Paul R. Eisenberg, M.D., M.P.H. F.A.C.P., F.A.C.C. Senior Vice President Global Regulatory Affairs and Safety

Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320 805.447.4632 - Telephone 805.375.7374 – Fax

December 20, 2013

Division of Dockets Management Food and Drug Administration Department of Health and Human Services 5630 Fishers Lane Room 1061 Rockville, MD 20852

COMMENTS OF AMGEN INC. ON GPhA AND NOVARTIS’S CITIZEN PETITIONS REQUESTING IDENTICAL NON-PROPRIETARY NAMES FOR BIOLOGICAL PRODUCTS AND THEIR RESPECTIVE REFERENCE PRODUCTS (DOCKET NOS. FDA-2013-P-1153; FDA-2013- P-1398, RESPECTIVELY)

Amgen Inc. (“Amgen” or “we”) respectfully submits these comments on the citizen petition (or petition) submitted on September 17, 2013, in which the Generic Pharmaceutical Association (“GPhA”) requested that the Food and Drug Administration (“FDA”) “implement its INN naming policy equally to all biologics” and asked that “all biologics” licensed under the new premarket review procedures established by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), 42 U.S.C. § 262(k), “share the same INN name as the RPP [reference protein product]” (Docket No. FDA-2013-P- 1153). These comments are also being submitted to the docket that has been established for the October 28 citizen petition (or petition) in which the Novartis Group of companies (“Novartis”) requested that FDA “require that a biosimilar[] be identified by the same [INN] . . . as the reference product” (Docket No. FDA-2013-P-1398). For the reasons set forth below, Amgen believes that both citizen petitions (or “petitions”) should be denied.

The non-proprietary names for biological products licensed under 42 U.S.C. § 262(k) have significant public health implications. Contrary to the position of GPhA and Novartis (collectively, “Petitioners”), we believe that a policy of identical non-proprietary names would pose significant public health risks, and is inconsistent with applicable legal requirements. Petitioners fail to take into account fundamental scientific principles of biological products as well as their distinctive posology and methods of administration in clinical practice. We believe that, both as a matter of public health and as a matter of law, biological products licensed under the BPCIA should have distinguishable non-proprietary names— that is, non-proprietary names comprised of common roots and distinguishable prefixes or suffixes, as deemed appropriate by FDA, to achieve the goals of patient safety through effective post-market surveillance, and widespread physician and patient acceptance and appropriate use of this important new class of medicines.

EXECUTIVE SUMMARY

Under the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), certain biological products (referred to under the statute as “biosimilar” and “interchangeable” biological products) can be brought to market through a new abbreviated pathway under new Section 351(k) of the Public Health Service Act (“PHSA”). We believe that the policy Petitioners are requesting would be inconsistent with Section 502(e) of the Federal Food, Drug, and Cosmetic Act (“FDCA”). Moreover, if implemented, Petitioners’ proposal would raise the types of patient safety, provider confusion, and pharmacovigilance issues to those that facilitated FDA in the past to require distinguishable names for non-identical biological products. We therefore believe that FDA should reject both the GPhA petition and the Novartis petition, and instead continue to provide for distinguishable names for products that have not been determined to be identical.

Amgen believes that FDA should reject Petitioners’ requests, for the following reasons:

First, as discussed below in Part I of Amgen’s comments, the petitions ignore the key respects in which biological products differ from other drugs. Unlike chemically synthesized drug products, no two biological products are identical, and small differences can have significant and unpredictable effects on patients’ immune responses. Biosimilars licensed under the BPCIA are appropriately neither required nor expected to be structurally identical either to their reference counterparts or to each other. Indeed, the product quality attributes for biosimilars may fall outside even the range of variability that is acceptable for the reference product, and differences in both structure and function will become increasingly prevalent as the complexity of the reference products increases. Because biosimilars cannot be—and are not—brought to market through the same abbreviated pathway as generic drugs, the legal requirements applicable to generic drugs (including the requirement that generics bear the same labeling and established names as their reference counterparts) do not apply to biosimilars. This difference in regulatory treatment is both appropriate and critically important to development of biosimilar medicines using state of the art technology. Moreover, although some biosimilar products have been granted marketing authorization in highly regulated jurisdictions with the same non-proprietary names as their reference products, some of these (i.e., several glycosylated biosimilars with differentiated glycosylation profiles) should have been evaluated by the World Health Organization (“WHO”) in accordance with its policy that requires a distinguishing Greek letter suffix in these situations. The fact that the European Medicines Agency (EMA) has not required a WHO evaluation is a matter distinct from the science and therefore should not influence FDA’s thinking on the matter.

Second, as discussed in Part II below, robust product-specific pharmacovigilance is important for biological products. Distinct safety and immunogenicity profiles are found among structurally related biological products. Similar biological products cannot be fully characterized in premarket clinical trials, but instead must be subject to effective post-market surveillance that distinguishes accurately among related products. For these reasons, both FDA and European authorities have recognized and supported the need for product-specific surveillance of new members of a biological product class, including biosimilars. Indeed, European authorities require manufacturers to develop post-authorization risk management plans providing for close monitoring of potential product-specific safety and efficacy issues.

Third, as discussed in Part III below, effective pharmacovigilance for biological products requires distinguishable non-proprietary names. In the U.S., precise tracking is not possible if biosimilars share the same non-proprietary name. Because FDA’s spontaneous reporting/post-market surveillance system does not encompass the separate tracking of producs sharing the same non-proprietary name to be

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separately tracked, biosimilars with the same non-proprietary names but potentially different immunogenic profiles will be difficult to distinguish, hampering immunogenicity tracking and optimal pharmacovigilance.

Petitioners urge that pharmacovigilance will not be compromised because other identifiers, such as brand names and NDCs, can be used to track and trace biosimilars, but Petitioners ignore the reality that non- proprietary prescribing is permitted and commonly practiced in the U.S. and that other identifiers often are used incorrectly or inconsistently by physicians and patients who report adverse events (AEs). To address similar challenges the European Union (EU) is now promoting brand/invented name traceability measures for all biologics, but we know of no corresponding proposals by the Petitioners to amend U.S. state medical practice and pharmacy practice acts to require brand-name prescribing and the entry of brand names into the patient’s medical record. Even if patient and prescriber education were implemented to increase use of other identifiers, that education would not mitigate the risk in the immediate term that reports of AEs associated with different manufacturers’ products would be conflated, important safety signals missed, and patient welfare compromised.

Fourth, as discussed in Part IV below, the petitions contain numerous unsupported and erroneous objections to the use of distinguishable names for biological products. For example:

 GPhA contends that the INN system does not distinguish among similar biological products.1 In fact, however, distinguishable INNs have been used in numerous instances for structurally related biological products from different manufacturers.2 Likewise, FDA not only uses distinguishable non-proprietary names to differentiate among biological products, but also can and does license products using non-proprietary names that incorporate distinguishing features extrinsic to the INN sponsored by the WHO.3

 Petitioners assert that the existence of distinguishable non-proprietary names would confound the ability to aggregate safety signals,4 but there is no evidence that the historical use of distinguishable names has had this effect, whereas the inability to disaggregate safety information could lead to significant safety risks.5

 Petitioners assert that distinguishable non-proprietary names would confuse medical professionals,6 but there is no compelling evidence that distinguishable names for similar biological products would increase the risk of medication errors. To the contrary, practitioners are familiar with distinguishable names for biological products and would properly interpret such names for biosimilars.7

 GPhA makes overly simplistic and misleading claims about AE reporting. It claims, for example, that report investigators can easily contact prescribers or pharmacists.8 GPhA assumes, further, that

1 See GPhA Pet. 3-4. 2 See infra Part IV.A. 3 See infra Part IV.B. 4 See GPhA Pet. 9; Novartis Pet. 7. 5 See infra Part IV.C.2. 6 GPhA Pet. 9-10; Novartis Pet. 6. 7 See infra Part IV.D.1. 8 GPhA Pet. 7.

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reporters will have access to product labeling.9 These assumptions frequently are not borne out by reality.10

 Petitioners equate common manufacturing changes with the management of multisource biological products,11 but the comparison is simplisitic and irrelevant. In the EU, where authorities both authorize biosimilars for marketing and review manufacturing changes, the standards are not the same. Moreover, whereas structural differences between two related biological products often can merit distinguishable non-proprietary names as a scientific matter, most process changes do not result in analytically distinguishable product profiles. If a process change were to result in an analytically distinct glycosylation profile, it could be consistent with international naming policy for the resulting biological product to have a non-proprietary name with a distinct Greek letter suffix. In any event, the use of distinguishable non-proprietary names for biosimilars is warranted by factors other than the formal scientific criteria for distinguishable names under international naming conventions. Such considerations include the avoidance of involuntary or accidental interchange.12

 Contrary to the assertion by Novartis, existing monographs for biological products provide no basis for “similar,” structurally related products to bear identical established names. Governing law does not, as Novartis suggests, require FDA to defer to others’ determinations regarding whether a product undergoing review pursuant to Section 351(k) will be subject to an applicable monograph.13

Fifth, as discussed in Part V below, a policy under which each biosimilar is licensed with the same non- proprietary name as its reference product would raise significant legal issues. Because such a policy would mirror the naming rules for generic drugs, it would create a significant risk of confusion regarding a biosimilar product’s bioequivalence or identity to its reference product. Moreover, given FDA’s obligations under the Administrative Procedure Act to treat like cases alike and to explain any departures from precedent, FDA would need to reconcile any naming policy with its past statements recognizing the potential safety risks of using identical established names for similar biological products, as well as instances in which FDA has required, for safety reasons, the use of distinguishable names for similar products. In contrast, the past statements and practices that Petitioners identify can be readily distinguished, and the potential retroactivity issues that GPhA purports to identify are illusory.

Sixth, as discussed in Part VI below, the need for better pharmacovigilance measures for all drug products does not obviate the need for distinguishable names to facilitate post-market risk management in the context of biosimilars. It is widely believed, and has been acknowledged by FDA, that a cornerstone of BPCIA implementation must be “optimal pharmacovigilance” for all marketed biological products licensed under 42 U.S.C. § 262(k). Distinguishable names are manifestly necessary to achieve that objective. A mere sweeping assertion that the existing approach to post-market reporting for new drugs marketed in the U.S. requires further innovation and improvement does not address the current realities.14

9 See id. at 7-8, 10-12. 10 See infra Parts IV.E, IV.F. 11 See GPhA Pet. 4-5; Novartis Pet. 3-4. 12 See infra Part IV.G. 13 See infra Part IV.H. 14 See infra PartVI.

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Finally, as discussed in Part VII below, GPhA’s suggestions of alternative pharmacovigilance mechanisms are not sufficient to address the need for robust post-market surveillance of biological products. While we support proposed federal tracing legislation to ensure the quality of pharmacovigilance data, current legislation is not capable of ensuring the robust pharmacovigilance systems necessary for biological products if biosimilars are assigned identical non-proprietary names to their respective reference products. Amgen believes that a robust pharmacovigilance system will rely on increased automation of transactions and records, and will contain all information necessary to identify a product accurately. Such a system is unlikely to become a reality by the time biosimilars are introduced to the market. As a result, distinguishable non-proprietary names are necessary to help achieve the goal of complete traceability. It is Amgen’s view that FDA should reject Petitioners’ proposed naming policy because it would preclude optimal pharmacovigilance and could undermine patient safety.15

I. BIOLOGICAL PRODUCTS DIFFER IN KEY RESPECTS FROM CHEMICALLY SYNTHESIZED DRUG PRODUCTS.

In requesting that FDA adopt a policy providing for biosimilars to bear established names that are identical to those of their reference products, GPhA is asking that the naming conventions applicable to a generic drug—which must bear the same established name as its pioneer16—also apply to biosimilars. In doing so, however, GPhA has ignored fundamental scientific principles governing biological medicines. Biological products differ in critical respects from chemically synthesized drug products, and the rules applicable to the naming of generic drugs cannot simply be transferred to biosimilars.

A. Unlike most chemically synthesized generic drug products, biosimilars are not structurally identical to their reference counterparts or to each other.

The relationship between a biosimilar and its reference biological product is significantly different from the relationship between a chemically synthesized generic drug product and the relevant pioneer drug. Whereas the active ingredient of a generic drug approved under Section 505(j) of the Federal Food, Drug and Cosmetic Act (“FDCA”) must be identical to the active ingredient of its reference listed drug,17 the drug substance18 in a biosimilar is not “identical.” To the contrary, biosimilars may, and are rightly expected to, contain certain physical and functional differences from their reference products and other biosimilars to that of the reference product.

As FDA officials have repeatedly recognized, “the variability and complexity of protein molecules, current limitations of analytical methods, and the difficulties in manufacturing a consistent product” mean that “it is unlikely that, for most proteins, a manufacturer of a follow-on protein product could demonstrate that its product is identical to an already approved product.”19 This is because, “[c]ompared

15 See infra Part VII. 16 See 21 U.S.C. § 355(j)(2)(A)(v). 17 See id. § 355(j)(2)(A)(ii)(II)-(III) (a generic drug’s active ingredient must be “the same as” the active ingredient of its reference listed drug); 21 C.F.R. § 314.92(a)(1) (“[T]he term ‘same as’ means identical in active ingredient(s).”). 18 For the purposes of this submission we refer to the active component of a biological product as the drug substance (or “substance”), and not the “active ingredient” which is terminology more suited for chemically synthesized drugs and not widely used for biologics. 19 Statement of Janet Woodcock, Dep. Commissioner, FDA, Before the H. Comm. on Oversight and Gov. Reform (“Woodcock Testimony”) at 7 (Mar. 26, 2007); accord Letter from Frank M. Torti, FDA, to Frank Pallone (Sept. 18, 2008) (“Torti Letter”) at 4 (same).

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to many chemically synthesized drug products,” the protein molecules of which biological products typically are composed are “usually substantially larger, more complex molecules that may be mixtures of distinct entities.”20 In addition, the “quality and nature” of biological products can vary depending on small factors in the manufacturing process, such as the condition of the natural source material and the processes used to extract the product.21 Indeed, current technologies have not even advanced to the point where it is possible to demonstrate, with certainty, the precise similarities and differences between a complex protein product and a proposed biosimilar product.22

Even ostensibly small differences between biological products, including between different biosimilar products to the same reference product, can have a significant impact on patient safety. Unlike most chemically synthesized drugs, biological products have the ability to stimulate potentially life- threatening immune responses. The immunogenicity of a particular biological product—i.e., its ability to produce an immune response—is extremely difficult to predict, particularly for more complex proteins.23 A finding that a biosimilar is as safe and effective as its reference product does not mean that it is identical to it or to other biosimilars from an immunogenicity standpoint, and a patient whose healthcare professional substitutes one product for another could therefore face a “significant potential” that this substitution may “have a negative impact on . . . safety and/or effectiveness.”24

B. The statutory and regulatory framework for the established names of chemically synthesized generic drugs is inapplicable to biosimilars.

The fact that identical established names are used for chemically synthesized generic drugs approved under Section 505(j) of the FDCA is inapposite in the context of biosimilars because the underlying statutory and regulatory requirements for biosimilars are markedly distinct.

1. Unlike with chemically synthesized generic drugs, differences between biosimilars and their reference products, and among biosimilars of the same reference product, are anticipated and acceptable.

Because the drug substances of proposed biosimilars and their reference products typically are not identical, the legal and scientific basis for the approval of generic drugs under Section 505(j) of the FDCA—which requires the generic’s active ingredient to be identical to that of the reference drug25—is not a viable means to bring to market a biological product that is similar (but not identical to) a product that FDA has previously found to be safe and effective.26 Thus, in order to enable biosimilars to be brought to market through an abbreviated process, Congress had created an entirely new pathway under Section 351(k) of the Public Health Service Act (“PHSA”), and a new category of “biosimilar” biological products. Unlike for generic drugs approved through the Section 505(j) pathway, there is no

20 Woodcock Testimony at 7. 21 Id. 22 See id. at 9 (explaining that current technologies are able to provide certainty only with respect to “the most rudimentary” aspect of a recombinant protein). 23 Id. at 11. 24 Id. 25 21 U.S.C. § 355(j)(2)(A)(ii)(II)-(III); 21 C.F.R. § 314.92(a)(1). 26 See, e.g., Woodcock Testimony at 7-8 (“[T]he section 505(j) generic drug approval pathway, which is predicated on a finding of the same active ingredient, will not ordinarily be available for protein products.”).

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requirement that biosimilar products approved through the Section 351(k) pathway have “active ingredients” that are identical to those of their reference products. Instead, biosimilars need only be “highly similar” to their corresponding reference products.27

The legal requirements applicable to these products reflect the differences in the relevant pathways to market. Consistent with the requirement that a generic drug be “bioequivalent” to, and have the “same” active ingredient as, its reference drug,28 a generic drug must also have the “same . . . labeling” as its reference drug29—a requirement that, by extension, means that it “must have the same nonproprietary name as the pioneer drug.”30 In contrast, there is no requirement that products approved through the Section 351(k) pathway have the same labeling as their reference products under the BPCIA. In omitting such a provision, Congress has deferred entirely to the FDA’s scientific expertise and labeling authority, recognizing that the same labeling (including labeling containing the same nonproprietary name) may not be appropriate for biosimilar products.

2. There may be wide variation between biosimilars and their reference products, exceeding the range of variability for the reference product.

Not only does the statutory standard of biosimilarity permit differences in the drug substance, but, according to draft guidance issued by FDA, those differences may occur within a wide range of variability that exceeds the range of variability permitted for the reference product. For example, FDA has communicated that “[a] sponsor may be able to demonstrate biosimilarity even though there are formulation or minor structural differences,” including “differences in certain post translational modifications, or differences in certain excipients,” provided they can be justified as having no clinically meaningful effect on safety, purity and potency.31 In addition, FDA has indicated that a biosimilar may differ from the reference product in its expression system, even though “the type of expression system and host cell will significantly affect the types of process- and product-related substances and impurities (including potential adventitious agents) that may be present in the protein product.”32 Even differences in product impurities may be tolerated—without the need for pharmacological/toxicological studies to

27 42 U.S.C. § 262(i)(2)(A); see id. § 262(i)(3), (k); cf. 21 U.S.C. § 355c(n)(1) (under Pediatric Research Equity Act, a biosimilar is considered to contain a new active ingredient). 28 21 U.S.C. § 355(j)(2)(A)(iv). 29 Id. § 355(j)(2)(A)(v). A generic drug is required to have the same labeling as the Reference Listed Drug (“RLD”) at the time of approval, except for changes required because of differences approved under a suitability petition, see Food Drug & Cosmetic Act § 505(j)(2)(C), 21 C.F.R. § 314.93, or because the drug product and the RLD are produced or distributed by different manufacturers, see Food Drug & Cosmetic Act § 505(j)(2)(A)(v). FDA has described those differences in 21 C.F.R. § 314.94(a)(8)(iv) as including, for example, differences in formulation, bioavailability, or pharmacokinetics; labeling revisions made to comply with current FDA labeling guidelines or other guidance; or omission of an indication or other aspect of labeling protected by patent or exclusivity 30 Novartis Pharms. Corp. v. Leavitt, 435 F.3d 344, 346 (D.C. Cir. 2006) (emphasis added). 31 FDA, Draft Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product 8 (Feb. 2012), http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance s/UCM291128.pdf (accessed Nov. 19, 2013). 32 FDA, Draft Guidance for Industry: Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product 9-10 (Feb. 2012), http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida nces/UCM291134.pdf (accessed Nov. 18, 2013).

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characterize potential biological effects of specific impurities—so long as the product-related impurities are “comparable” and appear “at similar levels between the two products.”33

3. Biosimilar products approved in Europe to date illustrate acceptance of structural and other differences for biosimilars.

Consistent with the FDA draft guidance, EMA’s general guidelines for biosimilars describes a range of possibilities to accommodate anticipated structural and drug product formulation differences. These differences may result in the potential for differential safety or efficacy profiles that are elucidated only over time, and sponsors are required to address these residual uncertainties with post-approval risk management plans and are being required to implement additional post-approval clinical studies and registries. This regulatory approach illustrates the inherent differences in burden of proof for the biosimilar pathway versus the generic pathway.

As the EMA has explained in current and draft revised guidance documents:

“It should be recognised that, by definition, similar biological medicinal products are not generic medicinal products, since it could be expected that there may be subtle differences between similar biological medicinal products from different manufacturers or compared with reference products, which may not be fully apparent until greater experience in their use has been established. Therefore, in order to support pharmacovigilance monitoring, the specific medicinal product given to the patient should be clearly identified.”34

“As for any biological medicinal product, the biosimilar medicinal product is defined by the molecular composition of the active substance resulting from its process, which may introduce its own molecular variants, isoforms or other product-related substances as well as process-related impurities.”35

“It is not expected that all quality attributes will be identical and minor differences may be acceptable, if appropriately justified.”36

“Data from pre-authorisation clinical studies are usually insufficient to identify rare adverse effects. Therefore, clinical safety of biosimilars must be monitored closely on an ongoing basis during the post- approval phase including continued benefit-risk assessment.

Within the authorisation procedure the applicant should present a description of the pharmacovigilance system and a risk management plan in accordance with current EU legislation and pharmacovigilance guidelines. The risk management plan should take into account identified and potential risks associated with the use of the reference product and, if applicable, additional

33 Id. at 12. 34 EMA, Guideline on Similar Biological Medicinal Products 4 (Oct. 30, 2005), http://www.ema.europa.eu/docs/ en_GB/document_library/Scientific_guideline/2009/09/WC500003517.pdf (accessed Nov. 19, 2013). 35 EMA, Draft Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues, 4 (May 24, 2012), http://www.ema.europa.eu/docs/en_GB/document_library/Scie ntific_guideline/2009/09/WC500003953.pdf (accessed Dec. 7, 2013). 36 Id. at 5.

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potential risks identified during the development programme of the biosimilar and should detail how these issues will be addressed in post-marketing follow-up.” 37

Specific examples of differences evaluated by the EMA during development are summarized below.

Retacrit (epoetin zeta), development code name SB309 is an EU authorized biosimilar of Eprex/Erypo (epoetin alfa). The EMA acknowledged the presence of quantitative structural differences in several glycosylation related attributes in SB309 relative to Eprex. These included higher levels of a glycoforms lacking an occupied O-glycan site, and lower levels of N-glycolyl neuraminic acid and O-acetyl neuraminic acid compared with Eprex. The product was also formulated to an analytically different strength than Eprex, although the resulting difference in dosing was not considered clinically meaningful for this titrated drug. Nevertheless, these differences at the drug substance level and in the drug product strength illustrate the latitude of the biosimilar pathway to permit measurable differences.38

Binocrit (epoetin alfa), development code name HX-575 is an EU authorized biosimilar of Eprex/ Erypo (epoetin alfa). The EMA acknowledged the presence of quantitative and qualitative structural differences at the drug substance level in several glycosylation related attributes in HX-575 relative to Eprex. These included higher levels of a phosphorylated high mannose structure compared with Eprex.39

Remsima (infliximab), development code name CT-P13 is an EU authorized biosimilar of Remicade (infliximab). The EMA acknowledged the presence of differences in product variants at the drug substance level including glycosylation related attributes in CT-P13.40 Specifically, the levels of afucosylated variants were lower in CT-P13 relative to the reference product, and these differences correlated to a lower binding affinity of CT-P13 to receptors, FcγRIIIa and FcγRIIIb, which can mediate immunologic functions relevant to the mechanisms of action of some therapeutic antibodies. These differences manifested in non-equivalent immunochemical activity (specifically, lower antigen dependent cellular cyotoxicity in sensitive in vitro assays). Nevertheless, CT-P13 exhibited similar pharmacology in other non-clinical studies, and also demonstrated similar safety and efficacy in clinical studies, and was therefore approved as a biosimilar.

37 EMA, Draft Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues, 11 (June 3, 2013), http://www.ema.europa.eu/docs/en_GB/docume nt_library/Scientific_guideline/2013/06/WC500144124.pdf (accessed Nov. 19, 2013). 38 See EMA, Retacrit: European Public Assessment Report : Scientific Discussion 4 (Jan. 2008), http://www.ema.euro pa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000872/WC500054374.pdf (accessed Nov. 19, 2013) (noting that the amount of N-clycolyl neuraminic acid was higher in epoetin alfa than in epoetin zeta) [hereinafter Retacrit EPAR]; see also V. Brinks et al., Quality of Original and Biosimilar Epoetin Products, 28 Pharmaceutical Research 386 (Feb. 2011). 39 EMA, Binocrit: European Public Assessment Report Scientific Discussion (Sept. 2007), http://www.ema.europa.eu/ docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000725/WC500053615.pdf (accessed Nov. 19, 2013) [hereinafter Binocrit EPAR]; see V. Brinks et al., Quality of Original and Biosimilar Epoetin Products, 28 Pharmaceutical Research 386 (Feb. 2011). 40 EMA, Remsima: European Public Assessment Report 4 (June 2013), http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Public_assessment_report/human/002576/WC500151486.pdf (accessed Nov. 19, 2013).

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Ovaleap (follitropin alfa), development code name XM17, is an EU authorized biosimilar of Gonal-f (follitropin alfa). 41 The EMA acknowledged the presence of a slight shift in sialic acid content and an increase in the non-human sialic acid variant N-glycolylneuraminic acid in XM17 relative to Gonal-f. These differences in glycosylation were taken into account in evaluation of clinical pharmacology, clinical efficacy, and immunogenicity evaluations and uncertainties were addressed, justifying a conclusion of similarity.42

These examples illustrate that European regulators have accepted quantitative and qualitative differences between biosimilar and reference products, and between the different manufacturers’ biosimilar versions of that reference product. Notwithstanding the findings that these differences were not clinically meaningful for purposes of approval, they are relevant for non-proprietary naming, both from the standpoint of identifying distinguishable drug substances according to WHO INN policies43, and for the purpose of ensuring traceability of the drug products in the context of multisource pharmacovigilance.44

4. Although relatively few glycosylated biosimilars have been authorized in other ICH regions, the available data show that certain analytical differences are acceptable for approval as a biosimlar.

Epoetin kappa (genetical recombination) [Epoetin Alfa BS injection [JCR] is a Japan approved biosimilar of ESPO (Epoetin alfa). A published report compared analytical attributes of epoetin kappa and four other erythropoeisis stimulating agents sold in Japan.45 Isoelectric focusing analyses demonstrated that epoetin kappa contains additional, basic isoforms relative to epoetin alfa, and also has a higher molecular mass. Epoetin kappa was studied in comparative clinical pharmacology, efficacy and safety studies and determined to be biosimilar.46

Novicrit® (epoetin lambda), development code HX-575, is an Australia approved biosimilar of Eprex (epoetin alfa). The Therapeutic Goods Administration, Australia Department of Health (TGA) has not made available a public assessment report describing analytical findings for this product also approved in EU under the non-proprietary name epoetin alfa. WHO INN, however notes that the TGA assessment highlighted differences in structural characteristics and made the following comments in their 50th Consultation report:

“This glycosylation difference has now also been recognised by TGA, which has led them to request a different Australian Biologicals Name (ABN) – epoetin lambda – as part of their licence in Australia. Thus, this substance has the INN epoetin alfa and a country name based on the INN principal but with a different Greek identifier. It is the responsibility of a company to apply for an

41 See EMA, Ovaleap: European Public Assessment Report 22 (July 2013), http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Public_assessment_report/human/002608/WC500152908.pdf (accessed Nov. 19, 2013) (“Biosimilarity with the referenced medical product Gonal-F has been sufficiently demonstrated.”). 42 Id. at 62–71. 43 See infra Part IV.A. 44 See infra Part III. 45 Okana et al., Doping Control of Biosimilar Epoetin Kappa and Other Recombinant Erythropoietins After Intravenous Application, 3 Drug Testing & Analysis 798 (Dec. 2011). 46 Teruyo Arato, Review Director, PMDA, Recent Regulations of Biosimilars in Japan, presentation at 47th Annual DIA Meeting (Jun. 19–23), http://www.pmda.go.jp/regulatory/file/english_presentation/biologics/B-E1arato.pdf (accessed Nov. 19, 2013).

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INN and unfortunately, the European regulators accepted Sandoz’s own INN assignment of epoetin alfa without question.”47

Further, the public summary document from the Australian Government Department of Health Pharmaceutical Benefits Advisory Committee noted the following:

“The PBAC noted that epoetin lambda had been approved by TGA under the Similar Biological Medicinal Product guidelines. When approving this product, the TGA had concluded although the amino acid sequence of epoetin lambda was the same as that of epoetin alfa, there were significant differences in the glycosylation pattern of this product and epoetin alfa which made it appropriate for the former to have the different Australian Biologic Name, epoetin lambda.”48

These examples illustrate that regulators outside of Europe have also accepted quantitative and qualitative differences between biosimilar and reference products while, at the same time, recognizing the importance of distinguishable non-proprietary names for these products.

5. Biosimilarity is not transitive.

The nature of biologics and the standards of approval for biosimilars result in another important distinction relative to the case for chemically synthesized active ingredients: the similarity of multiple members of a class can never be transitive in the same sense that the “same” active ingredients present in chemically synthesized drugs will always be the same. Specifically, as noted previously, biosimilars are permitted to differ in quantitative and qualitative aspects of their structural and functional attributes relative to a given reference product. But there is no mechanism or standard to ensure that all approved biosimilars would differ in the same manner or to the same extent. The epoetin case studies discussed above illustrate this point in that three different biosimilar epoetins differed from their reference products along three different axes of glycosylation (phosphorylated high mannose; O-glycan sialylation, and isoform distribution for epoetin alfa, zeta and kappa respectively). As none of these products were required to establish biosimilarity to each other, it cannot be concluded that the biosimilar products are highly similar to each other.

For chemical drugs, FDA has historically deferred to public standards for identity, quality, and quantity to provide absolute benchmarks for labeling of multisource drugs according to the FDCA misbranding and adulteration provisions.49 Namely, the active ingredient chemical identity and required quality and potency of the products must comply with the United States Pharmacopeia (USP). This provision ensures a common benchmark and controls for loss of transitivity in the “sameness” of the originator and multiple generic competitor products. FDA officials have stated that such public standards are not as relevant for approval of biologic products because they may reference quality attributes and

47 WHO, 50th Consultation on International Nonproprietary Names for Pharmaceutical Substances: Executive Summary, (May 18-20, 2010), http://www.who.int/medicines/services/inn/50thExecutiveSummary.pdf (accessed Oct. 30, 2013). 48 Australian Government Department of Health, Pharmaceutical Benefits Advisory Committee, Public Summary Document July 2010 PBAC Meeting, 3 (July 2010), http://www.health.gov.au/internet/main/publishing.nsf/Content/2 2C8C4368FC0D8C1CA257BF0001D7BE7/$File/Epoetin%20lambda%20NOVICRIT%20Novartis2.pdf (accessed Nov. 19, 2013). 49 See 21 U.S.C. § 351(b) (noting that a drug is deemed adulterated if it differs from standards set forth in an official compendium); 21 U.S.C. § 352(e)(1)(A)(i) (noting that a drug is deemed misbranded if does not bear the established name set forth in an official compendium).

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specifications that are not considered relevant to safety and efficacy, and may omit other attributes and specifications that FDA believes are critical to a product’s safety and efficacy.50 There is no public mechanism to ensure the transitivity of similarity among biosimilars made by multiple manufacturers.

6. Summary.

In summary, the biosimilar pathway expects and permits design flexibility in the nature and composition of structural variants and other quality attributes at the drug substance level. This is both appropriate and critically important to development of biosimilar medicines using state of the art technology. It is not the case, however, that biosimilar product quality attributes must fall entirely within the range of variability of the reference product. Both qualitative and quantitative differences may be acceptable and the function(s) of a biologic medicine often correlate with more than one attribute.51 These differences are assessed in terms of likely impact to safety and efficacy within the totality of evidence of the development program, including data from comparative non-clinical and clinical studies.

As expected, differences in both structure and function are increasingly prevalent as biosimilars are developed for increasingly complex reference products (e.g., as observed for the glycosylated epoetin, follitropin and infliximab biosimilar products discussed herein). In this context, it is likely that each of the glycosylated biosimilar products approved in highly regulated markets would have received a common root and distinguishing Greek letter suffix if those products were submitted to WHO INN for evaluation (see discussion of WHO INN rules in §IV.A).52 The fact that the EMA has not required a WHO INN evaluation is a matter distinct from the science.

Finally, the existence of quantitative and qualitative differences in quality profiles among glycosylated biosimilars and their reference products raises the question of whether any common definition of “active substance” could or should apply to all members of a class. Many regulatory jurisdictions defer to pharmacopeial identity and quality standards to define active ingredients or substances used in pharmaceuticals.53 These public standards are often based upon the originator product specifications.

50 See Steven Kozlowski, Director, FDA Office of Biotechnology Products, Overview of Approval Pathway under the Biologics Price Competition and Innovation Act of 2009, presentation at Biosimilar 2012 Workshop APEC (April 4,2012), http://www.apec-ahc.org/images/training/20120412/[Presentation]%2013_Steven%20 Kozlowski.pdf (accessed Nov. 19, 2013) (“Differences in the formulation may be acceptable if the proposed product meets the statutory standard for biosimilarity.”). 51 FDA, Draft Guidance For Industry: Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product 293-299 (Feb. 2012), http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformat ion/Guidances/UCM291134.pdf (accessed Dec. 18, 2013) (“However, acceptance criteria should be based on the totality of the analytical data and not simply the observed range of product attributes of the reference product. For example, some product attributes act in combination to define a product’s safety, purity, and potency profile and therefore their potential interaction should be considered when evaluating similarity and setting specifications. Thus, for some glycoproteins, the content and distribution of tetraantennary and N-acetyl lactosamine repeats can affect in vivo potency and should not be evaluated totally independently of each other.”). 52 WHO, 55th Consultation on International Nonproprietary Names for Pharmaceutical Substances: Executive Summary, 3 (16-18 Oct. 2012), http://www.who.int/medicines/services/inn/55th_Executive_Summary.pdf (accessed Dec. 8, 2013). “Non-glycosylated biosimilars are considered to have highly similar post-translational modifications and receive the same INN, whilst those that are glycosylated are considered comparable but distinct; they get the same INN name but are further qualified by a Greek letter suffix.” 53 E.g., 21 U.S.C. § 352(e)(1)(A)(i); 21 U.S.C. § 351(b) (referring, respectively, to identity and quality standards defined in an official compendium).

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This system may work well for chemically defined active ingredients which should have unambiguous criteria for identity, but it may not work for complex biological products for the reasons described here.

Because the specifications for biosimilar products’ post-translational modifications and other quality attributes will likely depart from those of the originator products, these products cannot be said to have the “same” active substance from either a scientific or legal perspective. This has important consequences for the treatment of these products in various legal, regulatory, and practice contexts where “same active ingredient” is commonly used as a pre-requisite for specific measures in labeling,54 coding,55 prescribing,56 and pharmacy practice57 for generic drugs.

II. ROBUST PRODUCT-SPECIFIC PHARMACOVIGILANCE IS PARTICULARLY IMPORTANT FOR BIOLOGICAL PRODUCTS.

The need for robust pharmacovigilance, at both the class and individual product level, applies to all biological products, whether originator, biosimilar, or interchangeable biosimilar. It is expected that each product licensed pursuant to a New Drug Application or Biologic Drug Application (351(a)) will have its own safety profile reflected in an independent label. This includes biological products, approved under the full BLA pathway, that have a similar molecular structure to another 351(a) biological product previously approved. The safety profile is typically based on pre-approval safety data, and updated as appropriate based on the results of post-approval commitments and periodic safety updates.

All new drugs and biologics, including biosimilars, require post-approval pharmacovigilance to help establish the safety profile of the product in clinical practice.58, 59, 60 Safety signal detection is primarily

54 See, e.g., 21 U.S.C. § 355(j)(2)A)(ii) (requiring, in relevant part, that an abbreviated application for a new drug (ANDA) contain information to show that the active ingredients of the new drug are the same as those of the listed drug); id. § 355(j)(2)(A)(v) (further requiring, in relevant part, that such ANDA “contain . . . information to show that the labeling proposed for the new drug is the same as the labeling approved for the listed drug”). 55 See, e.g., infra Part III.I. 56 See, e.g., infra Part III.F.2. 57 FDA considers drug products that contain the “same active ingredients,” as well as the same dosage form, route of administration and identical strength or concentration, to be “pharmaceutical equivalents.” See FDA, Orange Book Preface, 32d Ed. Pharmaceutical equivalency is a main component of therapeutic equivalency – the underlying basis for a drug’s inclusion in the FDA “Orange Book.” Id. FDA’s therapeutic equivalency determinations as listed in the Orange Book (and, derivatively, the “same active ingredient” requirement of pharmaceutical equivalency) expressly control substitution procedures by pharmacies in many states. See, e.g., 35 Pa. Stat. Ann. §960.2 (2013); S.D. Codified Laws §36-11-2(12) (2013); Vt. Stat. Ann. §4605(a) (2013). In several other states, the “same active ingredient” determination is a statutorily required component of interchangeability for drug substitution purposes. See, e.g., Cal. Bus. & Prof. Code § 4073(a)(permitting drug product selection by pharmacists based, in part, on whether the drug contains the “same active chemical ingredients of the same strength, quantity, and dosage form . . .”); Mass. Gen. Laws ch. 112, §12D (defining an interchangeable drug product as “containing the same amounts of the same active ingredients in the same dosage form as other products with the same generic or chemical name”); Me. Rev. Stat. tit. 32, § 13702-A (defining a “generic and therapeutically equivalent drug” as “any drug that has the same active ingredients in the same dosage form and in the same concentration that, when administered in the same amounts, will produce or can be expected to have the same therapeutic effect as the drug prescribed”). 58 See 21 C.F.R. §314.80 (Describing post-market adverse event reporting requirements for sponsors of § 505 NDA drugs). 59 See 21 C.F.R. §314.81 (Describing the obligation of sponsors of new drugs and § 505(j) drugs to submit an annual report with any relevant new safety information and associated plans to “submit a labeling supplement, add a warning to the labeling”).

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the role of spontaneous reporting systems (SRS) such as FDA’s Adverse Event Reporting System (FAERS). The sponsor is responsible for reviewing “all adverse experience information pertaining to its product”61 and for submitting timely reports to FDA. Depending on the findings from such reports, FDA or the sponsors may take measures to update safety information on the approved product labels, and may apply these findings to products sharing the same active ingredient or to members of a therapeutic class. It should be noted that signals can be aggregated for products with distinct chemically active ingredients (eg, statins and angiotensin-converting-enzyme inhibitors), and for products with the same active ingredient deemed therapeutically equivalent [eg, Lipitor (atorvastatin) and its generic equivalents]. Two recent examples of FDA Safety Communications include removal of prescribing restrictions for medicines containing rosiglitazone (Avandia, Avandaryl, Avandamet and generic verions) and rare cardiac risk with both regadenoson and adenosine (Lexiscan and Adenoscan respectively).62

Sponsors of generic drugs approved under 505(j) are also subject to pharmacovigilance measures63, although FDA has acknowledged that the tracking of safety events for generic drugs to individual sponsors is not typically done.

“Generally, OGD receives few AERs or similar reports since the reports may not specify a generic manufacturer for the drug product. Furthermore, the safety profile of a particular drug is usually well-known before generic versions are approved. Therefore, AERs associated with a generic drug are less likely to be reported.”64

In this context FDA has historically required that generic drugs share identical prescribing information (e.g., warnings and precautions) to that of the reference drug, although recent rulings associated with product liability cases may open the door to temporary departures from this historical practice.65

60 See 21 C.F.R. §600.80 (Describing adverse event reporting requirements for sponsors of § 351 BLA products). 61 21 C.F.R. §600.80(b). 62 See FDA, FDA Drug Safety Communication: FDA Requires Removal of Some Prescribing and Dispensing Restrictions for Rosiglitazone-Containing Diabetes Medicines (Nov. 15, 2013), http://www.fda.gov/Drugs/DrugSafety/ucm376389.htm (accessed Dec. 17, 2013); FDA, FDA Warns of rare but serious risk of heart attack and death with cardiac nuclear stress test drugs Lexiscan (regadenoson) and Adenoscan (adenosine) (Nov. 20, 2013), http://www.fda.gov/Drugs/DrugSafety/ucm375654.htm (accessed Dec. 17, 2013). 63 See 21 C.F.R. §314.98 (Describing post-market adverse event reporting requirements for sponsors of 505(j) ANDA generic drugs and cross-referencing 21 C.F.R. §314.80). 64 Office of Pharm. Sci., Ctr. For Drug Evaluation & Research, FDA, Manual of Policies and Procedures §5240.8 (2005), http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/Man ualofPoliciesProcedures/UCM079791.pdf (emphasis added) (accessed Nov. 19, 2013) [hereinafter MaPP]. 65 FDA has generally taken the position that a generic drug must maintain the same labeling as the RLD throughout the lifecycle of the generic drug product. See 21 C.F.R. § 314.150(b)(10). Notably, however, FDA has recently issued a proposed rule to change its current regulations to expressly provide that ANDA holders may distribute revised labeling that differs from the RLD upon submission of a CBE-0 supplement to FDA. See Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products, 78 Fed. Reg. 67,985 (Nov. 13, 2013). The proposed rule would create parity among application holders with respect to such labeling changes by permitting holders of abbreviated new drug applications (ANDAs) to distribute revised product labeling that differs in certain respects, on a temporary basis, from the labeling of its reference listed drug (RLD) upon submission to FDA of a “changes being effected” (CBE-0) supplement. If this proposed regulatory change is adopted, it may eliminate the preemption of certain failure-to-warn claims with respect to generic drugs. Id. at 67989.

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While aggregation of safety information by class will also apply to reference biological products and their biosimilar counterparts, it is especially important that pharmacovigilance measures account for the possibility of differences in the safety profiles of related biological products. These differences could be intrinsic to products as a result of their distinct methods of manufacture, or they could be emergent as a result of post-approval manufacturing changes.

A. As with all new biologics, biosimilars require product-specific post-approval safety monitoring to confirm the risk-benefit profile post approval.

1. FDA has supported the need for product specific safety surveillance of new members of a biologic class, including biosimilars.

FDA has appropriately indicated that patient welfare is a—if not the—top priority for the agency as it crafts a regulatory regime for biosimilars. In soliciting comments on the implementation of the BPCIA, FDA stated that it “considers the safety of patients who are taking any medical products to be of paramount importance.”66 “To that end,” it committed to “developing a framework for optimal pharmacovigilance for biosimilar and interchangeable products that is informed by our current experience and industry best practices.”67

For FDA to achieve optimal pharmacovigilance in the context of biologics, including biosimilars, it must develop a system that precisely tracks immunogenic trends. At present, the relatively small number of manufacturers for complex biologics has enabled streamlined communication of important safety data, provision of immunological assay services and scientific exchange with regulators. These will need to be codified for all manufacturers given that biological products, regardless of the approval pathway, differ from chemically synthesized drugs in material ways. Among them is that biologics uniquely present potentially life-threatening immunogenicity risks68 that are not easy to detect.69

Premarket clinical trials cannot fully characterize a biologic’s immunogenicity profile. First, as FDA has explained, “[r]are, but potentially serious, safety risks (e.g., immunogenicity) may not be detected during preapproval clinical testing [of therapeutic protein products], because the size of the population exposed may not be large enough to assess rare events.”70 Second, some immunogenic AEs cannot be tracked in the short term, because they occur months or longer after initiation of treatment. For instance, anamnestic antibody responses can occur in patients long after the causative agent has been administered. Third, immunogenicity may arise through off-label use, which is not tested during premarket clinical trials. Fourth, biosimilars, in following the abbreviated development provisions of BPCIA, will undergo targeted and ‘fit-for-purpose’ clinical evaluations, which while sufficient to resolve residual uncertainty pre-approval will lessen the likelihood of fully elucidating immunogenicity profiles

66 See Approval Pathway for Biosimilar and Interchangeable Products; Public Hearing; Request for Comments, 75 Fed. Reg. 61,497, 61,499 (Oct. 5, 2010) (emphasis added). 67 Id. (emphasis added). 68 See Letter from Frank M. Torti, FDA, to Frank Pallone (Sept. 18, 2008) [hereinafter “Torti Letter”] (“Proteins are more likely to engender an immune response than smaller molecules,” and “[i]mmune responses to administered protein products can be life-threatening.”). 69 Woodcock Testimony at 11. 70 See FDA, Draft Guidance for Industry: Immunogenicity Assessment for Therapeutic Protein Products 8 (Feb. 2013), http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM338 856.pdf (accessed Nov. 19, 2013).

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prior to approval. This is due to the reduced number and nature of exposed patients and the reduced duration of testing for chronically administered products. For these reasons, immunogenicity must be tracked in a post-market setting, and this has always been an expected and fundamental component of biosimilars approvals worldwide. Regarding biosimilars, FDA communication to the scientific community has been unambiguous:

“Tracking adverse events associated with the use of reference and biosimilar products will be difficult if the specific product or manufacturer cannot be readily identified, and appropriate strategies must be developed to ensure the implementation of robust, modern pharmacovigilance programs for biologics.”71

FDA also highlighted this purpose in the labeling review letter for tbo-filgrastim, a structurally related biological product approved under Section 351(a):

“FDA also has concluded that unique nonproprietary names will facilitate postmarketing safety monitoring by providing a clear means of determining which ‘filgrastim’ is dispensed to patients.”72

2. Europe also has a long history of recognizing the importance of tracking AEs for multisource biologics specifically to the manufacturer.

European authorities have taken the approach of advocating for and establishing specific policies that encourage traceability of brand (“invented”) names or other product-specific trade names73 in patient medical records. Early indications of this policy approach appeared in a 1993 bulletin from the UK Medicines Control Agency (MCA):

“In recent years various ‘biotechnology’ products have become available as medicines. Examples include human insulins, growth hormones, erythropoietins, recombinant tissue plasminogen activators (e.g. alteplase), growth factors (e.g. filgrastim and molgramostim), interferons and vaccines. These products usually closely resemble their naturally occurring counterpart, but are rarely identical. They may have a slightly different amino-acid sequence, or different glycosylation.

Unfortunately, doctors reporting suspected reactions sometimes use a non-specific name for the drug on the yellow card. For example, if a reaction to ‘erythropoietin’ is reported, it will not be clear to us whether epoetin alpha (Eprex®) or epoetin beta (Recormon®) was implicated. As more

71 See Steven Kozlowski, Janet Woodcock, Karen Midthun & Rachel Behrman Sherman, Developing the Nation’s Biosimilars Program, 365 New England J. Medicine 385 (Aug. 2011). 72 CDER, Proprietary Name Review: BLA 125294 - [xxx]-filgrastim (Aug. 2, 2012), http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125294Orig1s000NameR.pdf (accessed Nov. 19, 2013) [hereinafter FilgrastimProprietary Name Review]. 73 The EU does not require brand names (invented names), but in their absence does require centrally authorized medicines to use a trade name, typically incorporating the INN and the name or trademark of the MAH. See Council Directive 2001/83/EC, art. 1(20), 2001 O.J. (L 311) 67, 73 (as amended by Council Directive 2004/27/EC) (noting that the name of a medicinal product “may be either an invented name not liable to confusion with the common name, or a common name or scientific name accompanied by a trade mark or the name of the marketing authorisation holder”).

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biotechnology medicines become available it will be increasingly difficult to identify the product unless an approved or brand name is used.”74

More recently, with the increasing proliferation of structurally related biologics, European policymakers have increased their efforts to ensure traceability. The EMA highlighted this policy remit in the original biosimilar guideline published in 2005:

“It should be recognized that, by definition, similar biological medicinal products are not generic medicinal products, since it could be expected that there may be subtle differences between similar biological medicinal products from different manufacturers or compared with reference products, which may not be fully apparent until greater experience in their use has been established. Therefore, in order to support pharmacovigilance monitoring, the specific medicinal product given to the patient should be clearly identified.”75

In 2008, the UK Medicines and Healthcare Products Regulatory Agency (MHRA), the successor to the MCA, published the following Drug Safety Update:

“In view of the subtle differences that are likely to exist between biosimilar products, even though the clinical effect of the products may be similar, and in view of the complexity of these molecules, it is very important that adverse drug reactions (ADRs) are properly assigned to the suspect product. Particular care needs to be taken when reporting ADRs associated with biosimilar products.”76

Following continued and often insidious product specific safety issues for certain members of the recombinant erythropoietin class (both originator and biosimilar), most members of the class, including biosimilars, were required to update their prescribing information with the warning and precaution:

“In order to improve the traceability of erythropoiesis-stimulating agents (ESAs), the trade name of the administered ESA should be clearly recorded (or stated) in the patient file.”77

Subsequently, in the EU pharmacovigilance directive from 2010, specific references were made to traceability of biologics. All medicinal products with new active ingredients and biological products, including biosimilar products, are subject to enhanced pharmacovigilance and special monitoring in their post-approval period. Packaging for new products subject to this provision will be marked with a black triangle.78 These principles are also reflected in a 2013 guideline on good pharmacovigilance practice.79

74 Medicines Control Agency Committee on Safety of Medicines, Current Problems in Pharmacovigilance 7 (June 1993), http://www.mhra.gov.uk/home/groups/pl p/documents/websiteresources/con2024455.pdf (accessed Nov. 19, 2 013). 75 EMA, Guideline on Similar Biological Medicinal Products 4 (Oct. 2005), http://www.ema.europa.eu/docs/en_GB/d ocument_library/Scientific_guideline/2009/09/WC500003517.pdf (accessed Nov. 19, 2013). 76 MHRA, Drug Safety Update: Biosimilar Products (Feb. 2008), http://www.mhra.gov.uk/Safetyinformation/DrugSaf etyUpdate/CON084739 (accessed Nov. 19, 2013). 77 EMA, Aranesp: EPAR – Procedural steps taken and scientific information after authorisation 10 (Nov. 2013), http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000332/human_med_000651.jsp& mid=WC0b01ac058001d124 (accessed Nov. 19, 2013) [hereinafter Aranesp: Epar – Procedural Steps]. 78 See Council Directive 2010/84/EU of the European Parliament and of the Council of 15 Dec. 2010 Amending, as Regards Pharmacovigilance, Directive 2001/83/EC on the Community Code Relating to Medicinal Products for Human Use, 2010 O.J. (L 348) 74, 75 (“Medicinal products subject to additional monitoring should be identified as such by a black symbol.”).

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We note that the EU requirements for enhanced pharmacovigilance and special monitoring are not imposed on generic products with the same active ingredients as in previously approved medicinal products.

“It is essential that a strengthened system of pharmacovigilance not lead to the premature granting of marketing authorisations. However, some medicinal products are authorised subject to additional monitoring. This includes all medicinal products with a new active substance and biological medicinal products, including biosimilars, which are priorities for pharmacovigilance.”80

Furthermore, the EU directive takes steps to ensure that AEs for biological products are traceable to the specific manufacturer, and with due regard to their name, on an ongoing basis:

“The Member States shall: (e) ensure […] that all appropriate measures are taken to identify clearly any biological medicinal product prescribed, dispensed, or sold in their territory . . . with due regard to the name of the medicinal product”81

In some member states where (prescribing by INN) and automatic substitution are either required or encouraged, special statutory provisions have been implemented to create exceptions for biologics. Nine EU member states (Portugal, Lithuania, Estonia, Cyprus, Spain, Hungary, Romania, Greece, and Italy) have laws requiring mandatory INN prescribing, at least for non-biologic products,82 while other member states strongly encourage generic prescribing.

For example, prescribing by INN is heavily practiced in the UK,83 so the MHRA issued a Drug Safety Update in 2008 clarifying that biologics and biosimilars should (by contrast) be prescribed by brand name only:

“All biosimilar products are prescription only medicines (POM). When prescribing biological products, it is good practice to use the brand name. This will ensure that automatic substitution of a biosimilar product does not occur when the medicine is dispensed by the pharmacist. Products (biosimilar and reference) that have the same international non-proprietary name (INN) are not to be presumed identical for the reasons given above.”84

In 2012, the EC enacted an implementing directive concerning required information to be recorded in cross-border prescriptions. This directive requires the common name (either the INN or, if such name does not exist, the usual common name) to be recorded in the prescription in order to reduce possibility

79 See EMA, Guideline on Good Pharmacovgilance Practices 9 (Apr. 2013), http://www.ema.europa.eu/docs/ en_GB/document_library/Scientific_guideline/2013/04/WC500142282.pdf (requiring a black triangle to accompany listed medicinal products) (accessed Nov. 19, 2013). 80 Council Directive 2010/84/EU, 2010 O.J. (L 348) 74, 75. 81 Council Directive 2010/84/EC, art. 102(e), 2010 O.J. (L 348) 74, 84 (amending Council Directive 2001/84/EC). 82 Stefano Marino, Generic Prescribing Today, presentation at PTMG Conference (March 19, 2013), http://www.delegate.com/content/ptmg/spring/2013/documents/Stefano_Marino_-_Generic_prescribing_today.pdf (accessed Nov. 19, 2013). 83 Martin Duerden & Dyfrig Hughes, Generic and Therapeutic Substitutions in the UK: Are They a Good Thing?, 70 British J Clinical Pharmacoloy 335 (Sept. 2010). 84 See MHRA, Drug Safety Update: Biosimilar Products (Feb. 2008), http://www.mhra.gov.uk/Safetyinformatio n/DrugSafetyUpdate/CON084739 (accessed Nov. 18, 2013).

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of errors due to use of disparate brand names in member states.85 However, because prescription by common name/INN is not considered appropriate for biologics in the EU, this directive also explicitly stipulates that, by contrast, the brand names must be included for all biological medicinal products.

We know of no proposals by GPhA to amend U.S. state medical practice and pharmacy practice acts to require brand name prescribing or medical record traceability for biologics, nor is such an unprecedented undertaking either necessary or practical. Notably, both the EU emphasis on product-specific tracking and the EU solutions to this problem go unremarked in the GPhA petition.

3. The EMA requires risk management plans for approved biosimilars to examine the possibility of product-specific risk-benefit profiles.

Because European regulators have recognized that “[d]ata from pre-authorisation clinical studies normally are insufficient to identify all potential differences” between a biosimilar and its reference product, they require manufacturers of biosimilars to develop post-approval risk-management plans that closely monitor and address the “possible safety issues related to tolerability of the medicinal product that may result from a manufacturing process different from that of the originator.”86 The following examples illustrate how the EMA and the European Commission (EC) have worked with biosimilar sponsors to develop post-approval risk management plans that address both class-based safety signals and the potential for product-specific safety signals. Where observations or deficiencies were noted in the development package sponsors may be asked to address the attendant uncertainties through post- approval measures.

Retacrit (epoetin zeta), development code name SB309

No specific new safety information was found in the development package for Retacrit®. Nevertheless, EMA asked the sponsor to address long-term safety risks known to be relevant to the therapeutic class in the Risk Management Plan (e.g, thromboembolic events in oncology patients and immunogenicity in patients with renal anaemia). At the time of development the sponsor was unable to evaluate the immunogenicity of epoetin zeta with subcutaneous route of administration in renal anemia patients because the use of the reference product had been restricted to the i.v. route. Because EMA was concerned about potential off-label use of SB309 in the subcutaneous route, the sponsor committed to perform a comparative safety and efficacy study with Retacrit® and Eprex in this route of adminstration.87 This study was subsequently completed and the subcutaneous route of administration was approved in 2010.88

85 Commission Implementing Directive 2012/52/EU, 2012 O.J. (L 356) 68, 68. 86 EMA, Guideline on Similar Biological Medicinal Products Containing Biotechnology-Serived Proteins as Active Substance: Non-Clinical and Clinical Issues 6 (Feb. 2006), http://www.ema.europa.eu/docs/en_GB/ document_library/Scientific_guideline/2009/09/WC500003920.pdf (accessed Nov. 19, 2010). 87 See Retacrit EPAR: Scientific Discussion 3 (Jan 2008), http://www.ema.europa.eu/docs/en_GB/document_library/ EPAR_-_Scientific_Discussion/human/000872/WC500054374.pdf (accessed Nov. 19, 2010) (noting that the sponsor will perform a comparator study with the reference product). 88 See Retacrit EPAR - Variation Assessment Report 4 (June 23, 2011), http://www.ema.europa.eu/docs/en_GB/docu ment_library/EPAR_-_Assessment_Report_-_Variation/human/000872/WC500116652.pdf (accessed Dec 1, 2013) (noting the prior approval of the SC route of administration for indications of renal anemia).

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Binocrit (epoetin alfa), development code name HX-575

Binocrit® was developed and approved subject to similar constraints as Retacrit® with respect to ability to evaluate the subcutaneous route of administration in renal anemia patients. Therefore, the risk management plan and commitment to perform a comparative clinical study in this condition of use were similar to the provisions for Retacrit®.89 It is noteworthy that unexpected cases of neutralizing antibodies were detected in the post-approval clinical study evaluating use of HX-575 in the subcutaneous route of administration in renal anemia patients.90 This outcome illustrates the relevance of product-specific risk management plans for biosimilars.

Nivestim (filgrastim)

There was an observation of higher levels of bone pain in the Nivestim®-treatment group relative to the reference product, so the sponsor was recommended to follow-up on related AEs in the risk management plan. No other specific findings from the development package were linked to the Nivestim® risk management plan. However, the sponsors were asked to address inconclusive immunogenicity data through use of targeted questionnaires addressing potential loss of effect in the pharmacovigilance program. Other class-based risk management measures included evaluation of long-term safety in patients with severe chronic neutropenia and in long-term effects in healthy donors treated with filgrastim.91

Remsima (infliximab), development code name CT-P13

The EMA and the CT-P13 sponsors identified a number of class-based risks as well as product-specific risks that merited ongoing evaluation in a variety of studies.92 Some of these studies were extensions of pre-registration clinical studies as is typical for newly licensed products. Additional follow-up studies were planned to address data on long-term safety and efficacy in certain indications, as well as to confirm a favorable risk-benefit profile with respect to tolerability and risk of infections.

Of particular note, Remsima was approved for conditions of use in inflammatory bowel disease based on extrapolation of indication from completed studies in rheumatoid arthritis and ankylosing spondylitis. In the proposed risk management plan the sponsor committed to a randomized, double blind comparative

89 See Binocrit EPAR - Scientific Discussion 25 (Sept. 2007), http://www.ema.europa.eu/docs/en_GB/document_libra ry/EPAR_-_Scientific_Discussion/human/000725/WC500053615.pdf (accessed Nov. 19, 2010) (requiring the sponsor to conduct a comparative study as a condition of use). 90 Haag-Weber et al., Safety, Immunogenicity and Efficacy of Subcutaneous Biosimilar Epoetin-Alpha (HX575) in Non-Dialysis Patients with Renal Anemia: A Multi-Center, Randomized, Double-Blind Study, 77 Clinical Nephrology 8 (2012). 91 See EMA, Nivestim: European Public Assessment Report 45 (June 2010), http://www.ema.europa.eu/docs/ en_GB/document_library/EPAR_-_Public_assessment_report/human/001142/WC500093664.pdf (accessed Nov. 19, 2013) (proposing multiple pharmacovigilance activities to study the risk of malignant cell growth associated with GCSF). 92 See EMA, Remsima: European Public Assessment Report 97–100 (June 2013), http://www.ema.europa.eu/docs/ en_GB/document_library/EPAR_-_Public_assessment_report/human/002576/WC500151486.pdf (listing multiple studies the sponsor will take on in the post-market setting) (accessed Nov. 19, 2013).

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study to evaluate safety and efficacy in Crohn’s disease, and a long term observational study to evaluate safety and efficacy in Crohn’s disease and ulcerative colitis.93

4. Distinct safety and immunogenicity profiles are, in fact, found among members of structurally related biologics, including biosimilars.

The concerns described above are not just hypothetical. Product-specific safety and immunogenicity profiles have been observed among some members of structurally related biologics, including biosimilars. Examples of product-specific safety profiles are provided below, and are also discussed in Part IV.

Interferon beta

Safety related information on product labels differs among the interferon beta products. For example, the interferon beta-1b product labels have warnings related to injection site necrosis, a serious tolerability issue that is not described in the warnings for interferon beta-1a products.94

Similarly, the interferon beta products differ in their immunogenicity profiles. Some of these differences are intrinsic to the drug products, their routes of administration, and their methods of manufacture. Immunogenicity data cannot be accurately inferred from spontaneous safety reports, but are collected via interventional and observational studies. Differences observed from these studies may be relevant to other signals obtained from routine pharmacovigilance, and hence it is important to differentiate among similar products. Grossberg et al reported that frequencies and levels of neutralizing antibodies differed among patients treated with Avonex, Rebif and Betaseron.95 Creeke et al. surveyed the evidence for relevance of these neutralizing antibodies to efficacy of interferons and concluded that neutralizing antibody screening could be relevant to clinical management of multiple sclerosis patients.96 Clearly, in this context, differences among the immunogenicity profiles of interferon beta products could be important to certain patients.

Epoetin alfa

The immunogenicity of epoetin products is generally quite low compared with other chronically administered therapeutic proteins, but the rare occurrence of neutralizing antibodies is associated with a severe clinical consequence for some patients. As erythropoietin is absolutely required to stimulate formation of new erythrocytes, neutralizing antibodies can make inactive, endogenous and therapeutic versions of this growth factor and lead to severe anemia, known as pure red cell aplasia (PRCA).97

93 Id. 94 Betaseron Package Insert, http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/103471s5125lbl.pdf (accessed Nov. 18, 2013); Extavia Package Insert, http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125290 s0000lbl.pdf (accessed Nov. 18, 2013). 95 Grossberg et al., Frequency and Magnitude of Interferon β Neutralizing Antibodies in the Evaluation of Interferon β Immunogenicity in Patients with Multiple Sclerosis, 31 J. Interferon & Cytokine Research 337 (2011). 96 Creeke & Farrell, Clinical Testing for Neutralizing Antibodies in Interferon-β in Multiple Sclerosis, 6 Therapeutic Advances Neurological Disorders 3 (Jan. 2013). 97 Casadevall et al., Pure Red-Cell Aplasia and Antierythropoietin Antibodies in Patients Treated with Recombinant Erythropoietin, 346 New England J. Medicine 469 (Feb. 2002).

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Incidence of PRCA is generally extremely low in renal anemia patients treated chronically with epoetins (<1 case per 100,000 patient-years), but there have been one reported association of elevated incidence of PRCA with an intrinsic difference in manufacturing method for a European-sourced epoetin. The biosimilar product HX-575 (epoetin alfa) was compared with the Eprex® reference product in a post- approval clinical study to address the risk of immunogenicity with the subcutaneous route of administration in renal anemia patients. In this study neutralizing antibodies were detected in 2 patients out of 187 patients treated with biosimilar study drug, of which one patient was diagnosed with PRCA, and the clinical study was promptly suspended in 2009 pending an investigation.98

The unexpected incidence of neutralizing antibodies and PRCA in this relatively small patient cohort was investigated and associated with the presence of tungsten-induced erythropoetin protein aggregates in certain product lots.99 The sponsor’s manufacturing methods at the time did not specify use of component glass syringes with reduced tungsten content. (Such “low tungsten” components are commercially available in light of previously published reports on the sensitivity of therapeutic proteins to tungsten, and were already in use by other manufacturers).100 The sponsor’s manufacturing method has subsequently been revised to require these higher quality syringes.101 In the meantime the biosimilar epoetin alfa has remained on the market approved for the subcutaneous route of administration for other indications, but has still not been approved for this route of administration in renal anemia patients.

The shortcomings of the shared non-proprietary naming system as permitted by EMA for biosimilars and the need for additional identifiers are clearly illustrated by the response of the EMA’s Pharmacovigilance Working Party (PhVWP) to the above-mentioned unexpected immunogenicity findings. The biosimilar product in question was not identified in the PhVWP report,102 and, in addition to taking specific actions to manage the risks of the product in question, the PhVWP treated the occurrence of PRCA as a class risk effect. At its December 2009 meeting, the PhVWP recommended recording the trade name of the product, or name of the manufacturer, in the patient file in order to enable adverse reactions to be linked to “a specific epoetin product.” A statement encouraging increased traceability was therefore included in the Summary of Product Characteristics (SmPC) of many of the

98 Haag-Weber et al., Safety, Immunogenicity and Efficacy of Subcutaneous Biosimilar Epoetin-Alpha (HX575) in Non-Dialysis Patients with Renal Anemia: A Multi-Center, Randomized, Double-Blind Study, 77 Clinical Nephrology 8 (2012). 99 Seidl et al., Tungsten-Induced Denaturation and Aggregation of Epoetin Alfa During Primary Packaging as a Cause of Immunogenicity, 29 Pharmaceutical Research 1454 (2012). 100 Jiang et al., Tungsten-Induced Protein Aggregation: Solution Behavior. 98 J. Pharmaceutical Science 4695 (2009). 101 Seidl et al., Tungsten-Induced Denaturation and Aggregation of Epoetin Alfa During Primary Packaging as a Cause of Immunogenicity 29 Pharmaceutical Research 1466 (2012). 102 See CHMP Pharmacovigilance Working Party, Monthly Report Pharmacovigilance Working Party (PhVWP), December 2009 Plenary Meeting (7 Jan. 2010), http://www.ema.europa.eu/docs/en_GB/document_library/ Report/2010/01/WC500052067.pdf (accessed Nov. 18, 2013) (“In June 2009, a clinical trial to evaluate the safety and immunogenicity of a biosimilar epoetin product in the treatment of anaemia associated with chronic renal insufficiency in predialysis patients was stopped because of the occurrence of PRCA cases. While investigations on the cause of PRCA in these cases are still ongoing, the PhVWP considered it important that accurate medication histories are maintained for patients treated with epoetins, i.e., recording the trade name or the scientific name with the name of the manufacturer in the patient file. The identification and traceability of epoetin products used in patients will help to assess if PRCA cases and other reported cases of adverse reactions are related to any quality specifications of a certain epoetin product. The PhVWP recommended that the product information of all epoetins includes a request to maintain patient medication records.”).

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authorized erythropoiesis stimulating agents (ESAs) including biosimilar epoetin alfa, epoetin beta, epoetin zeta, and even darbepoetin alfa, a structurally modified ESA.

“In order to improve the traceability of erythropoiesis-stimulating agents (ESAs), the trade name of the administered ESA should be clearly recorded (or stated) in the patient file.”103

The EMA has thus focused on use of trade names to enhance traceability while following the “generic approach” to naming and labeling of biosimilar products. Yet recent survey data from the EU indicates that 24% of physicians only record non-proprietary name of the product in the patient record, that 53% of physicians believe identical non-proprietary name implies identical drug substance and 61% of physicians believe identical non-proprietary names imply approval for all indications of use. The latter is perhaps most concerning for public health given the above example.104

This case study highlights the importance of confirming product-specific safety profiles for all biologics, including biosimilars, in the post-approval setting. It also illustrates that, while EMA was reluctant to require product-specific warning or precaution in the biosimilar product’s labeling information, authorities responded by taking measures to enhance traceability of ESAs.

Somatropins

The first somatropin biosimilar approved in Europe was Omnitrope. During clinical development the drug substance manufacturing process was modified to improve removal of host cell proteins.105 The clinical trials revealed elevated incidence of anti-host cell protein antibodies and anti-hGH antibodies in children treated with the pre-change biosimilar product relative to the reference product (Genotropin). These levels declined after the process change was implemented. The EMA concluded that the purity and immunogenicity issues were resolved. Nevertheless, the risk management plan for Omnitrope included a requirement for a Phase IV clinical study to evaluate safety and immunogenicity in short children born small for gestational age. The related risk mitigation was to add a reference to the incidence of anti-HGH antibodies to the section 4.8 of the SPC.106 This trial is ongoing with no estimated completion date.107

In the interim, published reports on longer term evaluation of anti-HGH antibodies in patients treated with product containing the commercialized version of Omnitrope drug substance showed the incidence was approximately 7%.108 Nevertheless, the Summary of Product Characteristics (SmPC) for

103 See Binocrit SmPC Document History, http://www.medicines.org.uk/emc/history/21625/SPC/Binocrit+Solution+ for+Injection+in+a+pre-filled+syringe (accessed Nov. 27, 2013). 104 See Press Release, Alliance for Safe Biologic Medicines, ASBM Presents New European Survey Findings on Biosimilars and the Importance of Nonproprietary Naming (Nov. 22, 2013), http://safebiologics.org/press-releases.php (accessed Nov. 27, 2013) 105 See EMA, Omnitrope: European Public Assessment Report: Scientific Discussion (April 2006), http://www.ema.e uropa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000607/ WC500043692.pdf (accessed Nov. 19, 2013). 106 Id. 107 See Safety and Efficacy of Omnitrope® (rhGH) in Short Children Born Small for Gestational Age (SGA), ClinicalTrials.gov, http://clinicaltrials.gov/ct2/show/record/NCT00537914 (accessed Nov. 18, 2013). 108 See Romer et al., Seven Years of Safety and Efficacy of the Recombinant Human Growth Hormone Omnitrope in the Treatment of Growth Hormone Deficient Children: Results of a Phase III Study, 72 Hormone Research 359 (Dec. 2009).

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Omnitrope currently has identical language to that of the reference product with respect to incidence of anti-HGH antibodies, namely that the incidence is approximately 1%.109 The authors of the long term study justify the 7% anti-HGH incidence for Omnitrope primarily on the basis that it is not associated with any decrease in efficacy, and that it is within the range of other somatropin products. However, the reported incidence of the reference product is lower than 7%,110 so the authors reference publications for another somatropin, Nutropin AQ. Indeed, the public assessment report for Nutropin AQ notes that:

“However, the frequency of antibodies to hGH was higher following Nutropin Aq compared to other hGH preparations on the market (after 24 months still 7% of the children with GHD). Therefore the frequency of antibodies to Nutropin Aq and possible effects on growth should be thoroughly investigated in post marketing studies.”111

This example illustrates that there is the possibility that different members of the same class may have different levels of immunogenicity that should be documented via long term active pharmacovigilance studies. This also illustrates that the generic approach to product labeling, with identical language in the Warnings and Precautions sections, may not be appropriate for biosimilars, notwithstanding the fact that European regulators have generally followed this practice to date.

B. Of particular relevance to biologics, pharmacovigilance systems should be able to detect emergent signals for one member of a class.

In addition to addressing requirements for class-based signal detection and product-specific data, it is particularly important for pharmacovigilance systems for biological products to be sensitive to changes over time. Biologics are relatively sensitive to manufacturing conditions, and routine control measures may not always be able to detect potentially relevant changes in quality.112

Manufacturers implement systems to detect emergent signals that may be tied to product quality. For example, at Amgen we have implemented procedures to detect lot-based changes in the frequency of serious AEs over time. These methods include linkages between product complaint reports, AE reports and internal quality audit processes. Some AEs such as infections, injection site reactions, or loss of efficacy might potentially be tied to product quality issues, so we use additional signal detection procedures to determine if there is an association between the numbers of reports of such events with particular product batches/lots. These procedures are linked to both the cGMP quality systems and AE data such that the manufacturing records of batches can be evaluated and potentially investigated further if a signal is detected.

109 See Genotropin SmPC, http://www.medicines.org.uk/EMC/medicine/13860/SPC/Genotropin+5.3mg,+12mg/ (accessed Nov. 18, 2013); Omnitrope SmPC, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Product_Information/human/000607/WC500043695.pdf (accessed Nov. 19, 2013). 110 See Lundin et al., Development of Anti-hGH Antibodies During Therapy with Authentic Human Growth Hormone, 372 Acta. Paediatr. Scand. Suppl. 167 (1991). 111 NutropinAq: European Public Assessment Report: Scientific Discussion (July 2006), http://www.ema.europa.eu/e ma/index.jsp?curl=pages/medicines/human/medicines/000315/human_med_000939.jsp&mid=WC0b01ac058001d124 (accessed Nov. 18. 2013). 112 G. Grampp & S. Ramanan, Managing Unexpected Events in the Manufacturing of Biologic Medicines, 27 BioDrugs 305 (2013).

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In a single-source safety monitoring environment all of the reports associated with a given product are received by the responsible manufacturer, whether identified by brand name or nonproprietary name, and an uptick in the rate of AE reports may be readily detected. This permits the manufacturer to perform a timely and targeted investigation into potential causes.

In contrast, the ability to detect emergent safety signals in a multisource environment is dependent on accurate attribution of AEs to the correct manufacturer. When products share nonproprietary names, a given manufacturer might receive either a higher or lower proportion of relevant case reports over time, potentially frustrating the identification of statistical signal detection methods in a particular region or worldwide. If there is a manufacturing related issue for only one such product, the ability to detect changes in frequency of events may be compromised. The issue of attribution of an AE to the incorrect manufacturer is discussed in detail in Part III, infra.

To illustrate the importance of product-specific safety signal detection, we cite several historical examples of emergent safety issues tied to manufacturing changes from biologically sourced pharmaceuticals.113

Tryptophan

In the 1980’s an unusual number of cases of a rare disorder, eosinophilia myalgia, were noted in the safety reporting system.114 The cluster was investigated and ultimately tied to the emergence of novel impurities in the amino acid supplement, L-tryptophan, manufactured by a single supplier. While tryptophan is not a biologic product, it is manufactured using a biological fermentation process. The manufacturer had recently introduced a new microbial strain that, coupled with some changes in purification, may have been associated with the change in impurity profile.115 In this sense, the case illustrates the possibility of emergent safety signals arising from the sensitivity of biologically sourced products to their manufacturing conditions.

Heparin

A case study in which 246 fatal allergic-type reactions were reported among patients who received contaminated heparin before hemodialysis between 2007 and 2008 illustrates another emergent safety issue associated with biologically sourced products.116 The active ingredient was purchased from what proved to be an unreliable and unregulated foreign source and incorporated into a FDA regulated drug product in the U.S. FDA has subsequently increased their capacity to register and inspect all active ingredient manufacturers supplying the U.S. market. But at the time, the safety of the product hinged primarily on the reliability of the USP testing to ensure quality. Unfortunately, for a complex biologic

113 As discussed in Part IV.G.6, infra, this ability of a given manufacturer to detect changes in adverse event frequencies, and to investigate potential links to manufacturing, is one of the reasons why it is not necessary to change a product’s nonproprietary name following a manufacturing change. 114 See Belongia et al., An Investigation of the Cause of the Eosinophilia-myalgia Syndrome Associated with Tryptophan Use, 323 New England J. Medicine 357 (1990). 115 Id. 116 See U.S. Gov’t Accountability Office, GAO-11-95, Response to Heparin Contamination Helped Protect Public Health; Controls That Were Needed for Working With External Entities Were Recently Added (2010). The relevance of this case to pharmacovigilance systems is discussed in Section III.B.1. Here, we mention this case to highlight the emergence of the problem was associated with the fact that heparin is regulated as a drug, but is in fact a complex, biologically sourced product.

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product like heparin, the monograph was not sufficient to this purpose.117 The active ingredient supplier deliberately adulterated the product in such a way that it would pass the USP tests. While this case was due to deliberate malfeasance, it illustrates how routine controls may not be sufficient to prevent emergent quality and safety issues from occurring for biologically sourced products.

Intravenous immunoglobulin

There are presently several brands of intravenous human normal immunoglobulins (IVIG) marketed in Europe, including Kiovig, Privigen, and Octagam and Flebogamma DIF.118 Octagam® 5%, an intravenous immunoglobulin (IVIG) product approved by both the FDA and EMA has been in continuous use for nearly a decade and half since its original approval in 1995 with good track record of safety and efficacy. However, in 2010 a surprising increase in thromboembolic events (TEEs), a life threatening complication was observed after administration of this IVIG to patients, leading to suspension of EMA license of this product.119 Subsequent root cause investigation revealed that the increase in thromboembolic events was due to the presence of an impurity (FXI) carry over in the final drug product, which is normally removed during the early stages of the process.120 The reasons for increased levels of FXI were neither immediately apparent nor caught by routine release process.121 Only after further extensive studies and optimization studies which led to the process modification (introduction of a specific step to remove FXI by adsorption) and detection methods (both in-process and final container release assay for FXI), the license was restored.122

Epoetin alfa

A well-documented case of an emergent change in immunogenicity occurred with Eprex/Erypo (epoetin alfa) in 1998 to 2003. The Eprex marketing authorization holder (MAH) implemented an approved change in the drug product formulation to remove human serum albumin, with the intention of reducing potential safety risks that might occur with this human donor-derived excipient.123 This formulation change was subsequently correlated with a 10- to 20-fold increase in the incidence of PRCA

117 See Pew Health Group, After Heparin: Protecting Consumers from the Risks of Substandard and Counterfeit Drugs 31(Jul. 12 2011), http://www.pewtrusts.org/uploadedFiles/wwwpewtrustsorg/Reports/Health/Pew_Heparin_ Final_HR.pdf (accessed Nov. 19, 2013) (noting that the monograph in place at the time was insufficient to detect the heparin contaminant). 118 A search of the EMA Website’s EPAR database for “immunoglobulin” under INN/Common name/Active Substance leads to seven results. See EMA, European Public Assessment Reports, http://www.ema.europa.eu/ema/ind ex.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d125 (accessed Nov. 20, 2013). 119 Press Release, European Medicines Agency, European Medicines Agency Recommends Suspension of Octagam in all EU Member States (Sept. 24, 2010), http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/ 2010/09/WC500097037.pdf (accessed Nov. 19, 2013). 120 See EMA, CHMP Assessment Report: Octagam and Associated Names, 4 (March 15, 2012), http://www.ema.euro pa.eu/docs/en_GB/document_library/Report/2013/05/WC500143742.pdf (accessed Dec. 1, 2013). 121 See Commission Decision of October 4, 2010, Concerning, In the Framework of Article 107 of Directive 2001/83/EC of the European Parliament and of the Council, the Marketing Authorisations of Medicinal Products for Human Use “Octagam and Associated Names,” Annex I. 122 Juergen Roemisch, Risk Mitigation Strategies to Address Potential Procoagulant Activity in Immune Globulin Products, http://www.fda.gov/downloads/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/UC M260794.pdf (accessed Nov. 18, 2013). 123 Macdougall et al., Antibody-Mediated Pure Red Cell Aplasia in Chronic Kidney Disease Patients Receiving Erythropoiesis-Stimulating Agents: New Insights, 81 Kidney International 727 (2012).

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in some patients receiving subcutaneous Eprex124. (The subcutaneous route of administration is associated with higher risk of immunogenicity relative to the intravenous route.) The increased PRCA incidence was originally detected via spontaneous case reports for patients treated with various ESAs during their courses of therapy, but the signal was subsequently attributed specifically to Eprex after an in depth investigation of patient case histories.125

In response to this emergent safety signal the sponsor performed a root cause investigation to evaluate potential causative factors including drug substance manufacture, the formulation, the primary product container, and product handling practices. The probable root cause was ultimately attributed to an interaction between epoetin alfa and a chemical leaching from the drug product container, among other potential hypotheses including multifactorial causation.126 Concurrent with investigating the root cause, the sponsor improved the container to reduce the level of leaching, and took other measures to ensure safe transport and handling of Eprex. The incidence of PRCA returned to historical levels.127

Authorities took the additional measure of temporarily contraindicating the subcutaneous route of administration for renal anemia patients.128 This indication was restored after the situation was resolved.129 This example demonstrates the critical importance of product-specific attribution of AEs for the detection of and timely investigation of emergent safety signals.

C. In summary, policy and experience support the imperative for robust, product-specific pharmacovigilance for biological products.

We have cited authorities, laws and regulations, and historical experience in the U.S. and Europe to demonstrate that it is especially important for regulators and sponsors to support robust, product-specific pharmacovigilance for biological products. These measures are in addition to the mandatory, class- based safety signal detection required for all pharmaceutical products, and must account for the possibilities of either intrinsic differences or emergent differences in safety profiles among structurally and mechanistically related products. It is clear that policymakers in both regions do not accept the generic drug paradigm for post-approval safety monitoring, and that the distinct policies for biologics are based on historical experience with biological products.

For evaluation of the intrinsic safety profiles of biologics, time-bound post-approval commitments are typically required, potentially including interventional clinical studies, observational studies, registries, and targeted evaluation of spontaneous AE reports. However, such time-bound commitments are not intended to detect emergent differences in safety profiles in the long-term. Such differences could occur

124 Boven et al., The Increased Incidence of Pure Red Cell Aplasia with an Eprex Formulation in Uncoated Rubber Stopper Syringes, 67 Kidney International 2348 (2005). 125 Kai-Uwe Eckardt & Nicole Casadevall, Pure Red-cell Aplasia Due to Anti-Erythropoietin Antibodies, 18 Nephrology Dialysis Transplant 865 (2003). 126 Boven et al., The Increased Incidence of Pure Red Cell Aplasia with an Eprex Formulation in Uncoated Rubber Stopper Syringes, 67 Kidney International 2348, 2350 (2005). 127 Id. at 2349. 128 Id. at 2350. 129 See Eprex SPC Document History, http://www.medicines.org.uk/emc/history/889/SPC/Eprex+2000%2c+4000+an d+10000+IU+ml+solution+for+injection+in+prefilled+syringe ) (accessed Nov. 2, 2013) (noting removal of contraindication language for subcutaneous route of administration in July 2006 revision).

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at any time post-approval as a result of changes in manufacturing conditions. In this context, the spontaneous reporting system is currently the only sustained and mandatory mechanism with the capability to detect emergent safety signals for a given member of a therapeutic class.

For both the evaluation of intrinsic safety profiles and the detection of emergent safety signals, SRS and active surveillance (AS) will rely on accurate product identification. Reporting by HCP and patients in the SRS is an important principal on which PV activities are built, and distinguishable names will facilitate the reporting of AEs and thus support post-market PV and risk management in the context of biosimilars.130 European authorities have approached this policy challenge by emphasizing the use of brand/invented names for biological product prescribing, dispensing, record keeping, and AE reporting. This approach may be suitable for Europe, but will require multiple legislative measures to counter other trends towards encouraging or requiring generic prescriptions, and it is clear that the 2010 Pharmacovigilance Legislation mandating such measures has not been successfully and fully implemented by all 28 member states.131

We are not convinced that the EU policy solution is sustainable without further measures, and in any case, we do not believe it is applicable in the U.S. We believe such a measure is unnecessary, given the more achievable policy of using distinguishable non-proprietary names, and we suspect that GPhA members would share our perspective that such an undertaking would be unprecedented and impractical.

III. ROBUST MULTISOURCE PHARMACOVIGILANCE FOR BIOLOGICAL PRODUCTS REQUIRES DISTINGUISHABLE NAMES.

A. FDA has emphasized the need for enhanced traceability of biological products.

FDA has explained that “[p]ostmarketing safety monitoring for a proposed [biosimilar] product should … have adequate mechanisms in place to differentiate between the AEs associated with the proposed product and those associated with the reference product.”132 That is because, given their inherent variability, biological products manufactured by different sponsors may have different safety and immunogenicity profiles.133 These differences make it essential that AEs are attributed to the correct product in all administration settings, including hospital, clinic, and at home. According to FDA, “[t]racking adverse events associated with the use of reference and biosimilar products will be difficult if the specific product or manufacturer cannot be readily identified, and appropriate strategies must be

130 Vermeer et al., Traceability of Biopharmaceuticals in Spontaneous Reporting Systems: a Cross-sectional Study in the FDA Adverse Event Reporting System (FAERS) and EudraVigilance databases, 36 Drug Safety 617 (Aug. 2013). 131 See Minutes of the 71th meeting of the European Commission, DG Health and Consumers, Pharmaceutical Committee, 2 (Oct. 23, 2013) http://ec.europa.eu/health/files/committee/71meeting/pharm630.pdf (accessed Dec. 9, 2013) (“[T]he Commission services would be interested to know how the above mentioned provisions of the EU legislation are enforced and what is the experience of the Member States so far with the reporting of adverse events for biological medicinal products, including biosimilar medicinal products.”). 132 FDA, Draft Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product 20 (February 2012), http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM291128.pdf. 133 See supra Part I.A; Torti Letter at 4 (noting that “biosimilar” products can have different immunogenic profiles).

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developed to ensure the implementation of robust, modern pharmacovigilance programs for biologics.”134

Pharmacovigilance systems must also enable identification of latent immunogenic reactions by product and manufacturer. Necessarily, it is typically assumed that the product being administered at the time of the adverse event is the most likely to have a causal association with the clinical event; for events such as increased immunogenicity, which may be delayed in onset, this assumption may or may not be correct.

B. Contrary to GPhA assertions, history of multiple manufacturer biologics in Europe and U.S. does not prove that existing systems are sufficient.

Global and U.S. pharmacovigilance systems have not been able to accurately trace AEs for medicines marketed and distributed by multiple manufacturers. To the limited experience with biosimilars in Europe is instructive, it must be considered in light of biologics-specific policies and practices implemented in Europe that may not be applicable to the U.S. The U.S. federal framework for pharmacy and medical practice may require alternate measures.

1. The European Union has limited experience with biosimilars, and has introduced biologics-specific traceability policies.

Biosimilars have been approved in Europe only since 2006 and prior to 2013, biosimilars were authorized for only three product classes: somatropins, filgrastims and epoetins. Of these classes, somatropins and filgrastims are not known for sensitivity to manufacturing issues, and have not been associated with adverse clinical consequences of immunogenicity. Nevertheless, we note as referenced in Part II.A, supra, that one biosimilar somatropin exhibited unexpectedly high immunogenicity rates during clinical development, although the associated manufacturing issues were addressed prior to approval.135 The third product class is known to be sensitive to manufacturing, as we outlined with case studies of unexpected immunogenicity for two epoetin alfa products.136 Already, in the short history of EU experience with biosimilars, one of these products was associated with a manufacturing related immunogenicity issue that was detected in a post-approval clinical study after product containing the same drug substance was already marketed for other conditions of use.137

In this context European policymakers have taken several steps to enhance traceability of multisource biologics.

First, in reaction to the specific safety issue for biosimilar epoetin alfa, they required updated labeling provisions for other epoetins, including unrelated products (eg, darbepoetin alfa). These provisions were added to the “Special Warnings and Precautions for Use” section in the Summary of Product Characteristics (SmPC). The added precautions emphasized the need for prescribers and patients to be aware of the specific brand, manufacturer and batch number of epoetins administered to patients, and to

134 See Kozlowski, S et al., Developing the Nation’s Biosimilars Program, 365 New England J. Medicine 385, 387- 388 (Aug. 2011) (emphasis added). 135 See EMA, Omnitrope: European Public Assessment Report: Scientific Discussion (April 2006), http://www.ema.e uropa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000607/WC500043692.pdf (accessed Nov. 19, 2013). 136 See supra Part II. 137 See supra Part. II.A.4 (discussing the issues related to cancellation of the HX-575 SWEEP study).

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record this information in patient records and report it with any AE reports.138 It is noteworthy that the traceability precautions have not yet been applied uniformly to other multisource biologics classes. For example, the somatropin SmPCs do not include a traceability precaution.139 For the filgrastims, only the reference product (Neupogen) and one of the biosimilars (Zarzio) included the precaution on their labels prior to 2013, and these provisions were added only starting in 2010.140, 141

Second, in settings where non-proprietary name prescribing is encouraged or required for non-biologic medicines, policymakers have almost always/often created specific exceptions in law and guidance to encourage or require use of product specific trade names in biologic prescriptions or records.

Third, the EU adopted EU pharmacovigilance laws via a 2010 Directive that explicitly requires enhanced pharmacovigilance and traceability of biologics, including biosimilars. EU law directs member states to implement any required measures in pharmacy practice and medical practice to ensure biological medicinal products are traced, including by trade name.142

As many of these measures have not yet been fully implemented by European member states, it is premature to suggest that pharmacovigilance challenges have been successfully addressed. Furthermore, assuming these measures will be helpful in Europe, it is not clear that it would be practical to implement similar measures in the United States, where medical and pharmacy practice is regulated at the state level.

2. GPhA’s forecast that the current system will be sufficient for biosimilars is belied by FDA’s experience with other biological products produced by different manufacturers.

GPhA cites several historical classes of multiple versions of biological products with shared common names in order to infer that there have been no problems with safety monitoring with the current U.S. system. This argument is undermined by the fact that, for several immunologically sensitive members of those classes, FDA has implemented specific policies to ensure traceability and prevent inadvertent switching. As discussed further in Part V.B.2, infra, these products include blood clotting factors, recombinant insulin products, and vaccines.

C. Pharmacovigilance in the U.S. relies on both spontaneous reporting systems (SRS) and active surveillance systems (AS).

Post-approval safety monitoring in the U.S. is performed primarily using two types of signal detection systems: spontaneous reporting systems (SRS) via reports to the manufacturer and via the FDA’s

138 See id. (discussing the recommendations of PhVWP to update labels on all ESAs). 139 See Omnitrope SmPC, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/ human/000607/WC500043695.pdf (accessed Nov. 4, 2013) 140 See Neupogen SmPC Document History, http://www.medicines.org.uk/emc/history/23292/SPC/Neupogen+Singlej ect+30+MU+(0.6+mg+ml) (accessed Nov. 27, 2013). 141 See Zarzio SmPC, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/ human/000917/WC500046525.pdf (accessed Nov. 27, 2013). 142 See Council Directive 2010/84/EU of the European Parliament and of the Council of 15 Dec. 2010 Amending, as Regards Pharmacovigilance, Directive 2001/83/EC on the Community Code Relating to Medicinal Products for Human Use, 2010 O.J. (L 348) 74, 10.

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Medwatch program, and active surveillance (AS) via analysis of medical billing records related to drug and biologic reimbursement. The latter is the subject of the FDA’s Sentinel pilot program.143

Both of these systems have limitations in signal detection, but their attributes can be complementary for multisource biologics provided they can properly attribute AEs to specific products. For example, the SRS is subject to a relatively low, and somewhat variable, reporting frequency, and does not contain information about the total number of administered doses of a specific product across the patient population (i.e., doses per month).144 As a result, incidence rates are often difficult to estimate and interpret, limiting the utility of spontaneous reports to confirm a disproportionate prevalence of an AE for a given product, even when coupled with distribution/sales data.

In contrast, the billing and electronic health record databases upon which AS relies can, in principle, faithfully record all claims associated with a specific drug’s usage as well as the diagnosis codes linked to potential AEs, vastly improving the statistical resolution of the data. However, such systems are subject to the limitation that not all relevant AEs will be recognized and/or recorded and linked to a specific diagnosis or billing code.145 For example, when first discovered, osteonecrosis of the jaw, an adverse reaction related to bisphosphonate treatment, did not have a specific ICD 9 code.146 Identification of a specific product may be challenging with AS if product specific codes are not recorded, or there has been product switching and delayed onset events.

SRS play an important role in all regions where physicians, pharmacists, other healthcare professionals and patients can report serious reactions, product quality problems and therapeutic inequivalence/failure.147 Even in countries such as the U.S. where AS is becoming a reality it is important that the fidelity of SRS is optimized.

First, patient, physician and pharmacist spontaneous AE reports or product failures are important for hypothesis generation and could be a means of early identification of batch or product-specific problems as well-documented vulnerabilities of all biologic medicines.

Second, AS is also only sensitive to billable ICD diagnosis codes and diagnosis related groups (DRGs) used to link administration of a drug or biologic to a subsequent AE. It is not clear if immunologically relevant AEs, those considered most likely to diverge among multisource biologics, would be consistently or clearly coded in a way that could be linked to active surveillance.148,149 Examples of

143 FDA’s Sentinel Initiative, http://www.fda.gov/Safety/FDAsSentinelinitiative/ucm2007250.htm (accessed Dec. 10, 2013) (providing a general description of the Sentinel Initiative). 144 K. Getz et al., Evaluating_the_Completeness_and_Accuracy_of Medwatch, Am. J. Therapeutics (Sept. 2012), (E- publishing before print), http://journals.lww.com/americantherapeutics/toc/publishahead (accessed Dec. 10, 2013). 145 R. Platt et al., The U.S. Food and Drug Administration’s Mini-Sentinel Program: Status and Direction, 21 Supp. Pharmacoepidemiol Drug Safety S1, Table 1 (2012) (showing little utility of administrative data to identify health outcomes for anaphylaxis and hypersensitivity reations). 146 G. Wilkinson et al., Intravenous Bisphosphonate Therapy and Inflammatory Conditions or Surgery of the Jaw: A Population-Based Analysis. 99 J. Nat’l Cancer Inst. 1017 (2007). 147 See FDA, How Consumers Can Report an Adverse Event or Serious Problem to FDA (updated June 2013), http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053074.htm (accessed Dec. 10, 2013). 148 R. Platt et al., The U.S. Food and Drug Administration’s Mini-Sentinel Program: Status and Direction, 21 Supp. Pharmacoepidemiol Drug Safety S1 (2012). 149 B. Strom, Methodologic Challenges to Studying Patient Safety and Comparative Effectiveness, 45 Medical Care S13-S15 (2007).

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immunologically-related safety events would include anaphylaxis, infusion reactions, injection-site reactions, hypersensitivity and delayed immune responses (e.g., delayed hypersensitivity or loss of efficacy).150

Third, in discussing the applicability of product identifiers to pharmacovigilance it is important to consider the setting of use of the biological products and the nature of the information flow into the surveillance systems. The SRS relies overwhelmingly on the accuracy of information from human reporters. Therefore, in a multisource pharmacovigilance setting it is critically important that product identification is supported by robust, and if possible, redundant product specific identifiers. .

AS relies on automated flow of billing code information, and hence is less susceptible to human error. However, in order to be useful in a multisource pharmacovigilance environment it is critical that events are identified and properly coded, with accurate, product specific billing codes. As we discuss this is not always the case in certain settings of use.

D. Evaluation of pharmacovigilance system capabilities must consider all settings of use of therapeutic biologics.

GPhA argues that pharmacy dispensing and billing record systems will ensure robust pharmacovigilance in the U.S., specifically citing the almost universal use of the NDC in the pharmacy channel. Setting aside the merits of whether NDCs could be reliably used as a product identifier in SRS,151 an additional difficulty with the GPhA position is that the majority of therapeutic biological products are administered in the physician’s office or hospital outpatient or settings where the above mentioned pharmacy dispensing and billing systems do not always apply.152

For therapies administered in the hospital or physician office setting the systems for tracking and billing drugs are not well suited to supporting either the SRS or AS. In-house pharmacies used by such providers do not typically use NDCs unless required by certain payers.153 Instead, alternate billing codes are used that are not unique for each product. For example, hospital inpatient claims (reimbursed under Medicare Part A) typically use a Diagnostic Related Group (DRG) to assign a bundled payment according to ICD-9-CM diagnosis and procedure codes. With very rare exceptions procedure codes are not specific to a given biologic therapy or underlying event, so these codes would not be useful for

150 For review of immunological and non-immunological AERs and diagnoses, see M. Riedl & A. Casillas, Adverse Drug Reactions: Types and Treatment Options, 68 Am. Family Physician 1781 (November 1, 2003). For review of immunological events common biologics classes, see RT Purcell & RF Lockey, Immunologic Responses to Therapeutic Biologic Agents. 18 J. Investigational Allergology & Clinical Investigation 335 (2008). 151 This is discussed in Part III.G, infra. 152 In 2012, approximately 64% of top-selling biologics in the U.S. (each representing 1% or more of total biologics sales, and cumulatively representing 83.7% of total biologics sales) were distributed through physician office (clinics) and hospitals. Approximately 31% of top-selling biologics were distributed through the mail-order or retail pharmacy channel. The remaining 5% were distributed through other institutional settings (e.g, veterans‘ facilities, prisons, HMO’s, etc.). See Amgen Analysis of IMS Data (on file with author). 153 For example, Medicaid and Medicare/Medicaid dual eligible claims may require NDC.

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AS.154 Physician office and hospital outpatient claims (reimbursed under Medicare Part B) use HCPCS codes, but these may not always correlate to unique codes for each biologic.155

In the absence of distinguishable product names and product-specific billing codes there would not be an unique, verifiable identifier associated with an administered medicine in physician office and hospital out-patient setting. This could undermine the effectiveness of both the SRS and AS systems. Furthermore, as discussed in Part III.F.2, infra, when an office or hospital pharmacy has an option to purchase similar biologics from multiple sources, the specific information about the medicine purchased, dispensed, and administered to a patient may not be transparent to the prescriber. In such settings, the dispensing pharmacy is often at liberty to therapeutically interchange of one product for another (independent of whether criteria for interchangeability have been met), according to the judgment of the institutional pharmacy and therapeutics committee.156 Therefore, a discussion about the nomenclature and identification systems appropriate for multisource biological pharmacovigilance must take into account the specific challenges associated with biologics administered in the physician office or hospital setting.

E. Robust pharmacovigilance requires product-specific attribution of events through multiple identifiers.

As discussed in Part III.C, supra, we agree that, in a multisource pharmacovigilance setting, accurate attribution of an AE to the specific product associated requires multiple product identifiers. Notably, however, GPhA is incorrect in suggesting that this can be accomplished merely with one unique product name (i.e., the brand name) and a numerical identifier (i.e., the batch number or NDC). We believe that post-approval monitoring would be bolstered by the availability and use of additional, product specific identifiers.

1. The reality of the AE reporting process illustrates the need for reliable redundant identifiers for biological products.

In the U.S., there has been relatively little emphasis on precise, product-specific tracking of multisource chemical drug products sharing the same non-proprietary name. Instead, class-based tracking has been considered sufficient for the SRS. FDA officials have noted that, “[i]n general, FDA does not distinguish postmarket surveillance of brand products from follow-on or generic products.”157 Indeed, FDA has acknowledged that “Generally, OGD receives few AERs or similar reports since the reports may not specify a generic manufacturer for the drug product. Furthermore, the safety profile of a particular drug is usually well-known before generic versions are approved. Therefore, AERs associated with a generic drug are less likely to be reported.”158

154 DiMartino et al., Using Medicare Administrative Data to Conduct Post-Marketing Surveillance of Follow-on Biologics: Issues and Opportunities, 63 Food & Drug L.J. 896 (2008). 155 Id. at 896-987 156 See ASHP Formulary Management Guidelines, Guidelines on the Pharmacy and Therapeutics 176 (“Therapeutic interchange provides pharmacists with the authorization to use a formulary therapeutic alternative in place of a nonformulary medication or a non-preferred formulary medication without having to contact the prescriber.”), http://www.ashp.org/DocLibrary/BestPractices/FormGdlPTCommFormSyst.pdf (accessed Dec. 10, 2013). 157 Torti Letter at 16. 158 MaPP § 5240.8. (“Generally, OGD receives few AERs or similar reports since the reports may not specify a generic manufacturer for the drug product.”).

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The SRS is the cornerstone of passive pharmacovigilance,159 and under FDA’s current system, these reports may be submitted with minimal product identification. Post-market case safety reports must contain four data elements: (1) an identifiable patient, (2) an identifiable reporter, (3) a suspect drug or biological product, and (4) an AE or fatal outcome.160 Aside from the required name of the suspect drug or biological product, other, optional, product-related data elements may be submitted, if known, including manufacturer, lot number, expiration date, and NDC number.161

In an analysis of 10.2 million reports submitted to Medwatch, patient information was generally complete and accurate. Suspect product information, on the other hand, showed high levels of incomplete and inaccurate data. Start and end dates of suspect product use had 37% and 23% completion rates, respectively. Product lot numbers had only a 9% completion rate. Most importantly, more than 25% of the names of reported suspect products were inaccurate.162 There is currently no requirement to report redundant, product-specific identifiers. Indeed, FDA officials have explained that a “suspect drug” must be identified by, at minimum, its active ingredient.163 Thus, generally speaking, AE reports need only identify a drug by its non-proprietary active ingredient name,164 and drugs with the same non-proprietary name will be grouped together for pharmacovigilance purposes. While brand names are often used for AE reports, the reported brand names are not necessarily the names of the actual products administered. Thus, in the absence of a second product identifier, brand names may not suffice in a multisource environment.

2. Two case studies illustrate the consequences when pharmacovigilance relies on a single product identifier.

There is no perfect case study that can provide insight into what the world of AE reporting in the SRS will be like once biosimilars are introduced into the U.S., but two may have direct implications for biosimilars.

Post-Generic Entry AE Analysis

An analysis of AE reporting for non-biological drugs conducted by Lietzan et al. found that AEs are often attributed to the innovative product when in fact the patient likely took a generic product with the

159 WHO, Pharmacovigilance Focus, 23 Drug Information J. 87, 91 (2009). 160 See FDA, Guidance for Industry: Postmarketing Safety Reporting for Human Drug and Biological Products Including Vaccines (Mar. 2001), http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceCompliance RegulatoryInformation/Guidances/Vaccines/ucm092257.pdf (accessed Nov. 19, 2013). 161 Id. See also MedWatch 3500A Form Appendix C. 162 K. Getz et al., Evaluating_the_Completeness_and_Accuracy_of Medwatch, Am. J. Therapeutics (Sept. 2012), (E- publishing before print), http://journals.lww.com/americantherapeutics/toc/publishahead (accessed Dec. 10, 2013). 163 Gerald J. Dal Pan, Dir. Office of Surveillance and Epidemiology, CDER, Adverse Event Reporting and Medical Safety Considerations: A View from CDER’s Office of Surveillance and Epidemiology, presentation at CHPA Regulatory, Scientific, & Quality Conference (May 3, 2013), http://www.fda.gov/downloads/AboutFDA/ CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM352766.pdf (accessed Nov. 19, 2013). 164 FDA’s MedWatch voluntary reporting form includes sections for the inclusion of brand name, manufacturer, lot number, and NDC. FDA advises, however, that persons completing the form need not complete all sections if the reporter does not have all of the information and that the non-proprietary name should be used where a brand name is not available or is unknown.

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same nonproprietary name.165 Specifically, when the volume of dispensed prescriptions of the innovative product declined by 80% or more, the total rate of AEs attributed to the brand remained the same or even increased in the SRS. Assuming the safety of the brand product did not suddenly decrease after loss of market exclusivity, this finding implies that the majority of AE reports were attributed to the wrong product. Furthermore, this analysis found that meaningful product-identifying information (beyond product brand or nonproprietary name) is usually not included in information provided by reporters. Indeed, absent confirmatory details, the bias towards attributing AEs to the originator product is built into the SRS: Specifically, in the case of an ambiguous product attribution with multiple NDA/ANDA holders, FDA guidance encourages reporting of the AE to the original NDA holder.166

These findings support the need for distinguishable names for biologics (including biosimilars), which will help to ensure that AEs are traced to the correct product and that FDA, sponsors, healthcare professionals, and patients can rely on timely and more accurate AE data to make critical decisions regarding the use of biologics.

Of course, Lietzan et al. did not show that misattribution of AEs for these off-patent drugs contributed to any difficulties in traceability of intrinsic or emergent safety issues for any member of the class. But that would be highly unlikely to occur for chemically synthesized drugs. However, another case study illustrates that the existing system really can compromise an efficient and expeditious investigation.

Heparin Contamination

The emergent heparin safety issue involving 246 fatal allergic-type reactions was discussed in Part II.B, supra. Here we refer to the difficulties associated with the resulting post-marketing safety investigation. In this well-documented case, the U.S. Government Accountability Office (GAO) identified lack of manufacturer information and lot numbers in some AE reports as having hampered identification of the specific heparin that was the cause of the reactions.167 Although heparins do not exemplify complex biologics and the various heparin products are not biosimilars, this case study underscores the public health need to educate the healthcare community on the importance of accurate biologic product identification for AE reporting, as well as the need for national pharmacovigilance systems to accurately and reliably collect this information.

The circumstances that led to identification of the cause of the allergic-type reactions were in part serendipitous and would be unlikely to allow identification of the causative biologic in a similar future crisis. The heparin adulteration incident represents a case in which a biologic made by several manufacturers could not be readily distinguished for AE attribution. It is not impossible a similar

165 See Lietzan et al., Biosimilar Naming: How do Adverse Event Reporting Data Support the Need for Distinct Nonproprietary Names for Biosimilars?, FDLI Food and Drug Pol’y Forum, Vol. 3, Issue 6, March 27, http://www.fdli.org/docs/default-document-library/lietzan-faers-bio-final-3-27-13.pdf?sfvrsn=0 (accessed Nov. 19, 2013). 166 See FDA, Draft Guidance for Industry: Postmarketing Safety Reporting for Human Drug and Biological Products Including Vaccines 924-26 (Mar. 2001), http://www.fda.gov/downloads/BiologicsBloodVaccines/ GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm092257.pdf (accessed Nov. 19, 2013) (“However, if a drug substance has more than one application and it cannot be determined which of the approved applications is involved, the report should be submitted to the application for the drug product that was approved first . . . .”). 167 U.S. Gov’t Accountability Office, GAO-11-95, Response to Heparin Contamination Helped Protect Public Health; Controls That Were Needed for Working With External Entities Were Recently Added (2010).

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situation in the future could involve other multi-source biologics, such as biosimilars and their reference products. This case study underscores how the lack of distinguishable names and insufficient reporting routines can hinder resolution of an AE crisis, with possibly dire health consequences.

F. Contrary to GPhA’s suggestion, brand name reporting in AEs does not reliably address pharmacovigilance concerns.

In their proposal that consistent use of brand names will address multisource pharmacovigilance requirements for biologics the Petitioners are implicitly referring only to the use of brand names in the SRS. It is important to consider that product brand names are irrelevant for active surveillance, and what matters is whether a unique billing code is assigned for an administered product.

As noted previously, AE reports for the SRS must, at a minimum, include as an identifier the name of the suspect drug or biologic product. This means that pharmacovigilance for multisource products will be heavily dependent on accurate recording of a unique product name (brand name and/or a differentiated non-proprietary name).

In the context of discussing the SRS GPhA makes several incomplete and/or erroneous arguments to suggest that reporting of brand names would be adequate for multisource biologics in the U.S.

1. Existing U.S. law and federal structure make it unlikely that European- like biologics traceability policies can be applied.

The EU has implemented specific provisions to improve safety monitoring of multisource biologics, all heavily dependent on promoting the documentation of brand names or trade/invented names in the prescribing or dispensing process. We are not aware that GPhA has endorsed such policies in the U.S., but here we discuss some potential implementation challenges to such an approach as an alternative to the use of distinguishable nonproprietary names.

First, the FDA has no statutory authority to compel use of brand names for prescribing or for patient medical records in the U.S.168

Second, the U.S. does not have an analogous non-branded trade name labeling system as in Europe. In Europe, manufactures who do not register brand names are required to label their products with the INN followed by the company name, eg. “filgrastim Hexal”.169 This may become a de facto trade name subject to the brand/trade/invented name provisions in EU and member state law.170

Third, the regulation of prescribing, pharmacy dispensing, and applicable record keeping is the responsibility of each of the U.S. states. Given the clear delineation of legal authorities between the federal government and that of states, the prospect of a federal or other uniform mechanism to enable mandatory brand name prescribing is highly unlikely.

168 See 21 U.S.C. § 351(b); 21 U.S.C. § 352(e). 169 See Directive 2001/83/EC, art. 1(20), 2001 O.J. (L 311) 67 (defining the name of a medicinal product to be “either an invented name or a common or scientific name, together with a trade mark or the name of the manufacturer”). 170 Please note, however, that discussions relating to this issue are currently taking place in the context of a revision of the CHMP Guideline on the acceptability of names for human medicinal products processed through the centralised procedure.

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Even when brand names exist, they are not always used in AE reporting. Because, as FDA’s Biological Product Naming Working Group has recognized, “health care providers may use nonproprietary names instead of proprietary names when prescribing and ordering products, and pharmacovigilance systems often do not require inclusion of proprietary names, the use of distinct proprietary names is insufficient to address [safety monitoring] concerns.”171

Therefore, the ultimate utility of the European framework for the post-market safety monitoring of multisource biologics is not a useful template for FDA policy.

2. Brand names are not always used in U.S. prescribing practices.

As noted previously, brand names are not mandatory in the U.S., and are not common practice for the U.S. marketing of generics. If multiple biosimilars were licensed with only a non-proprietary name, then patients and physicians would be unlikely to distinguish among them for purposes of AE reports.

Current medical practice relies on prescription by nonproprietary name in a substantial share of prescriptions, and this share has increased over time. Based on data from 2003, one study showed that 21% of outpatient prescriptions for common drugs were written by the generic name when a generic was available,172 and some are advocating that medical training—including CME—should be designed to promote use of nonproprietary names.173 Indeed, USP adopted a resolution in 2005 to encourage use of only generic names in medical practice.174 Furthermore, in a recent survey of prescribers, 91% of whom prescribed biologic medicines in their practice, 17% of respondents indicated that they are more likely to use generic names for prescriptions, and a further 32% indicated that they use a combination of generic and brand name prescribing.175

In the context of formal pharmacology instruction, evidence suggests a preference for the use of generic versus brand names. For example, Goodman and Gilman’s Manual of Pharmacology and Therapeutics explicitly indicates a general preference for the use of generic names.176 Similarly, while not explicit on the point, Knowledge Objectives in Medical Pharmacology suggests that generic names should be utilized in prescription writing unless there is reason to believe that the brand drug would be more effective for the patient.177 The Association of American Medical Colleges (“AAMC”) describes Knowledge Objectives as “description of the competencies in pharmacology that should be obtained by

171 CDER, Filgrastim Proprietary Name Review. 172 Steinman et al., What’s in a Name? Use of Brand versus Generic Drug Names in United States Outpatient Practice, 22 J. Gen. Intern. Med. 645 (May 2007). 173 Kuo et al., Physician Use of Brand Versus Generic Drug Names in 1993-1994 and 2003-2004, 43 Ann. Pharmacother. 459 (Mar. 2009); Steinman et al., What’s in a Name? Use of Brand versus Generic Drug Names in United States Outpatient Practice, 22 J. General Internal Medicine 645 (May 2007). 174See USP, 2005-2010 Resolutions Adopted at the 2005 USP Convention (March 13, 2005), http://us.vocuspr.com/N ewsroom/ViewAttachment.aspx?SiteName=USPharm&Entity=PRAsset&AttachmentType=F&EntityID=96751&Atta chmentID=4ad0b4fa-805b-48d9-af25-ad7ea1b06b4f (accessed Nov. 19, 2013). 175 See Kevin Olson, Alliance For Safe Biologic Medicine : Prescriber Survey (Aug. 31, 2012), http://safebiologics.or g/resources/wp-content/uploads/2012/09/ASBM-Survey-3.pdf (accessed Nov. 19, 2013). 176 Laurence Brunton et al., Goodman & Gilman’s Manual of Pharmacology and Therapeutics 81 (2008) (instructing “[t]he nonproprietary or official name of a drug should be used whenever possible.”). 177 See Richard Eisenberg & Carl Faingold, Knowledge Objectives in Medical Pharmacology, 3 (2012) (noting that “[d]rugs may be prescribed by generic name, since often a less expensive drug product can be obtained in this way.”)

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students completing their basic medical education,” and a “detailed description of an optimal curriculum in basic medical pharmacology.”178

Selection and prescription of biologics is more commonly conducted via an electronic health record (EHR) interface known as a CPOE (computerized physician order entry) system. The National Academies defines CPOE as a system that accepts “physician orders (e.g., for medications and for laboratory/diagnostic tests) electronically in lieu of the physician’s handwritten orders on a prescription pad or an order sheet.”179 Prescriptions are one form of orders that are included in CPOE systems.180 CPOE/EHR systems accommodate selection of a medication by brand name, non-proprietary name, or drug class. Entry of a brand name into a CPOE/EHR search field typically yields the dosage forms related to that brand (see Figure 1). If the non-proprietary name is entered, a greater number of results are found, but the listed items will typically not include memorable, product specific identifiers such as manufacturer name or brand (see Figure 2). If a product entered into the CPOE is not on formulary,

Figure 1. Screenshot from a common CPOE/EHR: Results after searching for a brand name

Figure 2. Screenshot from a common CPOE/EHR: Results after searching for a non-proprietary name

178 See American Association of Medical Colleges, Report X, Contemporary Issues in Medicine: Education in Safe and Effective Prescribing Practices 20 (2008). 179 Institute of Medicine, Patient Safety: Achieving a New Standard for Care, 209 (Aspden et al., eds. 2004). 180 Bell et al., A Conceptual Framework for Evaluating Outpatient Electronic Prescribing Systems Based on Their Functional Capabilities, 11 J Am. Medical Informatics Ass’n 60 (2004).

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drugs that are determined to be therapeutically equivalent by a formulary committee are usually provided as available options.

In an effort to standardize electronic prescribing information181 the RxNorm nonproprietary “clinical drug” or “SCD” nomenclature standard (USAN + dosage form + strength) has been designed by the National Library of Medicine to facilitate electronic systems interoperability and with the intent to cover all prescription medicines approved in the U.S.182 The RxNorm standard also accommodates brand names in a “semantic branded drug” format, but this is not obligatory. In the RxNorm SCD standard, the nonproprietary name is the only element that communicates which product is to be dispensed (as vastly different products can have identical dosage forms and strengths). Thus, while the non-proprietary name is not the sole basis of prescribing; it is the primary and most important basis for selecting an appropriate product to fulfill a prescription written using the nonproprietary name.

For those prescribers who may choose to prescribe by brand name, that preference remains undisturbed. Distinguishable nonproprietary names function to facilitate the accurate and clear communication of the product prescribed (and that dispensed), while not impairing the current flexibility accorded to prescribing by other means, such as by brand name.

3. GPhA misinterprets statistics for AE reporting to imply that brand names are used with sufficient reliability.

GPhA claims that a survey privately conducted on its behalf suggested that prescribers would use the brand name in more than 70% of case reports.183 A copy of this survey cited by GPhA has not been posted to the docket,184 so its full context cannot be assessed. Even assuming arguendo, however, that GPhA has completely and accurately reported the findings of this survey, 70% is hardly reassuring since it leaves up to 30% of reports without a brand name. Further supporting that there are gaps in brand name reporting to the SRS, a separate publication by Tufts Center for Drug Development concluded that, on average, only 74% of reports for multisource drugs in the U.S. had accurate product name identifiers.185

In addition, GPhA cites data from analysis of three classes of biosimilars classes to claim that “Europe has been successful at tracking biosimilars which share INNs with their RPPs,” wherein the EU “has a successful product identification rate of 96.2% across all three marketed biosimilar classes”. These claims are derived from a presentation made by Dr. N. Vermeer, a Dutch academic, to a meeting of the EMA on May 25, 2012.186 The Vermeer presentation, in turn, is based on an article on traceability of

181 Pamela Lewis Dolan, E-prescribing Growing in Popularity Across the Country, American Medical News (Oct. 11, 2010), http://www.amednews.com/article/20101011/business/310119972/7/ (accessed Nov. 19, 2013). 182 Liu et al., RxNorm: Prescription for Electronic Drug Information Exchange, IT Pro. Sept–Oct. 2005, at 17 (2005); Nelson et al., Normalized Names for Clinical Drugs: RxNorm at 6 years, 18 J. Am. Medical Informatics Ass’n 441 (2008). 183 See GPhA Pet. 7 n.27 (referencing a privately conducted Brand Institute Study on behalf of GPhA). 184 GphA Pet. Docket posted at www.regulations.gov last accessed December 18, 2013. 185 K. Getz et al., Evaluating_the_Completeness_and_Accuracy_of Medwatch, Am. J. Therapeutics (Sept. 2012), (E- publishing before print), http://journals.lww.com/americantherapeutics/toc/publishahead (accessed Dec. 10, 2013). 186 See Niels Vermeer, Traceability of Biopharmaceuticals in Spontaneous Reporting Systems, presented on May 25, 2012, http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2012/05/WC500127934.pdf (access ed Nov. 19, 2013).

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biopharmaceuticals co-authored by Dr. Vermeer (Drug Safety (2013) 36:617–625).187 GPhA’s statement is inaccurate and misleading for several reasons.

First, GPhA fails to acknowledge the cautious overall conclusions of the Vermeer article. Vermeer and colleagues conclude that the system of tracking biosimilars does not work as well as it should and needs improvement, especially given the expected increase in sales of biosimilars. For example, the article notes that “the INN system . . . cannot be relied upon for product identification of biosimilars.”188 This means that the system needs to rely on other means of identification such as batch numbers. However, those other means might not always function properly. For example, the article states that less than 1 in 4 European safety reports assessed included the batch number and only 5% to 10% of reports for the three biologic classes with marketed biosimilar products included both an identifiable product name and a batch number.189. The degree of caution expressed in the article is incompatible with the unqualified claim of “successful tracing” made by GPhA.

Second, GPhA does not present complete data. The claim of 96.2% success in identifying biopharmaceuticals only relates to a subset of “suspected” biopharmaceuticals among the three product classes with biosimilar competition. For all reports listing those biopharmaceuticals, the identification rate was 90.4%. Moreover, Table 3 of that same study shows variability in rates of AE reports with the presence of identifiable product name by class of biologic: 94.4%, 76.4%, and 88.1% of all reports containing epoetin alfa, filgrastim, and somatropin, respectively, had identifiable product names.190.

When the complete data are considered, the European pharmacovigilance data show that distinguishable nonproprietary names may have a positive effect on product identification in AE reports. Specifically, the EudraVigilance database has a higher rate of product identification in AE reports (94.4%) associated with the one class of biologics that has some degree of distinguishable nonproprietary names (i.e., epoetin alfa, epoetin beta, epoetin zeta). An additional factor that may have contributed to the higher rate for epoetins is that the EMA imposed specific, class-based labeling warnings for the epoetin class to emphasize the need for traceability of AEs.191 Such precautions have only been added selectively to the other two product classes (i.e., for two of four competing filgrastims), and these changes were implemented after the 2010 cut-off date for the Vermeer analysis of EudraVigilance data.

Finally, even allowing for the most favorable statistics in the Vermeer analysis, the conclusion of 96.2% ‘successful’ identification is not merited, because the study did not discern whether or not those products identified were correctly identified.192 We next discuss mechanisms wherein SRS databases may be subject to inflated levels of product identification.

187 The Vermeer article was published online prior to the date of the GPhA petition, but is ignored by GPhA. See Vermeer et al. Traceability of Biopharmaceuticals in Spontaneous Reporting Systems: a Cross-sectional Study in the FDA Adverse Event Reporting System (FAERS) and EudraVigilance databases, 36 Drug Safety 617 (Aug. 2013), abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23771794 (accessed Nov. 18, 2013). 188 Id. at 623. 189 Id. at 621. 190 Id. at 622. 191 See supra Part III.B. 192 Vermeer et al. Traceability of Biopharmaceuticals in Spontaneous Reporting Systems: a Cross-sectional Study in the FDA Adverse Event Reporting System (FAERS) and EudraVigilance databases, 36 Drug Safety 617, 623 (Aug. 2013), abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23771794 (accessed Nov. 18, 2013).

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4. There is evidence that rates of reporting against the innovator brand may be inflated in current practice.

While experience from Europe suggests it may be possible to achieve apparently high rates of brand/invented name identification in AE reports for some product classes, this situation cannot be generalized. Moreover, even the somewhat encouraging statistics for brand name reporting may not tell the full story. In the context of generic drugs, FDA has acknowledged that relatively few AE reports specify a generic manufacturer, and therefore the Office of Generic Drugs receives relatively few AERs.193 As noted previously, there is evidence in the U.S. that a disproportionate proportion of AEs for off patent drugs are misattributed to the originator brand.194

We have identified at least two situations where AE reports may be incorrectly attributed to the responsible manufacturer.

a. Some reports may be erroneously submitted using the originator brand name.

One potential cause for proportional over reporting of AEs to originator brands is due to reference product name recognition by reporters and failure of health record systems to adequately track product manufacturer source, often defaulting to reference product identifiers. We have identified at least one hospital institution in the U.S. where this practice occurs as a result of the manner in which formularies are managed in the electronic health information system. This hospital administers medicines in both the in-patient and hospital out-patient settings, where the latter setting is particularly relevant to the traceability of AEs for commonly used biologics.

Figure 3, depicts how product identifiers used in AE reports from institutions are drawn from EHRs. Absence of product identifiers related to generic products lead to the use of originator product identifiers and mis-attribution of an AE to the originator. The left side of the schematic describes how medication supplies are ordered via wholesalers and ultimately administered to patients following a physician’s order. When a generic supply of a medication is added to the EHR system it takes the place of an originator, without the creation of new fields that clearly identify the new source, essentially allowing the generic to be disguised as the originator when viewed by all users of the system. Changes on formulary when a generic is available typically do not require a formal scientific review, so it is likely that the pharmacist in-charge of medication supply ordering is the only one aware of the generic source for a specific medication.

193 See MaPP § 5240.8 (“Generally, OGD receives few AERs or similar reports since the reports may not specify a generic manufacturer for the drug product.”). 194 See Lietzan et al., Biosimilar Naming: How do Adverse Event Reporting Data Support the Need for Distinct Nonproprietary Names for Biosimilars?, FDLI Food and Drug Pol’y Forum, Vol. 3, Issue 6, March 27, http://www.fdli.org/docs/default-document-library/lietzan-faers-bio-final-3-27-13.pdf?sfvrsn=0 (accessed Nov. 19, 2013).

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Figure 3. Schematic of prescription order entry and fulfillment and subsequent AE reporting at a U.S. medical institution

The right side of the schematic describes how AEs are catalogued, reviewed, and reported in the institutional setting. It is important to note that AEs are typically catalogued with other safety issues (e.g., falls, raised floor tiles, and surgical errors) in a separate safety database not typically interoperable with an institution’s EHR. It is likely that product identifiers entered in the safety database are drawn from memory or from the EHR by the person reporting the AE. An institution’s medication safety officer reviews the AEs and determines which AEs should be reported to the FDA via the Medwatch System. It is usually a hospital pharmacist or sometimes a pharmacy intern that will fill out the Medwatch 3500 report form. Patient, product, AE and reporter related information will be drawn from both the safety database and EHR System to enter these 4 essential components necessary to complete an AE report.

The center of the schematic highlights the role of the EHR in both drug ordering-administration and AE reporting. Failure of the EHR to contain generic product manufacturer information, consequently leads to a failure in accurate AE reporting if an AE arises for a generic product, leading to a report being filed wrongly implicating the originator product and manufacturer.

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It is important to note, institutional ordering for medicines is usually based on non-proprietary name and dosage form. In the future, a distinguishable name would likely force the development of a new line within the EHR system to track each biologic ordered by an institution with distinct manufacturer specific information.

b. Originator companies may process AE reports in such a manner that they are linked to the originator in national databases.

More than 90% of AE reports in the SRS come to FDA through reports submitted directly to manufacturers.195 When the report is ambiguous as to the specific product administered and is submitted to an originator company, it is likely that the report will appear in the FAERS database with clear attribution to the originator product. Specifically, in accordance with the conventions for individual case safety report processing at Amgen, and confirmed to us as standard practice for several other originator companies, reports made directly to sponsor call intake centers with the suspected product identified only by the active ingredient name are “tagged” and are ultimately attributed to our branded product when they are forwarded to the health authority pharmacovigilance system. An exception to this practice occurs when the call intake center solicits and receives disconfirming information from the reporter indicating that the AE was actually associated with a competitor product.

5. In the absence of compelling evidence for high rates of brand name reporting, multisource pharmacovigilance will remain compromised.

The statement that, “Health professionals typically report multiple elements whenever possible and include only the INN as the sole data point less than 30% of the time”196 is a striking admission that nonproprietary names are the sole element in almost 30% of AE reports. If nonproprietary names are anything but distinguishable, this implication of this admission is that the community’s ability to determine the cause of AE reports will be immediately eliminated in 30% of cases. We have demonstrated that analysis of brand name attribution as finally reported to regional pharmacovigilance databases can provide an inflated measure of accuracy of attribution of AEs.

The challenge we face today and that will increase over the next few years is that reports lacking confirmed product identification will undermine the sensitivity of multisource pharmacovigilance. Today, a sponsor that receives an ambiguous AE report will attribute it to their specific product unless clear disconfirming evidence exists. While this has worked historically for single-source biologic medicines, we need to closely examine whether additional steps could make the system more robust as the number of manufacturers expands dramatically worldwide.

To improve the robustness and accuracy of pharmacovigilance in a multisource biologics setting reporters should be encouraged to submit multiple, distinguishable identifiers. In this context, we agree with GPhA. The brand name, if it exists for a product, is a potentially useful identifier. But, given the apparent bias of reporters towards incorrectly using the originator brand in spontaneous AE reporting, additional identifiers are required.

Using ICH E2B standards for the communication of AEs between regions, regulators and industry, it is important to note that entities receiving the reports should make every effort to use the words of the

195 Brian Strom, Potential for Conflict of Interest in the Evaluation of Suspected Adverse Drug Reactions, 92 JAMA 2643 (Dec. 2004). 196 GPhA Pet. at 7.

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reporter verbatim.197 Multiple, reinforcing mechanisms to ensure that reporters (physicians, pharmacists and patients) have access to information specific to the product in question will result in more accurate 198 identification, action and response on the part of industry and government.

G. Contrary to GPhA’s suggestion, NDCs are also insufficient for multisource pharmacovigilance.

The National Drug Code (NDC) is a unique, 10-digit, three-segment identifier that FDA assigns to each medication listed under Section 510 of the U.S. Federal, Food, Drug, and Cosmetic Act.199 The Petitioners claim that NDCs will serve as a reliable backstop to ambiguous or indeterminate product names. This argument is made primarily in the context of the SRS, and here we examine the weaknesses of this claim. However, it is important to consider the role of NDCs in both the SRS and AS, and both pharmacy and non-pharmacy channels.

1. NDCs are not reliable as a product identifier for the SRS.

Regardless of setting of use, NDCs are rarely available to patients and rarely used by physicians, and hence of limited utility as a reliable product identifier to support the SRS. FDA officials have observed that, “while the [MedWatch] reporting system may include a field for NDC, I think it’s very rare we get that level of information.”200 A survey conducted by the Alliance for Safe Biologic Medicines201 determined that only 14% of respondents indicated they would use NDC or a combination of product name and NDC in an AE report.202

NDCs are infrequently used because they do not play a prominent role in drug labeling, prescribing, or record-keeping. NDCs are not required by federal law to appear on product labeling,203 and applicable

197 See ICH, Maintenance of the ICH Guideline on Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports E2B(R2) 19, http://www.ich.org/fileadmin/Public_Web_Site/ICH_Pr oducts/Guidelines/Efficacy/E2B/Step4/E2B_R2__Guideline.pdf (accessed Dec. 16, 2013). 198 Mechanisms could include 1) Redesign of CPOEs along with ‘prescribe by brand name for biologics’ encouraged by med-schools, states, FDA, pharmacy societies, medical societies, 2) Non-proprietary name distinguishable in e- prescribing system for when brand name is not used, 3) NDC easily retrievable in inter-operable EMR, 4) Batch number scanned into dispensing record at pharmacy. These are all independent mechanisms and policies that could improve information transparency. As far as we know, opponents of distinguishable naming are endorsing exactly none of these. 199 See FDA, National Drug Code Directory, http://www.fda.gov/Drugs/InformationOnDrugs/ucm142438.htm (accessed Nov. 19, 2013). 200 See Meeting Transcript, Dkt. No. FDA-2010-N-0477, at 169 (Nov. 2, 2010) (statement of J. Jenkins, Dir. OND, FDA); see also Zelentz, A. et al., NCCN Biosimilars White Paper: Regulatory, Scientific, and Patient Safety Perspectives, 9 J. Nat. Comprehensive Cancer Network S-1, S-14 (Sept. 2011). 201 The Alliance for Safe Biologics Medicines represents diverse stakeholders including patients, physicians, biotechnology companies, including those developing biosimilars, and others. See Alliance for Safe Biologics, http://www.safebiologics.org (accessed Dec. 18, 2013). 202 See Kevin Olson, Alliance For safe Biologic Medicine: Prescriber Survey Aug. 31, 2012, http://safebiologics.org/r esources/wp-content/uploads/2012/09/ASBM-Survey-3.pdf (accessed Nov. 19, 2013). 203 See 21 C.F.R. § 201.2 (“The National Drug Code (NDC) number is requested but not required to appear on all drug labels and in all drug labeling, including the label of any prescription drug container furnished to a consumer.”).

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state laws vary.204 The NDC is rarely found on the labels of dispensed prescription drugs that patients receive.205 Moreover, pharmacy tracking of NDC information is regulated under state law, and the Model State Pharmacy Act and Model Rules of the National Association of Boards of Pharmacy do not require pharmacies to track NDCs.206

Physicians do not prescribe by NDC, and NDCs are not always reported back to a prescribing physician if the patient obtains the prescribed drug from a retail pharmacy. In the physician office or hospital outpatient setting, other identifiers are often used by in-house pharmacies, and when biologics are dispensed by independent pharmacies that do use NDCs, patients fail to bring packaging that may include the NDC to their physician’s office. It is particularly unlikely that AEs related to immunogenicity will be reported using an NDC, because these events can occur weeks or months after the biologic has been administered and the packaging has been discarded.

When considering their use for reporting AE events via the Medwatch 3500 report form, they are typically not included in the majority of reports.207 Furthermore, The ICH E2B communication standard for transmission of AEs does not include a field for NDCs.208 NDCs not only play a limited role in modern surveillance systems, but also are prone to typographical error. The codes are lengthy, and seemingly modest deviations can result in the complete loss of their value as drug identifiers.

NDCs may not always be available and when available, they are prone to error. Ultimately, aside from the question whether brand names or NDCs are adequate backstops, patient welfare will be advanced through redundant identifiers. Multiple sources of information can only benefit patients by increasing the likelihood that immunogenicity trends will be identified.209

204 Some states, such as Florida and California, do not require it, and neither do The Model State Pharmacy Act and Model Rules of the National Association of Boards of Pharmacy. See Model State Pharmacy Act (2013); Model Rules of the Nat’l Ass’n of Bds. of Pharmacy (2013). 205 FDA, Instructions for Completing Form FDA 3500 (April 26, 2013), http://www.fda.gov/Safety/MedWatch/HowT oReport/DownloadForms/ucm149236.htm (“NDC # . . . is usually not found on dispensed pharmacy prescriptions”). 206 See Model State Pharmacy Act (2013); Model Rules of the Nat’l Ass’n of Bds. of Pharmacy (2013). 207 Meeting Transcript, Dkt. No. FDA-2010-N-0477, at 169 (Nov. 2, 2010) (statement of Dr. John Jenkins, Director of Office of New Drugs, FDA) (“while the [MedWatch] reporting system may include a field for NDC number, I think it’s very rare that we get that level of information”); FDA, Instructions for Completing Form FDA 3500, http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/ucm149236.htm (“NDC # . . . is usually not found on dispensed pharmacy prescriptions”). 208 See ICH, E2B(R) Clinical Safety Data Management: Data Elements For Transmissions of Individual Case Safety Reports (May 12, 2005), http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm129399.pdf 209 It has been suggested that the National Library of Medicine RxNorm initiative presents an opportunity to reduce over-specification in prescribing that occurs with reliance on NDCs, by enabling pharmacists to dispense drugs more consistently with prescriber intent. The RxNorm initiative was not intended to address the need for optimal pharmacovigilance in the biosimiar context, and indeed predated enactment of the BPCIA by a decade. Moreover, RxNorm does not address the pharmacovigilance needs unique to biosimilars, because the RxNorm designation for a drug relies on the established name, dosage strength, and dosage form. A prescriber using RxNorm would be unable to specify the drug product intended for a particular patient if non-proprietary names were shared among biosimilars.

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2. NDCs are also not a reliable mechanism for AS in common settings of use for biologics.

NDCs are commonly used in the community pharmacy setting where, in some cases, they can provide accurate and robust product identification for claims databases used in AS. 210 For example, retail pharmacy claim forms under Medicare Part D do include NDCs.

However, as we have demonstrated in Part III, supra, most therapeutic biologics are dispensed and administered in the hospital outpatient or physician office setting where NDCs are rarely used for either dispensing records or for billing transactions. Payer tracking systems do not regularly record the NDCs of biologics dispensed in the hospital outpatient and physician office settings, and federal claims databases do not include routinely NDCs. Specifically, Medicare Part B claim forms for physician- administered drugs—covering the vast majority of administered biologics—are billed by Health Care Common Procedure Coding System (HCPCS) codes, not by NDC. HCPCS codes are less specific than NDCs (which identify manufacturer, drug product and dosage form), and, furthermore, a single HCPCS code may correspond to multiple biologics.211 Also, Medicare and Medicaid inpatient claims typically do not include the NDCs of drugs or biologics administered during hospital treatment212, for which diagnosis codes following the ICD-9-CM standard are used for billing.

NDCs may be reported in some non-pharmacy settings, for example under a state Medicaid program to capture manufacturers’ rebates for physician administered drugs and biologics213, but these codes are not routinely processed into the claims databases.214 Also, “crossover” Medicare-to-Medicaid claims require NDCs for physician-administered drugs, but many state Medicaid agencies report that NDC information never gets transferred.215

When used for billing purposes, NDCs generally display a high degree of inaccuracy, with nearly two- thirds of states having reported difficulties collecting rebates for physician-administered drugs, often because of missing or incorrect NDCs submitted by providers.216 In addition, evidence suggests that

210 See, e.g., FDA, FDA’s Sentinel Initiative, http://www.fda.gov/Safety/FDAsSentinelinitiative/ucm2007250.htm (“The Sentinel System enables FDA to actively query diverse automated healthcare data holders—like electronic health record systems, administrative and insurance claims databases, and registries—to evaluate possible medical product safety issues quickly and securely.”). 211 DiMartino, et al., Using Medicare Administrative Data to Conduct Post-Marketing Surveillance of Follow-on Biologics: Issues and Opportunities, 63 Food & Drug L.J. 891, 896-97 (2008). 212 Id. at 896 (2008). 213 See, Deficit Reduction Act of 2005, S. 1932, 109th Cong. § 6002(a). (titled “Collection and Submission of Utilization Data for Certain Physician-Administered Drugs. Requirement for Submission of Utilization Data for Certain Physician Administered Drugs”). 214 Id. 215 HHS Office of Inspector General, OEI-03-09-00410, States’ Collection of Medicaid Rebates for Physician- Administered Drugs, 20 (Jun. 2011). 216 “Crossover” Medicare-to-Medicaid claims do require NDCs for physician-administered drugs, but many State Medicaid agencies report that NDC information never gets transferred. See Id.

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NDCs recorded in payer tracking systems are often unreliable, either commonly missing, invalid, or coded for the brand name when the generic was administered.217

Taking into consideration the incomplete usage of NDCs in the principle settings of use for biologics, and other reported issues with use of NDCs in reimbursement systems, other mechanisms for biological product identification are necessary to ensure robust, multisource AS in the U.S.

H. Current evidence suggests that while of primary importance, extremely limited reporting of batch numbers renders these data of limited use for purposes of pharmacovigilance.

In the context of the SRS, batch numbers are one of the optional fields that can be provided in voluntary case reports. Batch numbers, when available, are critical for assisting a manufacturer with linkage of a safety issue to specific manufacturing lots, but they are of limited utility, in practice, in helping to confirm the manufacturer of a suspected product that is otherwise ambiguously identified in the voluntary report.

Batch numbers are rarely recorded in dispensing records, and publications have demonstrated that they are available in a small proportion of AE reports in the U.S. For example, a study performed by the Tufts Center for Drug Development examined MedWatch reports between 2005 and 2010 for several product classes, including biologics and chemical drugs, and determined that batch numbers were completed in only 9% of reports.218 A similar study by Vermeer et al. covered FAERS from 2004 to 2010 and determined that batch numbers were available in 24.0% of reports for biotherapeutics, and 7.4% for chemical drugs.219

Furthermore, batch numbers are only usable in conjunction with an accurate product name because, if a report goes to a party other than the responsible manufacturer (eg, to another manufacturer or directly to regulators), it would be difficult for that party to assign a product based on only a batch number and non- proprietary name.

The GPhA claim also ignores the fact that prescribers are often the reporters of AEs, and accordingly, they would be unlikely to be able to confirm the batch number of a product dispensed at a pharmacy. For example, Vermeer noted that when physicians reported the AE in FAERS batch numbers were available in only 13% of reports versus 23% for pharmacist initiated reports. Furthermore, in European reports for biopharmaceuticals, batch number was included in less than 25% of all reports, and only 5%

217 See Minnesota Department of Human Services Drug Utilization Review Board, Drug Utilization Review Update, http://www.dhs.state.mn.us/main/idcplg?IdcService=GET_DYNAMIC_CONVERSION&RevisionSelectionMethod= LatestReleased&dDocName=id_016840 (accessed Dec. 18, 2013); North Dakota Department of Human Services, General Information for Providers: Medicaid and Other Medical Assistance Programs 43 (Apr. 2012), http://www.nd.gov/dhs/services/medicalserv/medicaid/docs/gen-info-providers.pdf (accessed Dec. 18, 2013) (listing invalid NDC as a common billing error). 218 K. Getz et al., Evaluating_the_Completeness_and_Accuracy_of Medwatch, Am. J. Therapeutics (Sept. 2012), (E- publishing before print), http://journals.lww.com/americantherapeutics/toc/publishahead (accessed Dec. 10, 2013). 219 Vermeer et al., Traceability of Biopharmaceuticals in Spontaneous Reporting Systems: a Cross-sectional Study in the FDA Adverse Event Reporting System (FAERS) and EudraVigilance databases, 36 Drug Safety 617 (Aug. 2013), abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23771794 (accessed Nov. 18, 2013).

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to 10% of reports for biologic classes with marketed biosimilars (e.g., epoetin alfa, filgrastim, and somatropin), included both an identifiable product name and a batch number.220

In the case of important, immunological related AEs for biologics the AE may lag the initial administration of the responsible product by days or months. For example, case studies of immunogenicity and resulting issues with safety or loss of efficacy in epoetins, interferons, or anti-TNF therapeutics demonstrate that full onset of neutralizing antibodies can take months.221 In such a case, the patient may present to the prescriber with symptoms well after the dosage form has been discarded, and it is very unlikely that the batch number information would be available. Therefore, it is especially important that the patient medical record reflects a prescription order with sufficient information to identify the manufacturer.

Finally, in the context of AS, batch numbers are never incorporated into billing information, and so have no utility in either confirming the identity of the administered product or in assisting a manufacturer in tracing a safety signal to specific manufacturing lots.

I. Summary.

We have demonstrated that, due to the reliance of the SRS on human reporters, it is critical that, if possible, reporters should provide multiple product-specific identifiers to reduce the possibility of misidentification due to human or system errors. A brand name, when available, can be one such identifier that is easily retrieved by reporters, but we have shown that NDCs and batch numbers cannot be relied upon as redundant identifiers for spontaneous reports. This leaves distinguishable non- proprietary names as the best remaining option for providing a retrievable identifier that can be used, with or without a brand name, in the spontaneous report. For AS, the NDC is useful primarily for biologics dispensed to patients by pharmacies, but it lacks utility for physician office or hospital administered biologics.

Clearly, the biggest challenges for either the SRS or AS of multisource biologics will lie in the physician office and hospital administered setting. In this context, a 2010 peer-reviewed publication by Hennessy et al summarized the options available for supporting robust, multisource pharmacovigilance of biologics upon the arrival of biosimilars.222 The options included:

1. Assigning different nonproprietary names for multisource biologics with resultant assignment of different HCPCS codes

2. Developing different HCPCS codes for biosimilar products that share the same nonproprietary name

3. Shift billing for physician-administered products from HCPCS codes to NDCs.

4. Establish prospective registries for all biosimilars linked to electronic health data

220 Id. at 621. 221 Casadevall et al., Pure Red-Cell Aplasia and Antierythropoietin Antibodies in Patients Treated with Recombinant Erythropoietin, 346 New England J. Medicine 469 (Feb. 2002). 222 S. Hennessy, CE. Leonard & R. Platt, Assessing the Safety and Comparative Effectiveness of Follow-On Biologics (Biosimilars) in the United States, 87 Clinical Pharmacology and Therapeutics 157 (Feb. 2010).

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5. Ensure that particular providers exclusively use a particular biological product (biosimilar or originator)

The first two options are most feasible in that they would be relatively straightforward for CMS to implement because, under current practice, CMS generally assigns a different HCPCS code to each product that qualifies as a “single-source drug” and a common HCPCS code for all drugs that qualify as “multi-source drugs.”223 The first option would have the additional advantage of providing redundant identifiers (that is, both the HCPCS code and distinguishable non-proprietary name) in the physician office and hospital outpatient settings.224

The third option, shifting of physician administered products from HCPCS codes to NDCs, is impractical because it would require a wholesale change in how physicians and hospitals code claims. It also would likely benefit AS, but as explained, the lack of NDC access by most health care providers (HCPs) would not benefit SRS. Moreover, HCPCS codes are the current standard medical data code set for drugs administered in physician office and hospital outpatient settings,225 and to make a change to a standard medical code set, CMS is required to undertake an exhaustive consensus-building process.226

Registries are expensive projects that should not be required for all biosimilars. Lastly, restricting institutions to only one biologic would reduce choice and be difficult to implement.

Optimal pharmacovigilance cannot be achieved if products share an identical non-proprietary name. In the U.S., precise tracking is not possible if biosimilars share the same non-proprietary name. Because FDA’s SRS does not encompass the separate tracking of products sharing the same non-proprietary name, biosimilars with the same non-proprietary names but different immunogenic profiles will be difficult to distinguish, hampering immunogenicity tracking and “optimal pharmacovigilance.” Further, if there are common non-proprietary names and common HCPCS codes, FDA’s AS system, Sentinel, would also be rendered ineffective in the settings where most biologic medicines are administered (physician office and hospital outpatient settings). Such shared names could mask an increase or qualitative change in AEs with respect to one product but not others, or could lead to the inappropriate attribution of a safety signal to an entire product class.

Nevertheless, GPhA urges that pharmacovigilance will not be compromised because other identifiers, such as brand names and NDCs, can be used to track and trace biosimilars. GPhA ignores the reality that other identifiers often are not used by physicians and patients who report AEs. GPhA’s own petition notes that health professionals report that they include the INN “as the sole data point less than 30% of the time”—but “less than 30%” is still a significant proportion, even assuming self-reported practices accurately reflect actual practices. It is high enough, certainly, to indicate a need for distinguishable non-proprietary names as biosimilars are integrated into the existing pharmacoviligance systems.

223 As an example, Granix® (tbo-filgrastim), a biologic product approved under 351(a) of the PHSA, is considered a “single-source drug” and has received a distinct HCPCS code. See CMS, 2014 Alpha-Numeric HCPCS, http://www.cms.gov/Medicare/Coding/HCPCSReleaseCodeSets/Alpha-numeric-HCPCS.html (accessed Dec. 16, 2013). 224 Note that, to date, CMS has declined to adopt a final policy position as to how it will assign HCPCS codes to biosimilar products. See Medicare Program: Payment Policies Under the Physician Fee Schedule and Other Revisions to Part B for CY 2011; Final Rule, 75 Fed. Reg. 73,170, 73,394 (Nov. 29, 2010). . 225 45 C.F.R. §162.1002(b)(3). 226 See 45 C.F.R. §162.910(c).

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Furthermore, we have provided examples of use of non-proprietary names in institutional CPOE,227 and this was associated with therapeutic interchange and with safety reporting practices where further confounding of attribution of AEs is likely. Therefore, even if patient and prescriber education were implemented to increase use of other identifiers, that education would not mitigate the risk in the immediate term that reports of AEs associated with different manufacturers’ products would be conflated, important safety signals missed, and patient welfare compromised.

Given these issues, FDA official Frank Torti explained the agency’s position in 2008 as follows: “FDA believes that legislation should recognize the potential impact on pharmacovigilance and prescribing and require that [follow-on biologics] be assigned a distinguishable, non-proprietary name for safety purposes.”228

Therefore, in the context of limited reporting with reliable, multiple identifiers, and ready access of the non-proprietary name to most reporters, we believe distinguishable non-proprietary names are a practical and efficient measure to improve traceability.

 Given increased non-proprietary prescribing it will help plug gaps in current reporting (20-30% generic prescribing).

 When ambiguous reports are received by companies, the non-proprietary name might be readily retrieved by the reporter from prescribing records (may help if batch number or NDC are not available to the reporter, eg. prescriber).

 In the context of EHRs, non-proprietary prescription order entries for biologics would not be ambiguous as to choice among non-interchangeable products. Records would reflect the product ordered.

IV. GPhA’S PETITION CONTAINS NUMEROUS OTHER MISCELLANEOUS UNSUPPORTED AND ERRONEUS OBJECTIONS TO USE OF DISTINGUISHABLE NAMES.

A. Contrary to GPhA’s contention, the INN system does use naming conventions to distinguish similar biologics.

1. WHO policy calls for the use of Greek letter suffixes to distinguish some categories of similar products.

Longstanding and current WHO policy has been to assign distinct Greek letter suffixes for glycosylated products having the same sequence, but differing in some aspect of their glycosylation patterns. Application for such a suffix has been voluntary, and is procedurally decoupled from a determination of similarity (or therapeutic equivalence for products regulated under FDCA).

This policy is documented in a 1997 WHO Guideline which states:

227 See supra Part III.F.2. 228 Torti Letter at 3 (emphasis added).

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“In addition for glycosylated compounds: selection of a Greek letter spelt out as a second part of a two-word name for glycosylated compounds with identical amino acid sequence and different glycosylation pattern.”229

And further, in context of recombinant erythropoetins:

“In the case of erythropoietins it was decided to select epoetin together with a Greek letter to differentiate between compounds of the same amino acid sequence as human erythropoietin which vary in the glycosylation pattern. INNs with different amino acid sequence will be named using the –poetin stem and a random prefix.”230

The guidance was reaffirmed in a 2006 update:

“Identification of the group with a stem, e.g. for erythropoietin: -poetin, indication of differences in the amino acid chain by using a random prefix and indication of differences in the glycosylation pattern by another designator, expressed by a Greek letter spelt in full and added as second word to the name (e.g. epoetin alfa (66)). The Greek letters are used in the Greek alphabetical order.”231

The policy was also extended to monoclonal antibodies:

“If future INN applications are received for mAbs with the same sequence as an existing mAb, but different glycosylation, the INN for the later application could be the existing INN but with a terminal beta added. Subsequent Greek letters could be used for further INN for mAbs with this antibody sequence, as for other glycoproteins.”232

As the glycosylated protein naming policy was established well in advance of the advent of biosimilars, WHO revisited the policy in a series of consultation meetings starting in 2006. GPhA cites a portion of FDA’s position in a 2006 consultation, but omits the remainder of the context. At these consultations, WHO reaffirmed its policy that glycoproteins with the same amino acid sequence, but that different glycosylation patterns should receive distinct Greek letter suffixes. Nevertheless, these consultations reflect the tension between the purpose of assigning a scientific name for the active substance and the regulatory considerations regarding interchangeability, tracing and pharmacovigilance.

To close the numerous gaps left by GPhA’s selective recitation, provided below is a more complete account of the evolution in WHO policy over the course of the past several years.

At an informal meeting in 2006, WHO officials and the attending regulators reaffirmed WHO policy of assigning scientific names based on the nature of the biologicals, and not based on the regulatory approval pathway.

229 WHO, Guidelines on the Use of International Nonproprietary Names (INNs) for Pharmaceutical Substances Annex 4 (1997), http://apps.who.int/medicinedocs/pdf/h1806e/h1806e.pdf (accessed Nov. 18. 2013). 230 Id. 231 WHO, International Nonproprietary Names (INN) for biological and biotenchnological substances 7 (2011), http://www.who.int/medicines/services/inn/BioRev2011.pdf (accessed Nov. 18, 2013). 232 WHO, International Nonproprietary Names (INN) Working Group Meeting on Nomenclature for Monoclonal Antibodies (Oct. 6-7 2008), http://www.who.int/medicines/services/inn/ApprovedFinalWHOINNWGroupMeeting NMAreport.pdf (accessed Nov. 18, 2013).

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“INNs should be based, as now, on considerations of molecular characteristics and pharmacological class. No specific process should be introduced for naming biosimilars. INNs for these products should be assigned according to the standard process for naming biologicals. There should be no change in policy and no distinctive INN designation introduced to indicate a biosimilar product.”233

As GPhA notes, FDA agreed with this position at the 2006 meeting.

Notably, however, what GPhA fails to acknowledge is this: Consultations in subsequent years revisited this policy recommendation in light of specific challenges of glycosylated products.

At an Ad Hoc consultation meeting in April 2007, participants debated the applicability of Greek letter suffixes and other identifiers in the context of increasing numbers of structurally related products. The WHO reaffirmed the existing Greek letter policy and also tabled the option of a discretionary manufacturing process code that could be used by regulators in conjunction with the INN to differentiate products.234

“Arguments were made for and against the present practice of including specific Greek letters to differentiate different glycoforms of a given molecular entity (e.g. epoetin). In view of the lack of consensus, no change in the INN nomenclature policy pertaining to post-translational modifications is recommended at this time. The proposal of eliminating the Greek letter therefore should not be considered, even in a prospective manner.”235

“Consideration should also be given to drawing up a list of internationally agreed codes to reflect different production processes (such as E. coli, yeast, CHO cells etc). The use of such codes would not be part of the INN but discretionary, and used in labelling when regulatory authorities wished to distinguish different production systems.”236

At the 45th Consultation in 2008, the discussions from the 2007 Ad Hoc meeting were summarized, and naming considerations were further analyzed. There was discussion of the difficulties faced by the INN committee in evaluating the relevance of glycosylation data for naming suffixes.

An expert also provided details regarding the growing family of recombinant erythropoetins, illustrating the use of the Greek letter suffix system to distinguish among related products.

“Recombinant proteins are used as a therapeutic agent to treat anaemia associated with chronic kidney disease and there are five (INN) forms commercially available – Epoetin alfa, beta, omega, delta and darbepoetin alfa, this latter form having five amino acid substitutions compared with the native form. Differences between these forms involve glycosylation and especially the extent of

233 WHO, WHO Informal Consultation on International Nonproprietary Names (INN) Policy for Biosimilar Products 11 (Sept. 4-5, 2006), http://www.who.int/medicines/services/inn/BiosimilarsINN_Report.pdf (accessed Nov. 18, 2013) 234 WHO, 44th Consultation on International Nonproprietary Names for Pharmaceutical Substances: Executive Summary Appendix 1, (22-24 May 2007), http://www.who.int/medicines/services/inn/FinalConsolidatedExecSum 44INN.pdf (accessed Nov. 18, 2013). 235 Id. 236 Id.

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sialylation which strongly affects the half-life in the circulation. Epoetin delta is derived from a human cell line and so most closely related to the native form.”237

The report mentioned that the biosimilar product Epoetin zeta received a distinct Greek letter suffix based on a presumption of a different glycosylation pattern.238

Following that, at the 46th Consultation, the WHO INN Chair discussed the applicability of the Greek letter suffix system to monoclonal antibodies, and raised the potential pharmacological importance of glycosylation.

“Post-translational modifications such as glycosylation should be identified somehow, e.g. by the use of a Greek letter suffix, as for all glycoproteins. It was further suggested that since the biological impact of posttranslational modifications such as fucosylation can be quite significant, that mAbs even with identical amino acid sequences should be considered different drug substances and therefore should have different INNs; however, it was acknowledged that this would only work if the policy is for those making new mAbs to apply for a distinct INN. The Chair noted that the INN system cannot demand that a manufacturer applies for an INN.”239

Interestingly, this 46th Consultation report discussion on monoclonal antibodies foreshadowed subsequent reports concerning a biosimilar of infliximab. The sponsor applied to the WHO to use the existing INN (a procedure that is not typically undertaken by the INN committee).240 As it is not the role of the INN committee to endorse use of an existing INN no official action was taken on this application. Subsequently, EMA approved the product as a biosimilar and permitted the applicant to use the existing INN, while at the same time stipulating to the existence of differences in glycosylation, including in the level of fucosylation, that correlated to differences in in vitro immunological functions.241 While the EMA judged these differences to be not clinically relevant to the mechanisms of action on the basis of the overall non-clinical and clinical data, this example illustrates the challenges of applying the INN system to biological drug substances.

The 46th Consultation report also included an extensive discussion of the glycosylation differences among epoetins and the relevance to the need to develop a more precise definition of glycoproteins.242 The report also cited the practical difficulties faced by the INN Committee in assessing names for glycosylated proteins:

237 Id. at 4. 238 WHO, 45th Consultation on International Nonproprietary Names for Pharmaceutical Substances: Executive Summary 5 (19-21 Nov. 2007), http://www.who.int/medicines/services/inn/45thINN_ConsExec_summ08.pdf (accessed Nov. 18, 2013). 239 WHO, 46th Consultation on International Nonproprietary Names for Pharmaceutical Substances: Executive Summary 3 (1-3 Apr. 2008), http://www.who.int/medicines/services/inn/46thINNConsultation_ExecSummary.pdf (accessed Nov. 18, 2013). 240 WHO, 54th Consultation on International Nonproprietary Names for Pharmaceutical Substances (1-3 May 2012), http://www.who.int/medicines/services/inn/54th_executive_summary_report_public.pdf (accessed Dec. 7, 2013). 241 EMA, Inflectra: European Public Assessment Report, http://www.ema.europa.eu/docs/en_GB/ (accessed Nov. 19, 2013). 242 WHO, 46th Consultation on International Nonproprietary Names for Pharmaceutical Substances: Executive Summary 4 (1-3 Apr. 2008), http://www.who.int/medicines/services/inn/46thINNConsultation_ExecSummary.pdf (accessed Nov. 18, 2013).

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“It has been discussed before that the INN Expert Group receives very little data in INN submissions concerning the glycoform structure of a glycoprotein, that the extent of the data provided is highly variable and that the Group does not necessarily have the expertise to assess critically the significance of any differences in glycoforms between two biosimilar glycoproteins. In addition, and very importantly, there are no rules as to what constitutes a significant difference. […] Consequently, the Group has taken a conservative view that post-translational modifications such as glycosylation are not going to be identical between any two otherwise similar glycoproteins and have adopted the Greek letter for distinction purposes.”243

At the 50th Consultation, the inherent conflicts in the sustainability of the existing INN policy were illustrated with a discussion of the biosimilar epoetin alfa. The sponsors of two other biosimilar epoetin products, epoetin zeta and epoetin kappa, applied to WHO for, and were granted, a distinguishable INN on the basis of differences in glycosylation relative to the epoetin alfa reference product. The sponsor of a third epoetin biosimilar, HX-575, chose not to apply to WHO for a distinguishable INN and instead received marketing authorization from EMA and permission to use the epoetin alfa INN of the reference product, notwithstanding some differences in the glycosylation pattern. However, another regulatory agency, the Australian Therapeutic Goods Administration, did not agree with the approach taken by EMA, and instead imposed a regional non-proprietary name, epoetin lambda. 244

“It is the responsibility of a company to apply for an INN and unfortunately, the European regulators accepted Sandoz’s own INN assignment of epoetin alfa without question. The WHO has expressed their concern about this situation to the EMA.”245

In this context, the 50th Consultation report extends prior commentary on the increasing complexity of the family of epoetins:

“The document provided structural data on glycosylation that had been gleaned from the scientific literature and from the Definitions for the various epoetins assigned an INN, which come to nine in total (epoetins alfa, beta, gamma, delta, epsilon, kappa, omega, theta and zeta), and proposed to define the various epoetins according to the features of the glycoform structures.”246

This example illustrates that, contrary to the GPhA position, generic product sponsors have not been satisfied with existing WHO policy. Thus, it seems disingenuous to pre-emptively criticize a potential FDA policy on the fallacious basis that it would undermine a (claimed, but non-existent) WHO policy that all biosimilars should have the same INN.

243 Id. 244 WHO, 50th Consultation on International Nonproprietary Names for Pharmaceutical Substances: Executive Summary 4 (18-20 May 2010) http://www.who.int/medicines/services/inn/50thExecutiveSummary.pdf (accessed Nov. 18, 2013). 245 Id. (emphasis added). 246 Id.

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2. GPhA’s citations of historical precedent are misleading in that they conspicuously ignore numerous instances in which distinct INNs have been issued to structurally related biologics sponsored by different manufacturers.

In citing historical examples where structurally similar biologics have shared the same INN, GPhA omits examples where distinct INNs have been issued to structurally related biologics sponsored by different manufacturers. Several examples are listed in Table 1 and Table 2. Some particularly noteworthy situations are described below.

 Interferon alfa-N3, interferon alfa-2A, and interferon alfa-2B are structurally related products with different manufacturing sources and a single brand and license for each version. The established names follow WHO INN conventions.

 Peginterferon alfa-2A and peginterferon alfa-2B are PEGylated versions of the corresponding interferon alfa-2A and interferon alfa-2B, respectively. The established names follow WHO INN conventions. There is a single brand and license for each version and FDA has approved these products for similar indications in treating viral infections.

 Interferon beta-1a and interferon beta-1b are structurally related products with similar, but slightly different amino acid sequences and post-translational modifications. The established names follow WHO INN conventions. There are two branded products for each established name. FDA has approved these four products for similar indications in treating multiple sclerosis.

 Follitropin alfa and follitropin beta are drug substances produced in Chinese hamster ovary cells, but with slightly different glycosylation-related isoform patterns and a single brand and license for each version. The established names follow WHO INN conventions. These products were determined by FDA to be therapeutically equivalent.247

 Although only a single recombinant erythropoietin (epoetin alfa) is currently marketed in the U.S., the WHO INN system has assigned names epoetin alfa, epoetin beta, epoetin delta, epoetin kappa, epoetin zeta, epoetin theta and epoetin omega to various commercialized biotechnological sourced versions of human erythropoietin248 (See Table 2).

o The drug substances in epoetin alfa, epoetin beta, epoetin kappa, epoetin zeta, and epoetin theta are all produced in Chinese hamster ovary cells and have similar (if not highly similar) gycosylation patterns.249

o A product produced in a human cell line, epoetin delta, was previously commercialized in Europe but has been withdrawn from the market.250

247 FDA, Orange Book Preface, http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ucm079068.htm (accessed Nov. 18, 2013) (“Based on available data derived from physico-chemical tests and bioassay, follitropin alfa and follitropin beta are indistinguishable.”). 248 WHO, International Nonproprietary Names, 24 WHO Drug Information 21, 2124 (2010), http://apps.who.int/medi cinedocs/documents/s17753en/s17753en.pdf (accessed Nov. 18, 2013). 249 Id. at 21.

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o Another commercialized product, epoetin omega, is produced in BHK cells, but has not been commercialized in ICH regions.251

o The EMA determined that epoetin zeta is a similar biologic product to epoetin alfa, notwithstanding quantitative and qualitative differences in the glycosylation profile.252

o The Japanese Ministry of Health, Labor and Welfare determined that epoetin kappa is a biosimilar of epoetin alfa.253

250 EMA, Public Statement on Dynepo (epoetin delta): Withdrawal of the Marketing Authorisation in the European Union (Apr. 1, 2009), http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2009/11/ WC500011292.pdf (accessed Nov. 20, 2013). 251 WHO, The Glycosylation Pattern of Epoetins, 24 WHO Drug Information J. 21 (2010). 252 See Retacrit EPAR. 253 PMDA, Products Approved in FY 2009: New Drugs, http://www.pmda.go.jp/english/service/pdf/list/ NewdrugsFY2009.pdf (accessed Nov. 18, 2013).

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Table 1. Examples of Structurally Related Biologically Sourced Products with Differentiated INNs and Associated U.S. Non-Proprietary Names

FDA Brand/Trade Non-Proprietary Original Sponsor Application Name Name Approval Date Number

Alferon N Interferon alfa-N3 Interferon Sciences October 10, 1989 BLA 103158 Injection

Roferon -A Interferon alfa-2A Hoffman LaRoche June 4, 1986 BLA 103145

IntronA Interferon alfa-2B Schering June 4, 1986 BLA 103132

Pegasys Peginterferon alfa-2A Hoffman LaRoche October 16, 2002 BLA 103964

Pegintron / Peginterferon alfa-2B Schering January 19, 2001 BLA 103949 Sylatron

Avonex Biogen May 17, 1996 BLA 103628 Interferon beta-1a Rebif Serono Inc March 7, 2002 BLA 103780

Bayer Healthcare Betaseron July 23, 1993 BLA 103471 Pharms Interferon beta-1b

Extavia Novartis August 14, 2009 BLA 125290

Gonal-f Follitropin alfa EMD Serono September 29, 1997 NDA 020378

Follistim Follitropin beta Organon USA September 29, 1997 NDA 020582

Organon USA Follistim AQ Follitropin beta March 23, 2004 NDA 021211 Incorporated

Note: Shaded rows represent products withdrawn from the market.

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Table 2. Examples of Structurally Related Erythropoietins with Differentiated INNs Authorized in Various Global Regions

Brand/Trade Original INN Sponsor Jurisdiction Name Approval Date

Eprex/Erypo Epoetin alfa Janssen-Cilag 1990 Multiple

NeoRecormon Epoetin beta Roche July 16, 1997 Multiple

Dynepo Epoetin delta Shire March 18, 2002 EMA

Retacrit Epoetin zeta Hospira December 18, 2007 EMA

Silapo Epoetin zeta Stada December 18, 2007 EMA

Binocrit Epoetin alfa Sandoz August 28, 2007 EMA

Epoetin alfa Epoetin alfa Hexal August 28, 2007 EMA Hexal

Abseamed Epoetin alfa Medice August 28, 2007 EMA

Eporatio Epoetin theta Ratiopharm October 23, 2009 EMA

CT Arzneimittel Biopoin Epoetin theta October 29, 2009 EMA GmbH

Epoetin Alfa BS JCR Epoetin kappa January 20, 2010 PMDA254 Injection [JCR] Pharmaceuticals

Epomax / Various non- Epoetin omega Elanex Pharma NA Hemomax ICH regions255

Note: Shaded rows represent products withdrawn from the market.

B. FDA frequently utilizes distinguishable—as opposed to fundamentally “unique”—established names.

1. FDA and other stakeholders have never proposed that structurally related biologics should receive fundamentally “unique” non- proprietary names.

Although FDA referred to “unique” names in posing this question, we believe the term “distinguishable” nonproprietary names more accurately conveys the system of nomenclature that FDA described, given

254 Id. 255 WHO, The Glycosylation Pattern of Epoetins, 24 WHO Drug Information 21 (2010).

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that the names would share common features indicating the shared structure and mechanism of action of the related biologics. The adjective “unique,” in contrast, has the potential to confuse stakeholders regarding the necessary degree of differentiation.

Indeed, contrary to the terminology used in the GPhA petition, we were unable to identify any proposal by FDA or other stakeholders that biosimilars or other structurally-related competing biologic products should have fundamentally “unique” (i.e., no common root) non-proprietary names relative to the originator product in the class. We stipulate that completely arbitrary non-proprietary names, lacking any shared component, could potentially create confusion, increase the possibility of medical errors, and confound pharmacovigilance. A good example of this would be the USAN acetominophan versus the INN paracetamol used in Europe for the same active ingredient.256

FDA has already made clear that it is willing to consider the use of prefixes and suffixes to differentiate similar products. Although FDA has not issued a policy for nomenclature of biosimilars, it has asked about the potential impact of prefixes or suffixes to a common USAN.257 In the questions submitted for public comment in the Federal Register announcing the 2010 Part 15 Hearing:

“If each product were given a unique nonproprietary name, should a distinguishing prefix or suffix be added to the nonproprietary name for a related biological product that has not been demonstrated to be biosimilar, a biosimilar product, or an interchangeable product to facilitate pharmacovigilance? What factors should be considered to reduce any negative impact on the healthcare delivery system related to unique nonproprietary names for highly similar biological products?”258

Moreover, FDA has used distinguishing prefixes on several occasions since it posed this question. Specifically, it has assigned interim established names for several structurally related biologics approved with a full 351(a) application, where a three letter prefix was affixed to the shared USAN. Examples include azo-aflibercept259 and tbo-filgrastim,260 where 3-letter prefixes were assigned to the common non-proprietary root names in order to reduce the possibility of confusion with related products containing the shared root name, and to prevent inadvertent substitution.

2. FDA can and does license products using non-proprietary names that incorporate distinguishing features.

In stating that FDA would be departing from precedent in establishing non-proprietary names incorporating distinguishing features extrinsic to the WHO INN or other common names, GPhA omits several historical examples where FDA has done just that. In particular, FDA has assigned distinguishable established non-proprietary names for estrogens, botulinum toxin, and blood clotting factors. The nomenclature features are not provided in the scientific nomenclature from the WHO INN

256 Hewett et al., Missed Paracetamol (Acetaminophen) Overdose Due to Confusion Regarding Drug Names, 8 Current Drug Safety 203 (2013). 257 Notice of Public Hearing, Approval Pathway for Biosimilar and Interchangeable Biological Products; Public Hearing; Request for Comments, 75 Fed. Reg. 61,497, 61,497 (Oct. 5, 2010). 258 Id. at 61,499. 259 CDER, Proprietary Name Review: BLA 125418 - [xxx]- aflibercept (July 27, 2012), http://www.accessdata.fda.go v/drugsatfda_docs/nda/2012/125418Orig1s000NameR.pdf [hereinafter Aflibercept Proprietary Name Review]. 260 CDER, Filgrastim Proprietary Name Review.

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system, and are instead intended to convey information about the source or nature of manufacture of the drug substance. Several examples are listed in Table 3.

Table 3. Examples of U.S. Non-Proprietary Names that Depart from INN Original FDA Brand/ Trade Non-Proprietary Non-Proprietary Sponsor Approval Application Name Name Name Date Number Kogenate octocog alfa Bayer Corp 1993 BL 103332 FS Genetics ReFacto moroctocog alfa March 6, 2000 BL 980137 Antihemophilic Factor Institute (Recombinant) Not marketed in Baxter Recombinate Prior to 1993 BL 103375 Europe Healthcare Novo October 15, Novoeight turoctocog alfa BL 125466 Nordisk 2013 Baxter Advate octocog alfa July 25, 2003 BL 125063 Antihemophilic Factor Healthcare (Recombinant)- Not marketed in February 21, Xyntha Plasma/Albumin Free Wyeth BL 125264 Europe 2008

Estrogens, Premarin Estrogens, Conjugated Wyeth Prior to 1982 NDA 004782 Conjugated261

Estrogens, Conjugated Not marketed in Teva March 24, Cenestin NDA 020992 Synthetic A Europe Branded 1999 Estrogens, Conjugated Not marketed in Teva Enjuvia May 10, 2004 NDA 021443 Synthetic B Europe Womens C. botulinum type A December 9, Botox onobotulinumtoxinA Allergan BLA 103000 neurotoxin complex262 1991 C. botulinum type A Ipsen Dysport abobotulinumtoxinA toxin-haemagglutinin April 29, 2009 BLA 125274 Biopharm complex C. botulinum Xeomin incobotulinumtoxinA Merz Pharms July 30, 2010 BLA 125360 neurotoxin type A Not marketed in December 8, Myobloc RimabotulinumtoxinB Elan BLA 103846 Europe 2000 Note: Shaded rows represent products withdrawn from the market.

261 There is no official INN for conjugated estrogens, but Premarin® is marketed in the UK and uses the common name “conjugated estrogens”. See Premarin SmPC, http://www.medicines.org.uk/emc/medicine/2232/SPC (accessed Dec. 10, 2013). 262 There is no official INN for botulinum toxins, but various common names have been assigned by European regulators.

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Although GPhA cites several pairs of blood clotting factor products with shared non-proprietary names, it fails to acknowledge that the non-proprietary nomenclature assigned in the U.S. differentiated among structurally related products manufactured through alternate sources and manufacturing processes. The blood clotting factors have had manufacturing related names “antihemophiliac factor (recombinant)” and “antihemophiliac factors (recombinant) plasma/albumin free”. These non-proprietary names are completely unrelated to the INNs which actually vary among the manufacturers, but are the same for the albumin containing and albumin-free versions.

FDA has also established distinguishable suffixes for conjugated estrogens and distinguishable prefixes for botulinum toxins, to reflect different methods of manufacture and the possibility of different compositions of the active ingredients or drug substances.263

C. There is no evidence that historical use of distinguishable nonproprietary names have had adverse impact to safety signal aggregation.

1. Regulators have successfully aggregated safety signals for biologic classes with differentiated names.

The Petitioners assert that the existence of differentiated non-proprietary names would confound the ability to aggregate safety signals. We note that some members of the Petitioners’ trade group, including a subsidiary of one of the Petitioners, have elected to file multiple duplicate MAAs (before such practices were constrained by the EC264) and market the same medicine under multiple brands in EU.265 Given that the Petitioners believe that brand names are more relevant than non-proprietary names for adverse event reports266, this use of multiple brand names poses an additional layer of complexity in post-market surveillance and appears to contradict a stated concern about aggregation of safety signals.

Setting that issue aside, we examine the claim about aggregation of safety signals on its merits. As demonstrated in the previous section there are already examples of differentiated non-proprietary names for biologicals, so examination of their safety-related labeling provisions and updates should resolve the question. We examined publications on safety issues and the labeling of three classes of multisource biologics: alpha interferons and beta interferons in the U.S., and erythropoetins in Europe. In all three examples the medical community and regulators have been able to detect class-based safety signals and take appropriate actions with labeling.

Interferon alfa

Alpha interferons are used to treat certain cancers as well as chronic viral infections. As indicated in Table 1 the product class includes non-PEGylated interferon alfa-2A and interferon alfa-2B, and their PEGylated versions. The FDA reviewed the safety profile of alfa interferons in a 1998 publication and

263 A. Albanese, Terminology for Preparations of Botulinum Neurotoxins What a Difference a Name Makes 305 JAMA 89 (January 2011). 264 The International Pharmaceutical Excipients Council Europe, Commission clarifies position on duplicate MAAs, October 30, 2011, http://www.ipec-europe.org/newsletter.asp?nlaid=265&nlid=19 (accessed Dec. 16, 2013). 265 For example, the Sandoz subsidiary of Novartis has obtained duplicate marketing authorizations for epoetin alfa and filgrastim, branded with either the Sandoz or Hexal trade names. Similarly, Teva Pharmaceuticals has obtained duplicate marketing authorizations for filgrastim, branded under the Teva and Ratiopharm trade names. 266 GPhA Pet. 7-8; Novartis Pet. 3.

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was able to aggregate class based safety signals including flu-like symptoms, fatigue, anorexia, and neurological symptoms.267 As indicated on the FDA website, in 2009 FDA issued class based safety labeling updates for interferons,268 including statements regarding possible risk of stroke, serious retinal detachment, peripheral neuropathy, and pulmonary hypertension. We examined the labels for interferon alfa-2A and interferon alfa-2B and confirmed the associated warnings as well as a common warning regarding risk of depression and suicidal behavior.269 The labels for the PEGylated versions of these products also include the class-based black box warning regarding “fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders.”270

Interferon beta

Beta interferons are used to treat multiple sclerosis. As indicated in Table 1 the product class includes four branded products with interferon beta-1a and interferon beta-1b. It should be noted that the two interferon beta-1a products (Avonex and Rebif) are made via distinct processes, whereas the interferon beta-1b products (Betaseron and Extavia) are manufactured under a shared supply agreement. Walther and Hohlfeld reviewed the safety profile of beta interferons as a class, demonstrating the ability of researchers to aggregate signals for these products.271 The labels for beta interferons include common class-based warnings for seizures and depression and suicide.272

Erythropoietin

Recombinant human erythropoieitins (epoetins) are used to treat anemia associated with several chronic or acute conditions. In the U.S. there are two branded epoetins, manufactured under a common regulatory license and supply agreement. As indicated in Table 2, in Europe there are currently 10 branded epoetins, manufactured by 5 independent sponsors, and identified via 4 distinguishable INNs (epoetin alfa, epoetin beta, epoetin zeta, and epoetin theta). The safety of epoetins has come under scrutiny in the past 10 years resulting in several label revisions for the class.

For example, the following class-based safety updates were included in the EMA labels in Europe since the introduction of biosimilars:

267 K. Weiss, Safety Profile of Interferon-Alpha Therapy, 25 Seminars in Oncology (1 Supp. 1) 9 (Feb. 1998). 268 FDA, New class safety labeling updates for alpha interferon products, Sept. 24, 2009, http://www.fda.gov/ForCons umers/ByAudience/ForPatientAdvocates/ucm181019.htm (accessed Nov. 19, 2013). 269 Intron® Package Insert, http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103132s5161lbl.pdf (accessed Nov. 18, 2013); Roferon®-A Package Insert http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/ 103145s5060LBL.pdf (accessed Nov. 18, 2013). 270 PegIntron™ Package Insert, http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103132s5161lbl.pdf (accessed Nov. 18, 2013); Pegasys® Package Insert, http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/ 103964s5245lbl.pdf (accessed Nov. 18, 2013). 271 EU Walter & R. Hohlfeld, Multiple Sclerosis: Side Effects of Interferon Beta Therapy and their Management, 53 Neurology 1622 (1997). 272 Avonex Package Insert, http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/103628s5206lbl.pdf; Betaseron Package Insert, http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/103471s5125lbl.pdf (accessed Nov. 18, 2013); Extavia Package Insert, http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/ 125290s0000lbl.pdf (accessed Nov. 18, 2013); Rebif® Package Insert, http://www.accessdata.fda.gov/drugsatfda_ docs/label/2013/103780s5140lbl.pdf (accessed Nov. 18, 2013).

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In 2008 EMA concluded a class-based safety review based on published reports of increased risks associated with certain conditions of use of epoetins with kidney disease patients and cancer patients.273, 274 Based on this review EMA updated the SmPCs for ESAs to include provisions for use, warnings and precautions related to managing risks of mortality in cancer patients or in renal anemia patients treated to high hemoglobin targets.275 These measures were included for epoetin alfa (originator and biosimilar), epoetin beta, epoetin delta (since withdrawn from the market), epoetin zeta, and even structurally altered ESAs, darbepoetin alfa and methoxy polyethylene glycol epoetin beta. Epoetin theta was not yet authorized in 2008, but the provisions were included in its SmPC upon authorization in 2009.276

In 2009 EMA required another class based SmPC update following analysis of risk management plans and results of a Cochrane meta-analysis. A meta-analysis, by definition, aggregates safety signals from multiple studies and products and hence this example illustrates that the existence of multiple Greek letter suffixes in ESAs has not impeded aggregation of safety signals for these products. These updates included additional warnings regarding use of ESAs in cancer patients and regarding risks of pure red cell aplasia in hepatitis C patients treated with interferons, ribaviron and epoetins.277 These measures were included for epoetin alfa (originator and biosimilar), epoetin beta, epoetin theta, epoetin zeta, and even structurally altered ESAs, darbepoetin alfa and methoxy polyethylene glycol epoetin beta.278

2. It is also relevant to disaggregate safety signals for related biologics.

GPhA emphasizes the need to aggregate safety signals among a class of related biologics, and as the previous section demonstrated, this important outcome has been successfully supported for several classes of multisource biologics, notwithstanding the historical existence of differentiated non- proprietary naming. However, as discussed in Part II.B, supra, it is also relevant to be able to disaggregate safety signals for multisource biologics due to the possibility that individual members of the class may have intrinsic or emerging safety profiles that differ from the other members.

To reinforce this point we cite a recent published case study of PRCA in a European kidney disease patient who was administered three different ESAs (epoetin theta, epoetin beta, and darbepoetin alfa) in

273 McCullough et al., Cardiovascular Toxicity of Epoetin-Alfa in Patients with Chronic Kidney Disease, 37 Am. J. Nephrology 549 (2013) (explaining that, in controlled clinical trials, chronic kidney disease patients had an increased risk of death, serious adverse cardiovascular reactions, and stroke when administered epoetins to target a hemoglobin level of greater than 11 g/dL). 274 See Aapro et al., Effects of Erythropoietin Receptors and Erythropoiesis-stimulating Agents on Disease Progression in Cancer 106 British J. Caner 1249 (March 2012) (showing that in studies of patients with breast, non- small cell lung, head and neck, lymphoid, and cervical cancers, epoetins shortened overall survival and/or increased the risk of tumor progression or recurrence). 275 See, e.g., EMA Binocrit: Procedural steps taken and scientific information after the authorization, Variation II/0009 8 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Procedural_steps_taken_before_authorisation/h uman/000725/WC500053616.pdf (accessed Nov. 2, 2013). 276 Biopoin SmPC 18, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/huma n/001036/WC500040793.pdf (accessed Nov. 2, 2013). 277 Rossert et al., Risk of Pure Red Cell Aplasia in Patients With Hepatitis C Receiving Antiviral Therapy and an Erythropoiesis-stimulating Agent, Clinical Gastroenterology Hepatology (Oct. 9, 2013) (E-publishing before print). 278 See, e.g., EMA Binocrit: Procedural steps taken and scientific information after the authorization, Variation II/0018 (Jan. 20, 2010), http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Procedural_steps_taken_and_scie ntific_information_after_authorisation/human/000725/WC500053682.pdf (accessed Nov. 2, 2013).

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the course of a year of therapy before the diagnosis of PRCA was confirmed and ESA therapy was appropriately stopped.279 Based on other clinical and diagnostic markers in the patient’s medical history the study authors attributed the initiation of immunogenicity to the first administered ESA, epoetin theta. They concluded that subsequent switching of the patient between ESAs had been counterproductive to the investigation and management of care, but that it was nonetheless essential that there had been clear identification of the three biologics in the patient’s record.280 This case illustrates how failure to disaggregate signals within a therapeutic class would have been a disservice to the patient, the health care providers, and to the pharmacovigilance system in Europe.

D. There is no compelling evidence that distinguishable nonproprietary names would have adverse impact to medical practice.

1. Practitioners are familiar with distinguishable names for biologics, and would properly interpret such names for biosimilars.

GPhA suggests that differentiated non-proprietary names will somehow confuse prescribers. The evidence, however, suggests otherwise. As stated previously,281 for therapeutic classes such as interferons, blood clotting factors, reproductive hormones, and botulinum toxins there is a long history of products approved by FDA with similar, but differentiated non-proprietary names. Endocrinologists, hematologists, and neurologists are well acquainted with the complexity of biologics and with the fact that there are pharmacologically similar products with related non-proprietary names.

The core of the Petitioners’ assertion is a claim that important safety information for the class of biologics would be “decoupled” by the distinguishable non-proprietary name. In order for this to be the case HCPs would somehow not be able to apply class-based pharmacology to a member of the class as a result of the appended suffix or prefix. It is difficult to give this assertion credence given that medical literature commonly discusses mechanism-based safety information that covers disparate members of a pharmacological class (i.e., bearing unique INNs, but sharing a common INN stem such as “statin”). Moreover, as discussed in Part IV.C, supra, regulators have successfully incorporated appropriate class- based warnings and precautions in to the prescribing information for families of structurally related biologics.

The Petitioners’ unsupported claim about ability to apply class-based safety information also ignores the alternative possibility that specific biosimilar products may have product-specific safety information of relevance to prescribers. In this situation a differentiated non-proprietary name might help avoid a presumption that the biosimilar has identical conditions of use, warnings and precautions to other products that would otherwise share a non-proprietary name.

A biosimilar is licensed on the basis of a demonstration of biosimilarity to only a single reference product. Biosimilars are not necessarily biosimilar to each other or to other innovative products with the same non-proprietary name. Indeed, the misperception that biologics that share the same non-

279 Clemens Wieser & Alexander R. Rosenkranz, Pure Red Cell Aplasia After Treatment of Renal Anaemia with Epoetin Theta, 6 Clinical Kidney J. 539 (2013). 280 Id. at 541 (“After a series of different products has been administered, the PRCA-triggering product can only be identified if the accompanying severe anaemia and/or antibodies have been detected before the switch. Therefore, traceability of all ESAs given to a patient is essential.”). 281 See supra Table 1.

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proprietary name are the same to each other is an important reason to require distinguishable non- proprietary names. Distinguishable names will help to mitigate the risk of prescribing errors, inappropriate automatic substitution and inappropriate attribution of safety signals associated with a single product to an entire class.

GPhA also suggests that medical errors could occur because HCPs would somehow fail to apply important safety information for the class of related biologics to a biosimilar product with a differentiated non-proprietary name. This, too, is erroneous. Distinguishable non-proprietary names that include a shared root will show that the products are related yet still distinct. They would thus permit HCPs and patients to identify related products. Moreover, most biologics are injectable or intravenously supplied medications that are administered in a hospital or clinic setting. HCPs will be aware of the various biosimilars and reference products available. A physician would need to actually prescribe two biosimilars of the same reference product, or both a biosimilar and a reference product, in an outpatient setting for an inadvertent double-dosing or similar medical error to occur due to prescriber confusion.

The Alliance for Safe Biologic Medicine conducted a survey of prescribers in 2012. Approximately 376 U.S. prescribers of biological products across a wide array of specialty areas participated in the survey. The majority (67%) of respondents indicated that they would interpret biosimilars with identical non- proprietary names as being interchangeable with the reference product.282 The American Academy of Dermatology Association issued a position statement advocating for unique non-proprietary names “to eliminate confusion, to allow providers to accurately track the therapeutic effect in a patient’s permanent record, and to allow for the collection of adverse event information.”283 Similarly, the American College of Rheumatology endorsed that “Biosimilars should have distinct names allowing them to be distinguished from their reference products.”284 These results flatly negate the theory that HCPs who prescribe biologics would be confused by differentiated non-proprietary names, especially where they are used for non-interchangable biosimilars.

2. There is no evidence that distinguishable, but clearly related names for similar drug substances would increase the possibility of medication errors.

With regard to the potential for medication errors, there is no need to speculate. There are existing publications on the common sources of medication errors. To the extent these are attributed to drug nomenclature the cause is typically associated with confusion over similar brand names for pharmacologically unrelated compounds, or for disparate brand names for pharmacologically related compounds.

There are also a few examples of medication errors associated with similar non-proprietary names, but these situations occurred when pharmacologically distinct products shared similar INN or USAN syllables. For example, the USAN for “amrinone” was changed to “inamrinone” in response to reports

282 See Kevin Olson, Alliance For Safe Biologic Medicine: Prescriber Survey (Aug. 31, 2012), http://safebiologics.org /resources/wp-content/uploads/2012/09/ASBM-Survey-3.pdf (accessed Nov. 18, 2013). 283 American Academy of Dermatology and AAD Association, Position Statement on Genetic Therapeutic & Biosimilar Substitution (as amended by the Board of Directors August 3, 2013), http://www.aad.org/forms/ policies/uploads/ps/ps-generic%20therapeutic%20and%20%20biosimilar%20substitution.pdf (accessed Nov. 18, 2013). 284 American College of Rheumatology, Position Statement: Biosimilars, http://www.rheumatology.org/Practice/ Clinical/Position/Position_Statements/ (accessed Nov. 18, 2013).

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of medication errors associated with confusion with another active ingredient “amiodarone.”285 Another example of the non-proprietary name causing a potential for overdosing is the unusual circumstance that the active ingredient of Tylenol is known as acetominophan in some regions, including the U.S., and as paracetamol elsewhere.286 As the only biologics nomenclature proposals that we are aware of concern distinguishable names with common roots, where the products are pharmacologically related, we don’t believe that either of the above-mentioned examples of USAN/INN confusion are applicable.

Review articles that discuss medication errors tend to emphasize that brand names are the source of confusion, either because similar products may have dissimilar brand names (and hence result in excessive dosing), or because dissimilar products have similar brand names. Schwab et al. note that exclusive use of brand names is a common source of medication errors, and cite a case of overdosing with verapamil due to brand name confusion.287 Hoffman and Proulx describe other examples of brand name confusion and list dozens of examples of confusing name pairs, none of which involved biologicals with different suffixes.288

In summary, GPhA’s allegation that distinguishable non-proprietary names could create confusion or increase risk of medication errors is unsupported based on reviews of documented errors.

E. GPhA makes an overly simplistic claim that case report investigators can simply contact the prescriber or pharmacist to obtain product dispensing data.

The Petitioners assert that the FDA “typically contacts the physician and then checks with the pharmacist to determine the product's manufacturer and precise batch information. This specific information, not the product's INN, enables FDA and the actual manufacturer to investigate possible causes of the AE.”289 This argument misses several important aspects of AE reporting.

First, most290 AE reports are received by manufacturers initially, and then are investigated, processed and forwarded to national health authorities such as FDA. As the manufacturer is required to make any patient identifier information anonymous in a forwarded report, it would be difficult for a 3rd party to contact the physician or pharmacist for more specific product identification data.

Second, case reporters are often prescribers or patients, not the pharmacists.291 Even if such reporters provide contact information for an investigator to follow-up for more details, the investigator (whether

285 Carlos Rados, Drug Name Confusion: Preventing Medication Errors, FDA Consumer Magazine July-August 2005, http://permanent.access.gpo.gov/lps1609/www.fda.gov/fdac/features/2005/405_confusion.html (accessed Nov. 18, 2013). 286 Hewett et al., Missed Paracetamol (Acetaminophen) Overdose Due to Confusion Regarding Drug Names, 8 Current Drug Safety 203 (2013). 287 Schwab et al., Using Trade Names: a Risk Factor for Accidental Drug Overdose, 162 Archives Internal Medicine 1065 (May 2002). 288 JM Hoffman & SM Proulx, Medication Errors Caused by Confusion of Drug Names, 26 Drug Safety 445 (2003). 289 GPhA Pet. 7. 290 See, e.g., Brian Strom, Potential for Conflict of Interest in the Evaluation of Suspected Adverse Drug Reactions 292 JAMA 2643 (Dec. 2004) (reporting that more than 90% of AERs come to FDA through manufacturers). 291 See FDA, FDA Adverse Event Reporting System (FAERS) (formerly AERS), http://www.fda.gov/Drugs/ GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/default.htm (noting that FDA receives adverse event reports from multiple sources, including physicians, pharmacists, nurses, patients, family members, and

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at FDA or the manufacturer) is not permitted to request or record unique patient identifier information such as name, social security number, or medical billing account number.292 Therefore, it is not possible for the investigator to contact a pharmacist for more details about the medicines dispensed: even aside from health care privacy compliance considerations, a pharmacist would be unable to provide such information for an anonymous patient. The case investigator might request that the original case reporter follow-up with the pharmacy to retrieve the requested information, and in some cases this may entail obtaining additional permission from the patient to contact the pharmacy.

Therefore, while it may be possible that a case reporter other than a pharmacist could be convinced to follow-up with the pharmacy to obtain the details suggested by GPhA, it is not likely that FDA or a manufacturer could do so directly.

F. GPhA makes an overly simplistic claim that reporters can simply read a product label to obtain the needed information.

The GPhA petition asserts that “Current regulations require the manufacturer's name on the product label, and GPhA member companies are committed to labeling biosimilar products with their corporate names and/or product proprietary (brand) names.”293 This argument relies on the fiction that all relevant AEs will occur in chronological proximity to the dose administration, and that the container or packaging would therefore be available.

In reality, however, systems that rely on product labels or pictures of product labels294 to aid AE reporting associated with biologics have only limited utility, because adverse reactions to biologics can be mediated by immunogenic reactions and thus may have an onset of symptoms months or years after initial administration of the causative agent, 295 which is likely well after the patient or biologic- administering HCP would have disposed of the packaging and package inserts associated with that particular biologic administration.

G. GPhA presents a overly simplistic and irrelevant comparison between common manufacturing changes and management of multisource biologics.

When considering treatment of manufacturing process changes under a naming policy, it is important to consider both the nature of the change and the intended purpose of the naming policy. There are at least two reasons—both supported by precedent—for distinguishable proprietary names to be assigned for biosimilars and structurally related biologics. As discussed in Part IV.A.1, supra, the non-proprietary name might be associated with a scientific determination by the WHO INN committee that the active substance has distinguishable attributes (e.g., sequence or post-translational modifications). Alternatively, as discussed in Part IV.B.1, supra, public health authorities such as FDA or the USAN Committee may consider the use of non-proprietary names to distinguish among similar products

lawyers); see also, Syed Ahmad et al., Spontaneous Reporting in the United States, in Pharmacoepidemology, 135- 159 (Brian L. Strom Ed., 2007). 292 See, e.g., 21 C.F.R. § 314.80(h) (“An applicant should not include in [adverse event reports] the names and addresses of individual patients.”). 293 Id. 294 Id. 295 Casadevall et al., Pure Red-Cell Aplasia and Antierythropoietin Antibodies in Patients Treated with Recombinant Erythropoietin, 346 New England J. Medicine 469 (Feb. 2002).

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produced using different methods, and without direct reference to WHO INN naming rules. In the latter case the purpose may be to ensure product identification and traceability. When discussing the relevance of product nomenclature to manufacturing process changes, it is helpful to consider these two situations and their applicability in turn.

Furthermore, it is important to take into consideration that, in contrast to process-change scenarios for a single-source biologic, a biosimilar product is intended to be marketed in parallel to the originator product and other biosimilars on an ongoing basis. This ongoing, multisource pharmacovigilance challenge cannot be addressed with measures that might otherwise be suitable for risk management of process change for a single-source biologic. Thus, in terms of the public health concerns, the biosimilar product that may be assigned a distinguishable name is not similarly situated to the post-change originator product.

1. Applicable EU regulatory standards for biosimilars and products undergoing manufacturing changes are not the same.

GPhA claims that the “highly similar” standard is “already being successfully used for biosimilar approval (as well as manufacturing changes to biosimilars) in other highly regulated markets.” In fact, the regulatory standards for reviewing manufacturing changes and for authorizing biosimilar applications in the EU are not the same.

The legal basis for reviewing manufacturing changes is Article 35 of the Medicinal Products Directive (Directive 2001/83, as amended). Procedural requirements are set out in the Variations Regulation,296 and there is specific EMA guidance containing material requirements, which notes specifically that it relates to “manufacturing process changes . . . made by a single manufacturer, including those made by a contract manufacturer, who can directly compare the processes, analytical in-process data and results from the analysis of pre-change and post-change product.”297 By contrast, biosimilar applications are based on Article 10.4 of the Medicinal Products Directive, and are subject to a range of general and product-specific guidelines which take account of the fact that the biosimilar applicant and the manufacturer of the reference product are not the same company. For instance, Article 10.4 sets out: “… biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the biological medicinal product and the reference biological medicinal product”.

In addition, for biosimilars there is no clear legal standard of comparison in EC statutes. In fact, the text of the EU Medicinal Products Directive contains no regulatory standard of comparison at all. Article 10.4 of the Medicinal Products Directive merely states that, if a biological medicinal product is not a generic, the applicant must submit “appropriate pre-clinical tests or clinical trials” in accordance with European guidance. In the relevant product-specific EMA guidelines, 298 a wide variety of standards of

296 Commission Regulation 1234/2008, 2008 O.J. (L 334) 7. 297 EMA, Guidelines on Comparability of Biotechnology-Driven Medicinal Products After a Change in the Manufacturing Process (19 Jul. 2007), http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_ guideline/2009/09/WC500003935.pdf (accessed Nov. 18, 2013). 298 EMA, Scientific Guidelines: Biosimilar, http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/ general_content_000408.jsp (accessed Nov. 18, 2013).

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comparison is used, ranging from “a similar profile in terms of quality, safety and efficacy” 299 to a “demonstration of “comparability”300 to “demonstration of comparable quality efficacy, and safety” 301 to a “demonstration of similar nature.”302 It is precisely because of this lack of a clear legal standard that the EMA is currently drafting a new guideline with a clearer and more consistent definition.303 Until a proper legal standard has been adopted in the EU, it is simply not possible to make statements such as those made by GPhA.

2. As a scientific matter, structural differences between two related biologics can merit distinguishable non-proprietary names.

To the extent that USAN nomenclature is derived from the scientific name (INN), it would be legitimate, and consistent with precedent, for two related products to have distinguishable nomenclature, even if they are considered therapeutically similar or equivalent. We have described the current WHO INN policy for glycosylated proteins in Part IV.A, supra. The WHO naming policy is used only to support taxonomy based on measureable structural attributes of the drug substance, and is not informed by the presence or absence of pharmacological and clinical similarity. Thus, WHO has historically assigned distinguishable names for therapeutically equivalent glycoproteins (e.g., follitropins) and for products subsequently shown to be biosimilar to (e.g., epoetin zeta and epoetin kappa).

3. Most process changes do not result in analytically distinguishable product profiles.

GPhA cites a publication showing the number of process change variations approved for certain EU- authorized biological products.304 For example, the cited publication mentions 37 process changes for Remicade (infliximab).305 GPhA uses this example in an attempt to support a claim that FDA should first address concerns associated with shared nonproprietary names for U.S. licensed products, such as

299 EMA, Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues (Feb. 22, 2006), http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_ guideline/2009/09/WC500003953.pdf (accessed Nov. 18, 2013). 300 EMA, Annex to Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Non-clinical and Clinical Issues. Guidance on Similar Medicinal Products Containing Recombinant Human Soluble Insulin (Feb. 22, 2006), http://www.ema.europa.eu/docs/en_GB/document_library/ Scientific_guideline/2009/09/WC500003957.pdf (accessed Nov. 18, 2013); EMA, Reflection Paper: Non-Clinical and Clinical Development of Similar Medicinal Products Containing Recombinant Interferon Alfa (Apr. 23, 2009), http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003930.pdf (accessed Nov. 18, 2013). 301 EMA, Guideline on Similar Medicinal Products Containing Interferon Beta (Feb. 21, 2013), http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/03/WC500139622.pdf (accessed Nov. 18, 2013). 302 EMA, Guideline on Non-clinical and Clinical Development of Similar Biological Medicinal Products Containing Low-Molecular-Weight Heparins (March 19, 2009), http://www.ema.europa.eu/docs/en_GB/document_library/ Scientific_guideline/2009/09/WC500003927.pdf (accessed Nov. 18, 2013). 303 See EMA, Draft guideline on Similar Biological Medicinal Products (May 22, 2013) http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/05/WC500142978.pdf. 304 GPhA Pet. 5 n.19. 305 Christian Schneider, Biosimilars in Rheumatology: The Wind of Change, 72 Annals Rheumatic Diseases 315 (March 2013).

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infliximab, that have experienced relatively frequent process changes.306 However, this citation is used out of context: the author described these historical process changes in order to draw parallels with the rigor of EMA’s pre-approval standards for biosimilars.307 At no point did the author question the measures that the EC and the EMA have taken to enhance traceability of multisource biologics.

Furthermore, in asserting that FDA should impose additional traceability measures to manage such process changes, GPhA has not demonstrated that each of these changes were associated with scientifically relevant shifts in the quality profile of the product. In reality, as the statistics cited in the cited publication demonstrate, process related changes are fairly routine, occurring approximately 1 to 2 times per year for many of the products.308 The source of these statistics is the EMA European Public Assessment Report system which provides transparency to regulatory actions taken for drugs and biologics.309 This system includes tabular lists of changes implemented after authorization. These lists are also available for biosimilars authorized by the EU. We have examined several of these to confirm that, since 2007, Omnitrope310 (somatropin), Retacrit311 (epoetin zeta), and Binocrit312 (epoetin alfa) had 7, 5, and 10 process or drug product presentation variations, respectively. Based on these examples, it appears that variations are quite common for both originator and biosimilar products.

What matters, and what GPhA has not addressed, is the relevance of these changes to post-approval monitoring of the products. The EPAR lists provide cryptic descriptions of the changes313 (e.g., “change to the process for active substance”), and hence do not convey meaningful information about the nature or extent of change, the attendant risks to quality, safety or efficacy, or if any measurable shifts in quality attributes were observed. It is difficult to imagine that regulators would permit measurable shifts in product quality on an annual basis, so these “variation counts” are not informative about the need for enhanced pharmacovigilance for these products following a particular change.

It is unclear how the WHO INN policy for glycoproteins should apply to process change that does not result in measurable shifts in quality attributes. In the absence of such a shift, there is no scientific basis for a sponsor to apply for a distinguishable INN.

306 GPhA Pet. 6. 307 Christian Schneider, Biosimilars in Rheumatology: The Wind of Change, 72 Annals Rheumatic Diseases 315 (March 2013). 308 See id. at 316. (Showing 37 changes for Remicade since 1999 and 21 for Enbrel® since 2000). 309 See id. (“All information taken and analyses made from data published in the EPAR.”). 310 EMA, Omnitrope: Procedural steps taken before authorisation, Sept. 2, 2013, http://www.ema.europa.eu/docs/ en_GB/document_library/EPAR_-_Procedural_steps_taken_and_scientific_information_after_authorisation/human/ 000607/WC500043694.pdf (accessed Nov. 18, 2013). 311 EMA, Retacrit: Procedural steps taken before authorisation, Sept. 12, 2013, http://www.ema.europa.eu/docs/ en_GB/document_library/EPAR_-_Procedural_steps_taken_and_scientific_information_after_authorisation/human/ 000872/WC500054376.pdf (accessed Nov. 18, 2013). 312 EMA, Binocrit: Procedural steps taken before authorisation, Nov. 6, 2013, http://www.ema.europa.eu/docs/ en_GB/document_library/EPAR_-_Procedural_steps_taken_and_scientific_information_after_authorisation/human/ 000725/WC500053682.pdf (accessed Nov. 18, 2013). 313 EMA, Retacrit: Procedural steps taken before authorisation, Sept. 12, 2013, http://www.ema.europa.eu/docs/ en_GB/document_library/EPAR_-_Procedural_steps_taken_and_scientific_information_after_authorisation/human/ 000872/WC500054376.pdf (accessed Nov. 18, 2013).

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4. If a process change resulted in an analytically distinct glycosylation profile it could be consistent with WHO policy for the resulting drug substance to have a distinct Greek letter suffix.

FDA has not historically required U.S. sponsors to seek a new INN / USAN based on post-approval changes in glycosylation pattern, even when such changes were of such magnitude that the sponsor to file a new license application. For example, in 2007 the sponsor of Myozyme (Alglucosidase alfa) filed an sBLA seeking approval for a manufacturing scale change, which previously had been unsuccessfully filed in 2005 as part of the original BLA. FDA noted that the product manufactured at the larger scale exhibited an altered glycosylation profile and the agency requested additional clinical bridging studies to evaluate the impact. The agency concluded that the post-change product was not clinically comparable to the pre-change product that was tested in the pediatric condition of use. Therefore, the sponsor submitted a new 351(a) application for the product manufactured at the larger scale, and was granted the condition of use in the adult patient population. This new product has a different brand name (Lumizyme), but was permitted to use the same non-proprietary name. In this example it might have been consistent with existing WHO INN glycoprotein naming policy, and within FDA’s authority, to have requested that the sponsor apply for a distinguishable non-proprietary name for Lumizyme.

For practical reasons discussed below, we do not take a position as to whether there should be a common standard for applying the historical WHO Greek letter suffix policy for glycoproteins equally to biosimilars and to applicable manufacturing changes.

5. The WHO has determined that the Greek letter suffix system is no longer sustainable or enforceable.

In recent INN Committee public consultations, WHO has communicated that the historical policy of assigning distinct Greek letter suffixes to INNs for glycoproteins is neither sustainable nor enforceable in the context of biosimilars.

First, with the proliferation of multiple manufacturers of intended copies of off-patent originator biologics, there would likely be an exhaustion of the available Greek letters if all parties applied for a distinguishable INN.314 This does not take into account the possibility of manufacturing changes involving significant shifts in glycosylation profile, which could put further pressure on the INN Greek letter system.

Second, with a diverse set of structurally related, but not identical, products, there would be increasing difficulty in assigning a precise definition of the glycosylation attribute space to any given Greek letter.315 In many cases, the original INN application lacked a precise Definition for the glyosylation profile of the reference product, leaving it up to third parties or the INN Expert Group to determine whether a structurally related product merits the use of a distinguishable Greek letter. The INN Expert Group is not well situated to adjudicate the complexity of such a classification system, even assuming it

314 WHO, 55th Consultation on International Nonproprietary Names for Pharmaceutical Substances: Executive Summary 3 (16-18 Oct. 2012), http://www.who.int/medicines/services/inn/55th_Executive_Summary.pdf (accessed Nov. 18, 2013). 315 WHO, 50th Consultation on International Nonproprietary Names for Pharmaceutical Substances: Executive Summary 4 (18-20 May 2010), http://www.who.int/medicines/services/inn/50thExecutiveSummary.pdf (accessed October 30, 2013).

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were scientifically possible. This is because they lack specific, side-by-side data on the reference product and subsequent biologics.

Third, the INN Expert Group has noted that it is entirely dependent on national regulatory authorities to enforce the use of the INN naming policy. When sponsors developed stand-alone competitor glycoprotein products with separate brands and evidence packages, they have been willing to apply for a distinguishable INN from the original (e.g “alfa”) product (e.g., epoetin beta, epoetin delta). However, when sponsors develop a biosimilar there may be a understandable reluctance to draw attention to any analytical differences via the INN nomenclature. No sponsor is obligated to apply for a new INN if national regulatory authorities believe that an existing INN would be suitable. In this context, the WHO has expressed disappointment that regulators have not referred certain biosimilar product sponsors to the INN Expert Group.

GPhA also asserts that the decision and criteria for product nomenclature should relate to a regulatory determination of “similarity” or “comparability,” thereby equating the bases of nomenclature for new biosimilars or for post-approval process changes.316 We have demonstrated that such a regulatory determination is not relevant to WHO’s historical INN nomenclature system, which is based purely on taxonomic rules for differentiating glycosylation profiles (irrespective of potential impact to safety or efficacy). Furthermore, the Greek letter scientific naming system cannot be sustained or enforced by WHO. Therefore, the analytical “similarity” or “comparability” cannot be the sole basis for evaluating the applicability of nomenclature rules to the two situations: post-approval process changes and new biosimilar product approvals.

6. As a matter of public health policy, distinguishable non-proprietary names for biosimilars need not be linked to the formal scientific criteria for distinguishable INNs.

In the absence of purely scientific criteria for naming rules, other considerations may apply that will distinguish process changes from biosimilar approvals. Specifically, national health authorities may determine that distinguishable nomenclature is required merely to avoid involuntary interchange of non- interchangeable members of a class of multiple versions of biological products, or to address pharmacovigilance problems.317 In this context, a manufacturing process change and a new biosimilar product approval represent very different situations.

316 GPhA Pet. at 4-5. 317 As Petitioners are aware, biosimilar substitution is not addressed in most current pharmacy laws, which instead are limited to the substitution of drugs approved under the Food, Drug, and Cosmetic Act. (other than the states that have recently enacted amendments to include). As biosimilars are not addressed, it is simply not the case that some sort of naming pre-requisite to biosimilar substitution exists. Based on the BPCIA definition of interchangeable, codified at 42 U.S.C. § 262(i)(3), and as reiterated by FDA, the key consideration, at least from a federal perspective, is whether FDA has determined the biological product to be interchangeable. See Biologics Price Competition and Innovation Act § 7002(b), 42 U.S.C. § 262 (amending the Public Health Service Act to add the definition of interchangeable at §351(i)(3), as meaning that “the biological product may be substituted for the reference product without the intervention of the healthcare provider who prescribed the product”); Kozlowski, et al., Developing the Nation’s Biosimilars Program, 365 New England J. Medicine 385 (Aug. 2011) (noting FDA’s intent to develop standards to ensure that products not deemed by FDA to be interchangeable are not inadvertently substituted for the reference product without the prescriber’s consent.)

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The WHO INN Committee has discussed options for identifying multiple versions of biological products.318 As discussed in Part IV.G.5, supra, the Greek letter system was considered and rejected as not sustainable.319 An alternative concept discussed by the WHO INN Committee is to assign a unique identifier code to be added to the INN for each biosimilar product.320 This code could be incorporated into a regionally assigned non-proprietary name to enhance identification and traceability of the product. This concept is similar, in principle, to biosimilar identifier policies implemented in Japan321 and recently proposed for implementation in Australia.322 It is also conceptually similar to the 3-letter prefix recently assigned by FDA to several related biologic products. 323

When the public health (eg, product identification and traceability) rationale for nomenclature is applied in the context of a post-approval change, the arguments made by GPhA lose relevance. Further damaging are emerging data from both Japan and Australia that the use of a distinguishable name is neither a detriment to biosimliars utilization or uptake.324

Most process changes are incremental, do not result in significant shifts in quality attributes outside of the historical experience with the product, and do not require clinical bridging studies.325, 326 Regulatory

318 WHO, 55th Consultation on International Nonproprietary Names for Pharmaceutical Substances: Executive Summary (16-18 Oct. 2012), http://www.who.int/medicines/services/inn/55th_Executive_Summary.pdf (accessed Nov. 18, 2013); WHO, 56th Consultation on International Nonproprietary Names for Pharmaceutical Substances: Executive Summary (15-17 Apr. 2013), http://www.who.int/medicines/services/inn/56th_Executive_Summary.pdf (accessed Nov. 18, 2013). 319 WHO, 55th Consultation on International Nonproprietary Names for Pharmaceutical Substances: Executive Summary (16-18 Oct. 2012), http://www.who.int/medicines/services/inn/55th_Executive_Summary.pdf (accessed Nov. 18, 2013) 320 Id. 321 Government of Japan, Ministry of Health Labor and Welfare, Pharmaceutical and Food Safety Bureau, Handling of nonproprietary and brand names of follow-on biologics, (March 4, 2009), http://www.phrma- jp.org/archives/pdf/others/PFSB-ELD%20Notification%20of%20Handling%20of%20names%20of%20follow- on%20biologics_No.%200304011.pdf (accessed Nov. 18, 2013). 322 See Australian Government, Department of Health, Therapeutic Goods Administration, Naming conventions for biosimilars, (July 30, 02013) http://www.tga.gov.au/industry/pm-argpm-biosimilars-10.htm (requiring that a biosimilar identifier consisting of “sim” and a three-letter code) (accessed Nov. 19, 2013). 323 CDER, Filgratsim Proprietary Name Review. 324 For example, the biosimilar epoetin in Japan has a distinguishable non-proprietary name, Epoetin Kappa (Genetical Recombination) [Epoetin Alfa Biosimilar 1].” In 2012, epoetin kappa accounted for 65% market share of short-acting epoetin alfa sales in Japan. (Source: EvaluatePharma, accessed 11/21/13). In addition, according to internal Amgen analysis of IMS data for the most recent full quarter of data in Australia (Q3 2013), the biosimilar epoetin lambda accounted for 19.5% volume share versus its reference product (Eprex® [epoetin alfa]), and two biosimilar filgrastims with measurable sales accounted for a combined 28.4% volume share versus the single originator filgrastim with the same non-proprietary name (Neupogen® [filgrastim]). 325 See, FDA, Draft Guidance for Industry: Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product 93-96 (Feb. 2012), http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatory Information/Guidances/UCM291134.pdf (accessed Dec. 18, 2013) (“Since 1996, FDA has approved many manufacturing process changes for licensed biological products, based on a demonstration of product comparability before and after the process change, as supported by quality criteria and analytical testing and without the need for additional nonclinical data and clinical safety and/or efficacy studies.”), http://www.fda.gov/downloads /Drugs/Guidance (accessed Nov. 18, 2013). 326 Lee et al., Comparability and Biosimilarity: Considerations for the Healthcare Provider, 28 Current Medical Research & Opinion 1053 (June 2012).

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agencies are not typically concerned with enhanced product safety monitoring following such incremental changes. Therefore, it is difficult to argue that this is realistic parallel with the development of a biosimilar product, where FDA and EMA have both indicated that it is a more complex exercise, subject to greater uncertainty, and requiring post-approval pharmacovigilance to address safety signals that could not be adequately studied prior to authorization.327, 328

In the case of more significant process changes that involve additional uncertainties regarding impact to quality, safety and efficacy (eg, when there is a shift in specifications and some level of clinical bridging studies required), it is typical practice to discontinue the pre-change process and replace the product supply entirely with the post-change material, following a transition period where distributed product may coincide on the market. In this situation, a distinguishable name might conceivably improve traceability of the post-change material relative to the pre-change material during the transition period, but it would have no durable benefit to traceability after that transition because there would only be post- change material available to treat patients.

We believe that regulators should work with sponsors to address any concerns about traceability of the product during a transition period following a major manufacturing change. There are many mechanisms to achieve an enhanced, time-bound safety monitoring commitment in these situations without requiring a change in either the brand or non-proprietary name. For example, for a single source biologic all suspected AEs from the SRS and relevant claims from AS would be properly attributed to the correct manufacturer, so that signal detection algorithms based on changes in frequency or severity of AEs over time would be able to trigger an investigation into possible association with the significant process change. This type of signal detection is possible, even without a high proportion of batch number reporting and without a distinguishable nomenclature, because the single-source manufacturer has access to a stable, historical safety signal baseline that is not confounded by misattribution.

In contrast to these process-change scenarios, a biosimilar product is intended to be marketed in parallel with other biosimilar products, other structurally related competitors, and the originator product on an ongoing basis. In this situation reports using an ambiguous product identifier would confound the product-specific signal detection that is required in SRS and AS. Unlike the situation with a process change for a single-source manufacturer, it would be difficult for the multiple sponsors to detect disproportionate signals among themselves or over time if reports did not go to the correct sponsors. Thus, in terms of the public health concerns, the post-change product and the biosimilar product are not similarly situated.

For these reasons, we conclude that the scientifically analogous bases of approval for new biosimilars and manufacturing changes (i.e., via a comparative “similarity” or “comparability” exercise, respectively) is irrelevant to the public health question of traceability in a multisource biologics environment.

327 See, FDA, Draft Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Pr otein Product (Feb. 2012), 181-192, 806-819, http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf (accessed Nov. 18, 2013). 328 Wiese et al., Biosimilars: What Clinicians Should Know, 120 Blood 5111 (Dec.2012).

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7. Transparency of regulatory action should be separated from traceability considerations in safety monitoring.

Separate from the topic of identification and traceability, GPhA attempts to link product naming to regulatory transparency, and thereby assert that FDA should publish information about routine process changes.329 GPhA cites the European “changes implemented since authorization” public assessment reports as an example. This linkage confuses two, different policy remits. Transparency for routine process variations is a matter of law in the EU and is not linked to traceability in the medical practice setting. Process variations are not described in sufficient detail to provide relevant information about risks. Most variation citations are not intended to inform prescribers in any manner that would impact their practice, and it is difficult to understand how a description limited to “change to the manufacturing process for active substance” is at all useful to a health care provider or patient.

We stipulate that some categories of listed changes in the EPAR may be relevant to health care providers: these concern the approval of new presentations, changes to the summary of product characteristics (i.e., prescribing information), and occasionally, situations involving clinical studies that are typically accompanied by separate scientific assessment reports. For example, Amgen implemented a major process change for Aranesp (darbepoetin alfa) that involved some shifts in quality attributes. This change was evaluated via an extensive comparability exercise that included clinical bridging studies as described in an EMA scientific public assessment report.330 It is entirely reasonable to evaluate the levels of transparency for these types of changes in other jurisdictions. But these rare situations have nothing to do with the more common changes cited by GPhA as relevant to the transparency of biosimilar development.

FDA is subject to different transparency requirements, but has similar transparency for label changes.331 With regard to manufacturing changes, FDA has historically applied varying levels of transparency; for example listing manufacturing changes or additions for FDCA biologics such as insulin, but not listing such information for PHSA biologics.332 As with the case for the EMA public information, the FDA website provides no detailed descriptions of most manufacturing changes unless they result in a label change.333 GPhA fails to make a case that increased transparency of manufacturing changes not requiring label changes would be relevant to prescribers, would improve product traceability, or that it would otherwise bear any relationship to measures to ensure product-specific monitoring of multisource biologics.

329 GPhA Pet. at 4-5. 330 Aranesp: EPAR – Procedural Steps. 331 Approval histories and label updates are listed for drugs and biologics regulated by CDER at the Drugs@FDA database. See CDER, Drugs@FDA, http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm (accessed Dec. 18, 2013). For biologics regulated by CBER the approval and label change supplements are found on their vaccine, blood, and biologics page. See CDER, Vaccines, Blood & Biologics, http://www.fda.gov/BiologicsBloodVac cines/ucm133705.htm (accessed Dec. 18, 2013). 332 See, e.g., CDER, Humulin R Approval History, http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ (search “humulin R,” follow “Humulin R” link, follow “Humulin R (NDA #018780) link,” then follow “Approval history, Letters, Reviews, and Related Documents” link) (accessed Dec. 9, 2013). 333 Most changes listed at the Drugs@FDA website are referenced simply as “Manufacturing Change or Addition” with no associated link to an approval letter or label. The exceptions appear to be for situations where there are revisions to the labeling text. See e.g., Letter from David Orloff, Director, ODE II, CDER, to James Balun, Regulatory Manager, Pharmacia & Upjohn Company, (March 28, 2003), http://www.accessdata.fda.gov/drugsatfda_d ocs/appletter/2003/20280scm038ltr.pdf (accessed Dec. 9, 2013).

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H. USP monographs do not determine non-proprietary names for biosimilars.

In its petition, Novartis incorrectly asserts that a biosimilar must, as a matter of law, be known by the official title of any “applicable” monograph published in the USP-NF.334 In describing FDA’s role in designating non-proprietary names for biosimilars, Novartis contends that FDA’s responsibility is limited to “the enforcement of USP standards,” and that the agency’s authority “to change a USP name” is limited to the situations (and procedures) described in Section 508(a) of the FDCA.335 Even then, according to Novartis, FDA is limited in its power, because “such a change would necessitate a parallel change to the USP name of the originator.”336

FDA’s power to designate a non-proprietary name for a biosimilar for which USP has devised a monograph is not, as Novartis claims, subordinate to the authority exercised by USP itself. To the contrary: As the text and legislative history of the relevant statutory provisions make clear, the effect of the 1962 amendments was to enhance FDA’s authority relative to nongovernmental naming organizations.337

As is clear from the statutory text, Congress intended that FDA would ensure that drugs “identical in chemical structure and pharmacological action” would share a single non-proprietary name,338 so that physicians could determine whether two drugs with different brand names were in fact the same.339 Under Section 508(c), FDA is authorized to consolidate monographs only for “drugs which are identical in chemical structure and pharmacological action.”340 By implication, Congress also clearly intended for FDA to ensure that drugs with non-identical chemical structures and pharmacological actions would be assigned different non-proprietary names; otherwise physicians would be hampered in their ability to make appropriate product comparisons.

In the FDCA, Congress recognized a role for USP,341 but it did so based on the understanding that articles with different chemical structures would be recognized in a different monograph.342 Were USP to adopt monographs for biological products whose specifications were broad enough to include non- identical biosimilars, the result could be non-proprietary names for biosimilars that are identical to the non-proprietary names for their corresponding reference products. Such a result would directly conflict with Congress’ intent that only products “identical in chemical structure and pharmacological action”

334 Novartis Pet. 4-5. 335 Id. at 5. 336 Id. at 5 n.26 (emphasis added). 337 E.g., Drug Industry Antitrust Act: Hearing Before the Subcomm. on Antitrust and Monopoly of the Comm. on the Judiciary, 87th Cong. 7 (July 5, 1961) (noting that pharmacopoeia compilers lack “real authority to compel a change” in generic names). 338 108 Cong. Rec. S5642 (daily ed. Apr. 12, 1962). 339 Id. at S5638. 340 21 U.S.C. § 358(c)(2). 341 Id. § 352(e)(3)(B). 342 See, e.g., id. § 358(c)(2) (authorizing FDA to require the consolidation of monographs only for “drugs which are identical in chemical structure and pharmacological action”); see also 108 Cong. Rec. S5642.

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share a non-proprietary name.343 A biosimilar product cannot be “recognized” in the monograph of its non-identical reference product within the meaning of Section 502(e)(3)(B).

This conclusion is further bolstered by the BPCIA’s silence on biosimilar naming, in contrast with the Waxman-Hatch Amendments’ clear directive that drugs shown to be “bioequivalent” to, and have the “same” active ingredient as, the reference drug share the same labeling, including the same non- proprietary name, as the reference product.344 As these two amendments make clear, Congress clearly knows how to provide for the use of identical non-proprietary names for reference and follow-on products when that is its intention. The omission from the BPCIA of language like that in the Waxman- Hatch Amendments reflects Congress’s intention that biosimilars not share the non-proprietary name of their respective reference products.

V. A POLICY THAT EACH BIOSIMILAR IS LICENSED WITH THE SAME NON- PROPRIETARY NAME AS ITS REFERENCE PRODUCT WOULD RAISE SIGNIFICANT LEGAL ISSUES.

In addition to raising troubling health and safety concerns, a policy that each biosimilar is licensed with the same non-proprietary name as its reference product would raise significant legal issues. In particular, such a policy—however it would be implemented—would conflict with the FDCA and would be arbitrary and capricious within the meaning of the Administrative Procedure Act (APA).345

A. A policy that provides for identical non-proprietary names for biosimilars and their reference products would conflict with the FDCA.

A policy that provides for identical non-proprietary names for biosimilars and their reference products would be contrary to the FDCA. Under Section 502 the FDCA, a drug (including a biological product regulated as a drug) “shall be deemed to be misbranded” if, among other things, its label does not “bear[ ] . . . [its] established name . . . , if there is such a name,”346 or “its labeling is false or misleading in any particular.”347 One way in which a drug’s labeling may be misleading is if it would cause confusion regarding that drug and a different drug,348 and FDA has recognized that “[a]n established name could contribute to product name confusion” if it is “similar in appearance or pronunciation to the proprietary or established names of existing products.”349 If a biosimilar were to be given an identical non-proprietary name to its reference product, it would cause the biosimilar’s labeling to be misleading in critical respects.

343 108 Cong. Rec. S5642 (daily ed. Apr. 12, 1962). 344 21 U.S.C. § 355(j)(2)(A)(ii), (iv), (v); 21 C.F.R. § 314.92(a)(1); see also Novartis Pharms. Corp. v. Leavitt, 435 F.3d 344, 346 (D.C. Cir. 2006). 345 5 U.S.C. § 706(2)(A). 346 21 U.S.C. § 352(e)(1)(A). 347 Id. § 352(a). 348 21 C.F.R. § 201.10(c). 349 FDA, Guidance for Industry: Contents of a Complete Submission for the Evaluation of Proprietary Names 12 (February 2010), http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm075068.pdf (emphasis added).

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First, it would improperly suggest that the biosimilar is identical or bioequivalent to its reference product when, in fact, it is by definition not. Throughout the FDCA, the provisions that authorize products to share the same non-proprietary name do so on the basis of shared identity. For example, for generic drugs approved under Section 505(j), the use of a shared non-proprietary name for a pioneer drug and its generic equivalents follows directly from the FDCA’s bioequivalence requirements. To be approved as a generic, a drug must be “bioequivalent” to, and have the “same” active ingredient as, its reference drug.350 Consistent with these regulatory requirements, generic drugs must also have the “same . . . labeling” as the reference drug351—a requirement that, by extension, means that the “generic drug must have the same nonproprietary name as the pioneer drug.”352 Likewise, FDA’s express authorization under Section 508 to designate a single official name for multiple products353 is limited to those circumstances in which “different nonproprietary names are being used for “drugs which are identical in chemical structure and pharmacological action and which are substantially identical in strength, quality, and purity.”354

Biosimilars, in contrast, are required only to be “highly similar” to their reference products;355 the statute does not require them to be bioequivalent to their reference products, or to be identical. As FDA testified before Congress, “it is unlikely that, for most proteins, a manufacturer of a follow-on protein product could demonstrate that its product is identical to an already approved product.”356 Indeed, it was necessary to create a new pathway for biosimilars under the BPCIA because “the section 505(j) generic drug approval pathway, which is predicated on a finding of the same active ingredient, will not ordinarily be available for protein products.”357 If biosimilars could satisfy the same standards of identity as generic drugs, there would have been no need for Congress to have established an approval pathway with such readily distinct requirements from those applicable to generic drugs.

Were a biosimilar product to be given a non-proprietary name that, like the established name for a generic drug, is identical to its reference product, it could create confusion regarding whether biosimilars are, like generic drugs, bioequivalent to their reference products. This concern is hardly hypothetical. According to a survey of physicians conducted by the Alliance for Safe Biologic Medicines, “76 percent of physicians would assume that biologics with the same name are identical to one another.”358

These concerns are particularly significant with respect to biosimilars that have not been found to be interchangeable with their reference products. Prior to the enactment of the BPCIA, FDA explained to Congress that it believed the “legislation should . . . require that these [follow-on biologic] products be

350 21 U.S.C. § 355(j)(2)(A)(iv). 351 Id. § 355(j)(2)(A)(v). 352 Novartis Pharms. Corp. v. Leavitt, 435 F.3d 344, 346 (D.C. Cir. 2006) (emphasis added). 353 Once FDA designates an official name for a product, that name becomes the product’s established name. 21 U.S.C. § 352(e)(3)(A). 354 21 U.S.C. § 358(c)(2) (emphasis added). 355 42 U.S.C. § 262(i)(2)(A). Indeed, non-interchangeable biosimilar products are considered to contain new active ingredients for purposes of the Pediatric Research Equity Act. 21 U.S.C. § 355c(n)(1). 356 Woodcock Testimony at 7 (statement of Dr. Janet Woodcock, Director, CDER). 357 Id. 358 Richard Dolinar, ASBM Chariman, It’s All About the Name: What Is the Imperative of Adopting Unique Names for Biologic and Biosimilar Therapeutics? at 5, Nov. 28, 2012, http://www.fdli.org/docs/members-only/dolinar-asbm- biosimilars-final-11-28-12.pdf?sfvrsn=0 (accessed Nov. 19, 2013).

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assigned a distinguishable, non-proprietary name for safety purposes” in light of the Agency’s “paramount concern . . . that patients not be exposed to an avoidable safety risk by being switched to a product not known to be interchangeable with the product they are currently receiving.”359 And since the passage of the BPCIA, FDA has explained in draft guidance that the interchangeability of a biosimilar (or lack thereof) must be clearly communicated in the labeling.360 Because, as FDA recognized, an identical name could improperly suggest interchangeability where it has not been determined to exist, the use of such a name would be misleading and could expose patients who are not under the supervised care of a physician to unknown safety risks. And, finally, since an FDA approval of a biosimilar as interchangeable will similarly be communicated, it is, as intended by Congress, that determination that will reflect FDA’s opinion as to substitutability, separate and apart from the non-proprietary name assigned.361

B. It would conflict with the Administrative Procedure Act for FDA to adopt a biosimilar naming policy that breaks from established practice without adequate justification.

FDA’s naming policy for biosimilars must account for both prior agency practice and intervening legislative action. Under the APA, the FDA may not act in ways that are arbitrary, capricious, or otherwise in conflict with law.362 Consistent with this requirement, FDA may not depart from its established prior practices without a reasoned explanation for doing so,363 nor may it treat similar circumstances differently without a reasoned explanation.364 As applied to FDA’s past practices regarding the non-proprietary names of biologic products, these requirements indicate that the policy change GPhA is advocating would be arbitrary and capricious because it would require an unexplainable departure from FDA’s practice of requiring distinguishable non-proprietary names for biological products to avoid the possibility of confusion and medication error (a practice GPhA does not even acknowledge), whereas the supposed past policies and practices are outdated, superseded by intervening legislation, or distinguishable based on their unique facts.

359 Torti Letter at 3(emphasis added). 360 FDA, Draft Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product 21 (February 2012), http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM291128.pdf (accessed Nov. 19, 2013). 361 As Novartis explains in its petition in discussing determinations of therapeutic equivalence for generic drugs, “It is this [therapeutic equivalence] determination by FDA and the subsequent listing of the products as therapeutically equivalent – and not the products’ INN – that informs physicians, pharmacies, state agencies and other stakeholders that the products can be substituted with the full expectation that they will produce the same clinical effect and safety profile. Similarly, FDA will have to make a separate determination of interchangeability with respect to a biosimilar, and it will be that determination and its reflection on the biosimilar’s label that will inform of the biosimilar’s interchangeability with its reference product.” Novartis Pet. 5 (emphasis supplied in original). 362 5 U.S.C. § 706(a)(A). 363 E.g., FCC v. Fox Television Stations, 129 S.Ct. 1800, 1811 (2009). 364 E.g., Westar Energy, Inc. v. FERC, 473 F.3d 1239, 1241 (D.C. Cir. 2007).

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1. Any naming policy must be reconcilable with FDA’s recent naming decisions regarding related biologic products approved under 351(a) Pathway.

Even before enactment of legislation establishing a statutory pathway for FDA approval of related biological products approved under the 351(a) pathway, FDA had already begun to consider issues relating to the proper identification of such products through their non-proprietary names in the context of specific biological products. Although GPhA has completely failed to address these recent naming decisions, any final policy on naming must account for these precedents.365

In 2009, FDA decided to use prefixes to differentiate the non-proprietary names of several botulinum toxin products in order “to ‘help reduce the potential for dosing errors.’”366 In accordance with this decision, Botox and Botox Cosmetic were renamed “onabotulinum toxin A”; Dysport was approved as “abobotulinum toxin A”; and Myobloc was renamed “rimabotulinum toxin B.”367

Likewise, since the enactment of the BPCIA, FDA has used its authority to require the use of prefixes to differentiate structurally related biological products from the previously approved products to which they were related. For example, in 2012, FDA approved two biological products through the Section 351(a) pathway—Teva’s Granix (tbo-filgrastim) and Sanofi’s Zaltrap (zivaflibercept)—only after requiring the use of prefixes to differentiate them from Neupogen (filgrastim) and Eylea (aflibercept), respectively.368 With respect to Granix™, FDA required the use of a prefix to differentiate it from Neupogen®. FDA explained that distinguishable names were necessary “to minimize medication errors by (1) preventing a patient from receiving a product different than what was intended to be prescribed and (2) reducing confusion among healthcare providers who may consider use of the same nonproprietary name to mean that the biological products are indistinguishable from a clinical standpoint.”369 In addition, FDA concluded that unique nonproprietary names would “facilitate post- marketing safety monitoring by providing a clear means of determining which ‘filgrastim’ product is dispensed to patients,” explaining that “the use of distinct proprietary names [was] insufficient to address these concerns” because “health care providers may use nonproprietary names instead of proprietary names when prescribing and ordering products” and “pharmacovigilance systems often do not require inclusion of proprietary names.”370 Moreover, while declining in the context of that application to establish an across-the-board policy with respect to the naming of biological products, FDA stated that it “does not anticipate that any decision on nomenclature for biosimilar and interchangeable products will conflict with [its] determination regarding the nonproprietary name for this product.”371

In light of these decisions, any future policy on the naming of biological products will need to address not only FDA’s past conclusions that distinguishable names were required in these circumstances, but

365 See Westar Energy, Inc., 473 at 1241. 366 Botox Safety Emphasized By FDA As Botulinum Toxins Get New Generic Names, The Pink Sheet DAILY, (Aug. 3, 2009). 367 Id. 368 CDER, Filgrastim Proprietary Name Review; CDER, Aflibercept Proprietary Name Review. 369 CDER, Filgrastim Proprietary Name Review. 370 Id. 371 Id. FDA made nearly identical statements in its decision regarding Zaltrap®. See CDER, Aflibercept Proprietary Name Review.

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also its explanations as to why distinguishable names were required—including its conclusions regarding the risks of medication errors and the insufficiency of existing pharmacovigilance systems.

2. The policies and practices GPhA identifies are readily distinguished.

Rather than address FDA’s past decisions regarding the non-proprietary names of structurally related biological products, GPhA, in essence, mischaracterizes, select FDA actions as establishing some sort of FDA commitment to adopting a policy of identical names for biosimilars and their reference products. Nothing GPhA identifies, however, provides a basis for FDA to reject the positions and conclusions it reached in its recent decisions regarding, inter alia, Granix™ and Zaltrap®.

First, GPhA suggests that FDA is bound by statements it made in a 2006 paper submitted to the World Health Organization,372 which GPhA construes as “reject[ing] distinctive INN designations for biosimilars.”373 This paper, however, is significantly outdated and does not reflect current FDA policies, or even its current thinking on the matter. As an initial matter, this paper was submitted years before the enactment of the BPCIA, and therefore does not reflect any thinking on numerous issues relevant to a final naming policy, including (for example) the statutory definitions of “biosimilar” and “interchangeable.” Moreover, FDA has repeatedly refined and amended its position since this time, including through letters to and testimony before Congress,374 as well as in recent decisions to approve prefixes to differentiate among products.375

Second, GPhA asserts that FDA cannot adopt a policy requiring distinguishable established for biosimilars and their reference products because “FDA routinely allows originator biological products in the same class approved under separate 351(a) or 505(b) applications and using different manufacturing methods implemented by different sponsors to share the same INN.”376 But, when FDA has decided to license a biological product with the same non-proprietary name as another biological product, the Agency’s decision reflected unique historical or product specific circumstances that justified use of the same name, and that do not apply in the ordinary course. For example:

Anti-Hemophilic Factors

The example citing anti-hemophilic factors sharing the same INN is not relevant. These products, first, have been evaluated by FDA under a non-abbreviated premarket review procedure, and each anti- hemophilic factor cited in the GPhA petition was licensed based on its own quality, safety, and efficacy data. These products are not biosimilars. Antihemophilic factors were recognized by FDA no later than 1980 as “blood derivative[s] prepared by fractionation from pools of human plasma,” and all “of these products [were, by then] . . . derived from human sources.”377 As a result, FDA determined that they should be assigned a common proper name, which also provided the advantage of permitting the use of

372 FDA, US FDA Considerations: Discussion by National Regulatory Authorities with World Health Organization (WHO) On Possible International Non-proprietary Name (INN) Policies for Biosimilars (submitted to WHO in Sept. 2006). 373 GPhA Pet. 2-3. 374 See e.g., Woodcock Testimony; Torti Letter. 375 CDER, Aflibercept Proprietary Name Review (adding a three letter prefix to the nonproprietary name to help minimize medicatoin errors); CDER, Filgrastim Proprietary Name Review (same). 376 GPhA Pet. 2. 377 Changes in Proper Names of certain Biological Products, 45 Fed. Reg. 72,404, 72,404-72,405 (Oct. 31, 1980).

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simplified and uniform labeling. Notably, the explicit purpose of FDA’s decision to designate all antihemophilic factors with a common, shorter proper name was “to decrease the incidence of human error”—an objective that clearly would not be served if GPhA’s petition were granted. That the blood product proper name changes occurred as part of FDA’s broader initiative to facilitate automated data processing for blood products under the auspices of the National Blood Policy provides an additional reason to regard with caution GPhA’s assertion that the use of a single non-proprietary name for all anti- hemophilic factors operates as a precedent for FDA’s approach to naming conventions for biosimilars under the BPCIA.

The administration of anti-hemophilic factors is subject to extraordinary precautions, which GPhA is not advocating with respect to biosimilars generally. The treatment and management of hemophilia is closely monitored by treating physicians. In the event a patient is switched from one product to another the patient is monitored for inhibitor development according to standards and guidelines developed by the World Hemophilia Foundation. These guidelines provide: “Patients switching to a new factor concentrate should be monitored for inhibitor development. (Level 2).”378 This guideline was included in the U.S. Department of Health and Human Services national guidelines clearinghouse publication379 according to the clinical practice inclusion criteria developed by the Institute of Medicine.380

Since the clinical practice of anti-hemophilic medicines occurs under the close care of attending physician, any AE or inhibitor formation is well tracked and traced to the specific anti-hemophilic drug that was administered to the patient. Additionally, “the inhibitor usually disappears after withdrawal of the new product.”4381

Patients with inhibitor formation after treatment with anti-hemophilic products often have several clinical alternatives such as Immune Induction Therapy (ITI) or alternative treatment with products such as Factor VIII Inhibitor By-Passing Activity (FEIBA™) or rFVIIa (Novoseven™). Such options may not be available for all biologics and biosimilars.

The shared non-proprietary names for some subsets of products used to treat blood clotting disorders cannot be considered a broadly applicable precedent for appropriate distinguishing nomenclature for all biologics. These products are subject to extraordinary precautions in clinical practice that serve to elevate awareness of the prescriber and patient regarding the exact product being used in therapy, and

378 World Federation of Hemophilia, Guidelines For the Management of Hemophilia 61 (2nd Ed. 2012); see also World Federation of Hemophilia, Guidelines For the Management of Hemophilia 12 (1st Ed. 2005) (“Therefore, patients switching to a new factor concentrate should be monitored for inhibitor development.”). Labeling for antihemophilic factor products includes similar recommendations. See, e.g., Kogenate FS Package Insert (“it is highly recommended that, whenever possible, appropriate laboratory tests including serial factor VIII activity assays be performed”), http://www.fda.gov/downloads/biologicsbloodvaccines/bloodbloodproducts/approvedproducts/ licensedproductsblas/fractionatedplasmaproducts/ucm059018.pdf (accessed Nov. 19, 2013); Xyntha Package Insert (“Patients using coagulation factor VIII products, including XYNTHA, should be monitored for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests”), http://www.fda.gov/downloads/ BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProduct s/ucm055498.pdf (accessed Nov. 19, 2013). 379 US Department of Health and Human Services, National Guideline Clearinghouse, Guideline for the management of hemophilia, http://www.guideline.gov/content.aspx?id=39323, (accessed Nov. 19, 2013). 380 US Department of Health and Human Services, National Guideline Clearinghouse, Inclusion Criteria, http://www.guideline.gov/about/inclusion-criteria.aspx (accessed Nov. 19, 2013). 381 World Federation of Hemophilia, Guidelines For the Management of Hemophilia 61 (2nd Ed. 2012).

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which highlight precautions to be taken prior to switching therapies. To our knowledge, GPhA has not supported the notion that such precautionary measures ought to be imposed on all biosimilar products.

The market introduction and naming of anti-hemophilic products predated both enactment of the “established name” provisions of the FDCA and FDA’s adoption of the current regulatory approach to designating non-proprietary names. The current non-proprietary name, “antihemophilic factor,” was designated by FDA pursuant to its “proper name” authorities in 1980.382 For this reason, GPhA’s comparison of the adopted official name of “antihemophilic factor” products to potential classes of biosimilar products is inappropriate.

Vaccines

GPhA cites several examples of branded vaccines with shared common names. Omitted from this discussion is that vaccines are subject to special traceability measures that are enforced at the federal and state levels. When a vaccine is administered at a community pharmacy, the pharmacist is frequently compelled by state pharmacy practice acts to complete a notification memorandum to be provided to the primary care physician, including information on the specific brand of the vaccine administered, and in some cases, the lot number. An example of a template notification form is referenced, listing by brand name, the Hepatitis A and Hepatitis B examples with shared non-proprietary name from the GPhA CP Appendix A.5.

The GPhA argues that distinguishable names have not been historically required by FDA to improve traceability of biologics made by multiple manufacturers, but in the case of vaccines other measures exist to improve traceability.383

Insulin Products

As is clear from Appendix A in the GPhA petition384, insulin products are subject to a combination of distinguishable names indicating their method of manufacture and origin. For example, there is insulin

382 As early as 1958, the federal government licensed blood and blood derivative products called “antihemophilic globulin,” as well as “antihemophilic plasma.” See Licensed Biological Products, 23 Fed. Reg. 5,512, 5,513, 5,516 (July 19, 1958). By 1965, the Department of Health, Education and Welfare had licensed establishments to manufacture “Fibrinogen with antihemophilic factor,” see Biological Products, 30 Fed. Reg. 4,418, 4,418 (April 6, 1965), and in 1968, the Department recognized a condition called a “deficiency of antihemophilic factor.” See Rights and Benefits Based on Disability, 33 Fed. Reg. 7,244, 7,255 (May 16, 1968). By 1969, antihemophilic factor was recognized as a separate product. See Biological Products, 34 Fed. Reg. 5,858, 5,863 (March 28, 1969). In 1980, FDA changed the proper name from “antihemophilic factor (human)” to “antihemophilic factor,” as “the products are recognized by the medical community as originating from humans.” See Changes in Proper Names of certain Biological Products, 45 Fed. Reg. 72,404, 72,404-05 (Oct. 31, 1980). USP is currently soliciting proposals for new monographs for antihemophilic factors. USP, Monograph Modernization and Monographs Needing Sponsors, http://www.usp.org/usp-manufacturers/biologics-biotechnology/usp-documentary-standards-biologics- biotechnology/monograph-modernization-monographs (accessed Nov. 19, 2013). 383 Many states require pharmacists to maintain records of directly administered vaccines that include drug and manufacturer name. See, e.g., 3 Colo. Code Regs719-1, 19.01.40; Ill. Admin. Code tit. 68 § 1330.50(c); 02-392-004A Me. Code R. § 2 (LexisNexis2013). Some states also require pharmacists to provide notice of the vaccinations to the patient’s primary care physician, which can include the name of the administered vaccine. See Notification of Vaccination Letter Template, Immunize.org, http://www.immunize.org/catg.d/p3060.pdf, (accessed Nov. 20, 2013) (federal version); N.H. Rev. Stat. Ann. § 318:16bb. (LexisNexis 2013) (state version); S.D. Admin R. 20:51:28:05 (same). 384 GPhA Pet. 14-18 Appendix A.

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pork, insulin purified pork, insulin recombinant human, and insulin recombinant purified human, among others. Thus, it is far from true that the class of short-acting insulins has always had identical established names. These products have been distinguished at both the brand and the common name level because individual patient responses could depend on the method of manufacture and source material.385

Many of these variations have been withdrawn from the market and replaced with recombinant human insulin. Nevertheless, we will address the example of two branded “insulin recombinant human” products. An evaluation of the prescribing information supplied by the manufacturers reveals that the information contains prominent warnings that any change in insulin should be “made cautiously and only under medical supervision”.386, 387 We expect that GPhA would not support such a prominent warning to be placed on the prescribing information for biosimilar or interchangeable products. GPhA’s use of examples of branded insulins with shared non-proprietary names does not represent a good precedent for nomenclature of biosimilars.

In 2009, for instance, observational studies in Europe suggested a statistically significant increased risk of cancer associated with insulin glargine, an insulin analogue (marketed in the U.S. as LANTUS®). FDA issued two safety communications in response to the studies. There are more than 15 non- proprietary names for marketed insulin products, but in the U.S. and the EU, there is only one insulin glargine product. A significant factor underlying the original studies, and the ability to detect a small but potentially meaningful cancer risk associated with insulin glargine, was the ability to separate AE outcomes among patients who had received insulin glargine only, insulin glargine plus other types of insulin, or insulin therapy but never insulin glargine. An inability to distinguish among similar but not identical insulin products would likely have masked any safety signal associated with insulin glargine specifically.388

Third, GPhA suggests that identical names are necessary for conformity with FDA’s policies allowing “originator manufacturers to modify biologics’ manufacturing processes and develop biologics that have minor changes and differences that are not clinically meaningful without requiring a change in non- proprietary name.”389 But nothing in an approach requiring distinguishable names for biosimilars and their reference products would create insoluble conflict with these policies. Reference products undergoing these sorts of changes are subject to statutory and regulatory controls that assure that the process does not result in product changes necessitating a new non-proprietary name.390 Moreover, FDA

385 American Diabetes Association, Insulin Administration, 26 Diabetes Care S121 (Jan. 2003). 386 Humulin R Information for the Physician, http://pi.lilly.com/us/humulin-r-u500-pi.pdf (accessed Oct. 29, 2013). 387 Full Prescribing Information for Novolin R, available at http://www.novonordiskmedicalinformation.com// file_upload/Novolin%20R%20Prescribing%20Information,%20March%202013.pdf (accessed October 29, 2013). 388 See e.g., J. Jonasson, et al., Insulin Glargine Use and Short-Incidence of Malignancies – A Population-Based Follow-up Study in Sweden, 52 EPUB. 1745 (Sept. 2009). These data were based on publicly available information; there are other insulin glargine products in development both in the EU and US. 389 GPhA Pet. 3. 390 See, e.g., 21 U.S.C. § 351(a), (b) (adulteration of a drug based on improper manufacturing processes or changes); id. § 351(o) (postmarket surveillance); id. § 374 (inspection of manufacturing facilities); 21 C.F.R. § 211 (good manufacturing practices).

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officials have acknowledged that the Agency’s ability to analyze and track changes by a single manufacturer is far superior to its ability to analyze differences among different manufacturers.391

Finally, GPhA is incorrect in suggesting that a policy providing for distinguishable names would require retroactive application to all biologics, including process changes.392 First, as discussed above, the examples in GPhA’s petition are distinguishable, and there is no reason why any new policy necessarily would apply in such cases even on a forward-looking basis, let alone retroactively. Moreover, even assuming arguendo that a new policy might apply to certain process changes, there would be no basis for the blanket retroactive review of “virtually every licensed biologic on the market in the US today” that GPhA describes.393 To the contrary, the FDA has “the decision not to retroactively apply a per se rule . . . is not irrational,” so long as “the agency continues to ensure . . . safety on a case-by-case basis.”394 Indeed, FDA can—and often does—alter the requirements applicable to the approval of generic drugs through the abbreviated 505(j) pathway, and courts have recognized that the process would become “unworkable” if every change to the requirements—even changes involving the demonstration of safety—required retroactive application.395 There is no reason retroactivity would be uniquely required in the context of the non-proprietary names of biological products.

VI. THE NEED FOR BETTER PHARMACOVIGILANCE MEASURES OVERALL DOES NOT OBVIATE THE NEED FOR “OPTIMAL PHARMACOVIGILANCE” IN THE CONTEXT OF BIOSIMILARS.

As discussed in significant detail at the outset, biologics present a risk of immunogenicity that makes robust post-market surveillance uniquely important. Even if that were not true, however, we disagree with GPhA’s contention that FDA should avoid taking measures specific to biosimilars when measures to address universal shortcomings in the pharmacovigilance system are needed.396 It is always appropriate to take preemptive steps to facilitate patient welfare, even if those steps are taken only for a subset of regulated products. If it is possible to strengthen the post-market surveillance system and advance patient welfare by designating distinct non-proprietary names for biosimilars, FDA should do so. This is particularly true as more and more products come on the market, increasing the likelihood of confusion.

391 See, e.g., Woodcock Testimony at 8 (statement of Dr. Janet Woodcock) (“Typically, demonstrating the similarity of a follow-on protein product to a reference product will be more complex, and thus require more new data, than assessing the similarity of product before and after manufacturing changes made by the approved product’s sponsor.”). 392 GPhA Pet. 4 (asserting that “all existing products that share INNs would need to be renamed, and new INNs would be needed in every instance of a manufacturing change to a currently licensed product”). 393 Id. 394 Serono Labs., Inc. v. Shalala, 158 F.3d 1313, 1322-23 (D.C. Cir. 1998). 395 Id. at 1323 (“If every pending application had to be revised each time the FDA changed its regulations, the process would become much more lengthy—even Sisyphean if the rules of the game changed each time the application neared the finish line.”). 396 See, e.g., GPhA Pet. 7 (“This [sic] data supports GPhA's view that the INN [sic] is only one of several identifiers of a product that is important to capture for purposes of pharmacovigilance, and further demonstrates that creating a unique or differentiated INN is not likely, in and of itself, to result in a substantive improvement in pharmacovigilance practices.”).

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GPhA also suggests that optimal pharmacovigilance requires shared, as opposed to distinguishable, non- proprietary names, because shared names will allow AEs to be aggregated and trends spotted earlier. This argument is illusory. Distinguishable names do not preclude aggregation. On the contrary—and particularly if names share common roots—separately-tracked AEs can be pooled at FDA’s discretion in order to identify broader trends. It is precisely for this reason that distinct names are necessary. They permit pooling and broader trend tracking, but they do not preclude more precise tracking in cases when risks associated with a specific manufacturer’s product arise. Given FDA’s top priority of patient safety, it is incumbent upon the agency to choose a naming system that differentiates among biosimilar products.

VII. GPhA’s SUGGESTIONS OF ALTERNATIVE PHARMACOVIGILANCE MECHANISMS ARE NOT SUFFICIENT TO ADDRESS THE NEED FOR ROBUST POST-MARKET SURVEILLANCE OF BIOLOGICS.

A. GPhA mentions that federal track and trace legislation can assure the quality of pharmacovigilance data.

The recently enacted Drug Quality and Security Act (DQSA) does contain measures that, when implemented, will improve traceability of medicines from the manufacturer to the pharmacy. While these measures will improve supply chain security and facilitate product recalls, they have little bearing on pharmacovigilance. Indeed, a recent publication from academic experts on pharmacovigilance policy suggested that the term “traceability” should encompass:

“The ability to trace each individual unit of a medicinal product from the source to its final destination, and vice versa.”397 We agree that traceability of pharmaceuticals is critical, and thus support measures such as the DQSA directed toward improving supply chain security in the U.S. However, unless the detailed product identification information required for supply chain traceability also makes it the last step of the journey into the patient’s health record, it will remain challenging to trace the product from its final destination (the patient) back to the source.

The enacted legislation includes some provisions that might ultimately be helpful towards improving traceability of drugs dispensed to patients.398 Among other provisions, the DQSA requires the eventual implementation of bar code labeling that would facilitate automated capture of product identifiers including NDC and batch number with each transaction between the manufacture and dispenser.399 However, we note that pharmacy dispensing transactions themselves are expressly excluded from the draft legislation.400 To the extent that bar coding could help pharmacovigilance, if and when these proposed labeling requirements are implemented, additional incentives and systems would be required

397 Cromellin et al., Different Pharmaceutical Products Need Similar Terminology, AAPS J. (Sep. 2013), http://link.sp ringer.com/article/10.1208%2Fs12248-013-9532-0 (subscription required). 398 See Drug Quality and Security Act, Pub. L. No. 113-54 (2013) 399 Id. at § 202 (adding § 582 to the FDCA, directing the Secretary to issue guidelines requiring bar-code transaction recording) 400 Id. (adding § 582(24)(B)(iv) to the FDCA, exempting pharmacy dispensing from the proposed bar-code requirements of § 581).

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for pharmacists to automatically capture the detailed information into a patient’s electronic health record.401

B. Amgen believes increasing automation of transactions and records in all settings of use can be harnessed to improve PV.

Contrary to GPhA, Amgen believes claims-based safety data analysis, such as the FDA’s Sentinel program, can be a useful adjunct to voluntary/spontaneous safety reporting system for biologics so long as assigned HCPCS codes are product-specific and ICD coding identifies biologic-relevant diagnoses such as loss of efficacy. We have assessed one potential objection to use of NDCs for pharmacovigilance, namely that claims based systems in important settings such as hospital outpatient and physician offices do not track the NDC in most cases and do not transfer NDC where submitted to claims databases. As CMS has explained, this is in large part a systems capacity constraint given approximately 6,000 HCPCS codes and 90,000 NDCs in comparison.402 It is feasible for CMS to assign unique HCPCS codes to biosimilars. This simple policy measure would facilitate active surveillance in the physician office and hospital outpatient settings. Even if the coding challenges can be addressed, we note that, as cited by the Petitioners, some experts have expressed reservations about whether the Sentinel system can detect certain immunological AEs.403, 404 We believe that claims based systems can be an important adjunct to SRS in monitoring multisource biologics, but the utility will depend on the setting and the nature of the safety signals being evaluated.

We support further evaluation of the utility of the Sentinel program for post-approval monitoring of multisource biological products. In this context, we believe that distinguishable nonproprietary names and advances in HIT deployment could improve traceability of AEs in institutional settings, whether linked to spontaneous reports or claims-based reports. Nevertheless, we note that under current regulations, manufacturers are required to work with the SRS, and as we have previously noted, with current levels of HIT interoperability, NDCs are of limited utility to spontaneous reporting for both pharmacy and non-pharmacy (physician office and hospital outpatient) settings.

C. Amgen’s vision for the future of pharmacovigilance for biosimilars and other biologics

Biologics, including biosimilars, are different than chemical drugs and generics and they are utilized differently in patient care. The biosimilar marketplace must have rules that are based on the science and medicine of biotechnology; these are not the same rules that make sense for generic drugs. Competition in the biosimilars marketplace must be based on increased transparency, identification and recordkeeping approriate to the nature of biologic products.

401 See L. DiMartino et al. Using Medicare Administrative Data to Conduct Postmarketing Surveillance of Follow-On Biologics: Issues and Opportunities, 63 Food & Drug Law J. 900 (2008). 402 See Cynthia Hake, Centers for Medicare & Medicaid Services, presentation at Engleberg Center for Health Care Reform at Brookings Workshop: Developing Systems to Support Pharmacovigilance of Biologic Products, (Nov. 15, 2013), agenda available at http://www.brookings.edu/events/2013/11/20-systems-support-pharmacovigilance- biologic-products (accessed Dec. 11, 2013). 403 GPhA Pet. 11 n.43 (citing Platt et al., The U.S. Food and Drug Administration’s Mini-Sentinel Program: Status and Direction, 21 Pharmacoepidemiology and Drug Saf. (S1) 1 (2012)). 404 Brian Strom, Methodologic Challenges to Studying Patient Safety and Comparative Effectiveness, 45 Medical Care S13-S15 (2007).

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We have long experience managing manufacturing risks and designing rigorous quality systems both to prevent errors and to quickly address those that cannot be predicted. We have seen both predictable and surprising changes in product quality—with our biologics and with others. Through this experience we have pioneered systems to perform post-market safety surveillance and statistical signal-detection for biologics. We have also experienced misattribution of adverse events to the wrong manufacturer and adverse events that have changed the benefit/risk assessment for entire classes of medicines.

In this context our vision is for increasing access to biologic medicines and doing so in a manner that ensures patient and physician confidence and a successful and lasting U.S. biosimilars program.

 We believe in supporting the biosimilars and complete and accurate patient medical records.

 We believe in adverse event reporting where specific products are identified and lot numbers and NDCs provide confirmation.

 We believe physicians and patients should be able to use biosimilars with confidence in the products and the manufacturers.

A forward-looking and accurate and effective pharmacovigilance system is attainable. A future system would likely constitute a wholly electronic, national system where 2D barcodes would contain all necessary information to accurately identify a medicine. Such barcodes could be scanned at multiple points in the supply chain on dedicated equipment or on smartphones by health care professionals or patients prior to administration, uploading data instantly to secure databases be held confidentially and available for immediate access when necessary. When investigating product problems such as adverse events, FDA would be able to identify precisely which medicines a patient has received, when and where they received it. However, such a comprehensive national system, while conceivable, is several years or more from being a reliable reality for all patients, all medicines and all healthcare systems.

With biosimilars potentially available in the U.S. within the next year and a clear regulatory need for accurate biologic product identification that exceeds the capabilities of the current system – there exists an immediate need for a practical solution to ensure that the pharmacovigilance systems can accurately collect information to accurately identify biologics associated with AEs. To achieve this goal, healthcare professionals will need to be educated on their responsibility to accurately report AEs, and regulators will need to facilitate accurate reporting by ensuring that biosimilar products are uniquely identified via an appropriately redundant system so that whatever the identifier used, the event can be traced to the actual associated product.

We believe if we are transparent, specific, science-based, and most importantly, accountable, then we will earn the trust and confidence of physicians, of patients, and of their families. And we will see a meaningfully more successful biosimilars program in the United States.

VIII. CONCLUSION

For the reasons set forth above, we believe that a policy under which a biosimilar approved through the Section 351(k) pathway would bear the identical non-proprietary name as its reference product would create significant public health risks, would impair rather than improve existing pharmacovigilance systems, and could not be implemented in a manner consistent with applicable legal requirements. We urge FDA to reject such a policy, and for the emerging biosimilars industry to join FDA in continuing a policy of distinguishable non-proprietary names that utilizes common stems but differentiating prefixes

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or, if preferable, suffixes. A policy of distinguishable names would enable the non-proprietary names to reflect the biological similarity between a biosimilar and its reference product, without creating the misleading impression that non-identical products are in fact identical, and would improve, rather than diminish, existing pharmacovigilance systems.

Respectfully submitted,

Paul R. Eisenberg, M.D., M.P.H., F.A.C.P., F.A.C.C. Senior Vice President

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