reference Product.” http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/webcontent/ucm314767.pdf (April 24, 2014) .
14.See FDA, Biosimilars (Draft Guidances) , http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/default.htm (April 21, 2014). The three primary guidances are entitled Scientific Considerations in Demonstrating Biosimilarity, supra , Note 4; Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product , http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291134.pdf (April 21, 2014); and Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 , http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM273001.pdf (April 21, 2014)
15.DC Writer, The Pharmaceutical Industry Tussles Over Biosimilars (April 2014)(reporting comments by Kris Kelly, an FDA spokeswoman, at a public workshop held by the Federal Trade Commission (FTC) on the “Impact of Recent Legislative and Regulatory Naming Proposals on Competition”), http://wa-dcwriter.blogspot.com/2014/04/the-pharmaceutical-industry-tussles.html (April 24, 2014). Materials relating to FDA Workshop are found at http://www.ftc.gov/news-events/events-calendar/2014/02/follow-biologics-workshop-impact-recent-legislative-regulatory (April 24, 2014) .
16.See FiercePharma, The 10 best-selling drugs of 2013 , March 25, 2014 (reporting that Humira ($11.02 billion in global sales), Enbrel ($8.776 billion), Remicade ($8.386 billion), Lantus ($7.59 billion), Rituxan ($7.50 billion), Avastin ($6.751 billion), and Herceptin ($6.56 billion) were among the top 10 drugs), http://www.fiercepharma.com/special-reports/10-best-selling-drugs-2013 (April 24, 2014). In the US, sales of these seven biologic RPPs totaled more than $23.25billion. See Medscape, Top 100 Selling Drugs of 2013 , http://www.medscape.com/viewarticle/820011 (April 24, 2014); Drugs.com, U.S. Pharmaceutical Sales – 2013 , http://www.drugs.com/stats/top100/2013/sales (last accessed April 24, 2014); and FirstWord Lists, Which biologics face the most competition from biosimilars? , http://www.firstwordpharma.com/node/1118043?tsid=17#axzz2zqdnDEl9 (April 25, 2014)
17.Under the BPCIA, approval of a biosimilar application may not be made effective until 12 years after the date on which the RPP was first licensed by FDA. 42 U.S.C. § 262(k)(7). See, e.g ., D. C. Ohly & S. Patel, There Is No Orange Book: The Coming Wave of Biological Therapeutics , 6 Oxford J. Intell. Prop. L. & Practice 464, 476–479 (2011), and Appendix, at 481 (list of RPPs and exclusivity dates), http://jiplp.oxfordjournals.org/content/early/2011/05/16/jiplp.jpr048.full.pdf+html (April 25, 2014) .
18.See GABI, US$67 Billion Worth of Biosimilar Patents Expiring Before 2020 , http://www.gabionline.net/Biosimilars/General/US-67-billion-worth-of-biosimilar-patents-expiring-before-2020 (April 24, 2014). See also H. Schellekens, Follow on biologics: challenges of the next generation , Nephrol Dial Transplant (2005) 20 [Suppl 4]: iv31–iv36 (Table 1)(listing several “smaller” biologics); and H. Grabowski et al., Implementation of the Biosimilar Pathway: Economic and Policy Issues , 41 Seton Hall L.Rev. 512, 546–547 (2011)(listing patent expirations), http://fds.duke.edu/db/attachment/1664 (April 25, 2014)
19.See FDA, Contents of a Complete Submission for the Evaluation of Proprietary Names , at 4 (2010), http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075068.pdf (April 25, 2014) (In the United States, “health care providers rely on the proprietary name as the critical identifier of the appropriate therapy….”). The publication sets forth FDA's authority for treatment of proprietary names: “Proprietary names are used in a product's labels and labeling, as well as in other promotional materials. Under section 502(a) of the Act (21 U.S.C. 352(a)), a drug, including a biologic, is misbranded if its labeling is false or misleading in any particular. In addition, section 351(b) of the Public Health Service Act (42 U.S.C. 262(b)) prohibits falsely labeling or marking any package or container of any biological product. …” Id ., at 7–8
20.See S. Kopp-Kubel, International Nonproprietary Names (INN) for pharmaceutical substances , Bulletin of the World Health Organization, 1995, 73(3): 275–279. In the US, local non-proprietary names are assigned by the United States Adopted Name (USAN) Council. USAN aims to select simple and informative non-proprietary names (also called generic names) for drugs and biologics by establishing logical nomenclature classifications based on pharmacological and/or chemical relationships. USAN works with the WHO INN Expert Committee to standardize drug nomenclature and establish rules for classification of new substances. Usually USAN and INN names match.In the U.S., USAN is the official body responsible for nomeclature of drug and biologic products. The USAN Program assigns names through the USAN Council (USANC), a group of five volunteers nominated to the USANC based on their extensive and relevant knowledge and experience. Three USANC members represent the three organizations that jointly sponsor the Program: The American Medical Association (AMA), United States Pharmacopeia (USP) and the American Pharmacists Association (APhA). A liaison from the FDA and a member-at-large complete the USANC .
21.Before a name can be adopted the sponsoring firm, the USAN Council and the International Nonproprietary Names Expert Group (INN) must agree on a single name for the substance. (American Medical Association Website: http://www.ama-assn.org//ama/pub/physician-resources/medical-science/united-states-adopted-names-council/generic-drug-naming-explained.page) .
22.A drug (including a biologic) may be deemed “misbranded” unless its label bears the “established name” of the drug. By statute, FDA has authority to create an “established name,” 21 U.S.C. §352(e)(3), which “means (1) the applicable official name that FDA designates pursuant to [21 U.S.C. §358]; or, if none, (2) the official title of the drug or ingredient in an official compendium; or, if none, (3) the “common or usual name” of the drug. See also 21 C.F.R. §299.4(b), §299.4(e) and 21 U.S.C. §358 .
23.WHO, The Use of Stems in the Selection of International Nonproprietary Names (INN) for pharmaceutical substances (2009), http://www.who.int/medicines/services/inn/StemBook2009.pdf (April 25, 2014) .
24.Id ., at 168 et seq
25.See 21 CFR Part 207
26.See FDA, Standards for Securing the Drug Supply Chain - Standardized Numerical Identification for Prescription Drug Packages (Final Guidance, March 2010), at 6, http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM206075.pdf (April 26, 2014) .
27.FDA, US FDA Considerations: Discussion by National Regulatory Authorities with World Health Organization (WHO) On Possible International Non-proprietary Name (INN) Policies for Biosimilars , http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm375086.htm (April 25, 2014) .
28.See GPHA, Citizens Petition , FDA Docket No. 2013-P-1153, http://www.regulations.gov/#!documentDetail;D=FDA-2013-P-1153-0001 (April 25, 2014)
29.See Novartis Group, Citizens Petition , FDA Docket No. 2013-P-1398, http://www.regulations.gov/#!documentDetail;D=FDA-2013-P-1398-0001 (April 25, 2014)
30.See C.K. Schneider, supra , Note 5 (“scientific principles of a change in manufacturing process of an originator mAb/cept molecule and the generation of a biosimilar are the same.”)
31.Weise, et al., Biosimilars: what clinicians should know . Blood, 20 December 2012, Vol. 120, No. 26, 5111, at 5112 (“this principle is not new to biotechnology; even consecutive batches of originator products are never identical to each other—this is normal and is why adequate controls on batch to batch consistency have to be imposed.”) http://bloodjournal.hematologylibrary.org/content/120/26/5111.full.pdf+html (April 25, 2014) .
32.See M. Schiestl, et al., supra , Note 9. See also M. McCamish, et al., Biosimilar by Name and Biosimilar by Nature , http://www.sandoz-biosimilars.com/cs/groups/public/@sbs_com/documents/document/n_prod_844479.pdf (April 25, 2014)
33.See, e.g ., EMA, Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (June 2013 Draft Rev.) http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/06/WC500144124.pdf (April 25, 2014); EMA, Guideline on Similar Biological Medicinal Products, supra , Note 8. Compare EMA, Guidance on Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process (ICH Q5E) , http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002805.pdf (April 25, 2014); EMA, Guideline on Comparability of Biotechnology-Derived Medicinal Products After a Change in the Manufacturing Process (2007 Draft), http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003937.pdf (April 25, 2014); and FDA, Q5E Comparability, supra , Note 8
34.J. Woodcock, FDA, Testimony before the House Committee on Oversight and Government Reform - Follow on Proteins , March 26, 2007, http://www.fda.gov/NewsEvents/Testimony/ucm154070.htm (April 25, 2014) .
35.See FDA, Scientific Considerations, supra , Note 4, at 5--6 (Demonstrating that a proposed product is biosimilar to a reference typically will be more complex than assessing the comparability of a product before and after manufacturing changes made by the same manufacturer.)
36.See Janssen Pharmaceuticals, Citizens Petition , FDA Docket No. 2014-(-0077, http://www.regulations.gov/#!documentDetail;D=FDA-2014-P-0077-0001 (April 25, 2014)
37.See Amgen, Inc., Comments , FDA Docket No. 2013-P-1153, http://www.regulations.gov/#!documentDetail;D=FDA-2013-P-1153-0003 (April 25, 2014)
38.See WHO, Definition of Pharmacovigilance , http://www.who.int/medicines/areas/quality_safety/safety_efficacy/pharmvigi/en/ and http://apps.who.int/medicinedocs/pdf/s4893e/s4893e.pdf?ua=1 at 7. See also FDA, Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (2005), at 4, http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126834.pdf
39.A letter jointly sent to FDA by the American Pharmacists Association (APhA), the National Association of Chain Drug Stores (NACDS) and the National Community Pharmacists Association (NCPA), stated that they “recommend that biosimilar products maintain the same name as their reference biologic counterparts and not use suffixes. We are concerned that mandating the use of unique individual nonproprietary names (INNs) could create the very public health issues that FDA wishes to avoid: therapeutic duplication and general confusion relative to the appropriate use, safety and efficacy of biologic products. … Unique INNs for common active ingredients may generally increase confusion, leading to increased safety concerns and possibly medication errors. …” See Joint Letter, May 25, 2012, at 2, http://www.ncpanet.org/pdf/leg/may12/joint_biosimilar_letter.pdf (May 1, 2014) .
40.“Switching” would involve “[c]hanging the product (e.g ., from RPP to biosimilar or vice versa ) in a patient during the course of treatment .” See Cromellin et al., Different pharmaceutical products need similar terminology , AAPS J. (Sep. 2013), at 13 https://link-springer-com.web.bisu.edu.cn/article/10.1208%2Fs12248-013-9532-0 (emphasis added), cited in Amgen Comments, at 86, n. 397.FDA has said that “Pharmacists will be responsible for knowing which biological products are interchangeable and which will require prescriber prescription before substitution.” See FDA, Information for Consumers (Biosimilars) , http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241718.htm .
41.FDA, Contents of a Complete Submission for the Evaluation of Proprietary Names , at 3, (“Carton and container labels communicate critical information including proprietary and established name … ) http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075068.pdf .
42.FDA, Scientific Considerations, supra , Note 4, at 21, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf .
43.See U.S. FDA Considerations, supra , Note 27
44.Id ., at 8–9
45.See, e.g ., Surescripts, Electronic Prescribing Guide , (connection to “over 85 percent of the nation's retail pharmacies and six of the nation's largest mail order pharmacies”), http://www.surescripts.com/media/267954/e_prescribing_quickstart-guide_07_2011.pdf
46.See Surescripts, Benefits of E-Prescribing , (“Prescribers can check for harmful drug interactions by reviewing patient medication history at the point of care. And because there is no handwriting for the pharmacist to interpret, there is less potential for errors caused by similar-sounding drug names.”), http://www.surescripts.com/medication-network-services/benefits-of-e-prescribing_for-everyone
47.Existing innovative products also facilitate tracking-and-tracing of drug products for purposes of pharmacovigilance through adverse event reporting applications, similar to the MedWatcher Mobile App. See FDA, MedWatcher Mobile App , http://www.fda.gov/medicaldevices/safety/reportaproblem/ucm385880.htm (May 1, 2014) .
48.See Note 39, supra
49.
50.Under the DQSA, the term “transaction information” means: (A) the proprietary or established name or names of the product; (B) the strength and dosage form of the product; (C) the National Drug Code number of the product; (D) the container size; (E) the number of containers; (F) the lot number of the product; (G) the date of the transaction; (H) the date of the shipment, if more than 24 hours after the date of the transaction; (I) the business name and address of the person from whom ownership is being transferred; and (J) the business name and address of the person to whom ownership is being transferred. 21 U.S.C. § 581 .
51.See Transcript of Hearing Before House Committee on Energy and Commerce, Securing Our Nation's Prescription Drug Supply Chain , April 25, 2013, at 32
52.Id ., at 32–33
53.Id ., at 34
54.The reporting to FDA of adverse events resulting from use of biologic products is governed by 21 C.F.R. 600.80, which was adopted under authority granted in 21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371, and 374; and in 42 U.S.C. 216, 262, 263, 263a, 264, and 300aa–25. See also 21 C.F.R. 314.80. The processes for reporting adverse events is the subject of FDA guidance, including its guidance on Postmarketing Safety Reporting for Human Drug and Biological Products Including Vaccines , http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm092257.pdf, Adverse events are ordinarily reported on FDA Form 3500A. See id ., at Appendix C. See also id ., Appendix E and F, FDA Website, Drug/Biologic/Human Cell, Tissues and Cellular and Tissue-Based Product Manufacturers, Distributors, and Packers , http://www.fda.gov/Safety/MedWatch/HowToReport/ucm085692.htm .
55.FDA, Sentinel Program Home Page , http://www.fda.gov/safety/fdassentinelinitiative/default.htm (April 26, 2014). The Sentinel Initiative created an important system designed to aggregate comparative, controlled data on products collected from patient claims, and outcome data acquired from the nation's major hospitals, health care plans, insurance companies and PBMs. The system enables rigorous review of the data and a proactive system for signal detection. The Academy of Managed Care Pharmacies, which is conducting a similar effort, has said that the Sentinel system captures data from approximately 75% of the patients in the United States and that it should provide the most reliable kind of information for safety signal detection. Academy of Managed Care Pharmacies, Where We Stand on Biosimilar Drug Therapies , http://www.amcp.org/WorkArea/DownloadAsset.aspx?id=16640 (April 26, 2014) .
56.Many post-marketing adverse events are quite rare and if each product is analyzed separately, the risk that a product's safety signals would remain undetected would increase. As such, when an adverse event is first observed in the RPP or a biosimilar, unique INNs will limit the investigation to a single manufacturer when all the biosimilar products need to be considered. This is precisely how class effects are captured today for RPPs, which may be manufactured at different manufacturing facilities, and for products made by different companies which share the same active ingredient as represented by the INN .