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Biologics and Biosimilars: Background and Key Issues

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Biologics and Biosimilars: Background and Key Issues

October 27, 2017Updated June 6, 2019 (R44620)
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Summary

A biological product, or biologic, is a preparation, such as a drug or a vaccine, that is made from living organisms. Compared with conventional chemical drugs, biologics are relatively large and complex molecules. They may be composed of proteins (and/or their constituent amino acids), carbohydrates (such as sugars), nucleic acids (such as DNA), or combinations of these substances. Biologics may also be cells or tissues used in transplantation.

A biosimilar, sometimes referred to as a follow-on biologic, is a therapeutic drug that is highly similar but not structurally identical, to thea brand-name biologic made by a pharmaceutical or biotechnology company. In contrast,(i.e., the reference product). This is in contrast to a generic chemical drug, which is an exact copy of a brand-name chemical drug (i.e., the reference listed drug). Because biologics are more complex than chemical drugs, both in composition and method of manufacture, biosimilars will not be exact replicas of the brand-name product, but may instead be shown to be highly similar. The Food and Drug Administration (FDA) regulates both biologics and chemical drugs.

Biologics and biosimilars frequently require special handling (such as refrigeration) and processing to avoid contamination by microbes or other unwanted substances. Also, they are usually administered to patients via injection or infused directly into the bloodstream. For these reasons, biologics often are referred to as specialty drugs. The cost of specialty drugs, including biologics, can be extremely high.

In April 2006, the European Medicines Agency (EMA) authorized for marketing in Europe the first biosimilar product, Omnitrope, a human growth hormone. The EMA lists a total of 40 biosimilars on its website; 2 products were refused authorization and 3 were withdrawn, leaving a total of 35 biosimilars authorized for the European market. The introduction of biosimilars in Europe has reduced prices for biologics overall, in some cases by 33% compared with the original price of the brand-name product. For one drug in Portugal, the price reduction was 61%.

In contrast, the pathway to marketing biosimilars in the United States has had several barriers. FDA approved Omnitrope in June 2006, following an April 2006 court ruling requiring the FDA to move forward with consideration of the application. At the time Omnitrope was approved, FDA indicated that this action "does not establish a pathway" for approval of other follow-on biologic drugs and stated that Congress must change the law before the agency can approve copies of nearly all other such products.

Four years later, in March 2010, Congress established a new regulatory authority for FDA by creating an abbreviated licensure pathway for biological products demonstrated to be "highly similar" (biosimilar) to or "interchangeable" with an FDA-licensed biological product. The new authority was accomplished via the Biologics Price Competition and Innovation Act (BPCIA) of 2009, enacted as Title VII of the Affordable Care Act (ACA, P.L. 111-148). Congress authorized FDA to collect associated fees via the Biosimilar User Fee Act of 2012 (BsUFA, P.L. 112-144). The five-year biosimilars user fee authority was set to expire on September 30, 2017. Congress reauthorized the biosimilar user fee program via the Food and Drug Administration Reauthorization Act of 2017 (FDARA, P.L. 115-52).

As more biosimilars enter the U.S. market, analysts expect to see U.S. price reductions similar to those that have occurred in Europe. However, of the seven biosimilars approved by FDA, sales of five biosimilars have been delayed, or (allegedly) adversely impacted, by actions of the brand-name manufacturers. Three biosimilars (Erelzi, Amjevita, and Cyltezo) have had their marketing launch delayed by patent infringement lawsuits filed by brand-name manufacturers. In addition, Pfizer has sued Johnson & Johnson (J&J) alleging that J&J has entered into anticompetitive contracts with insurers that prevent coverage of Pfizer's biosimilar (Inflectra), a less expensive substitute for J&J's best-selling biologic (Remicade). The alleged anticompetitive practices would be expected to have a negative impact on another recently approved biosimilar (Renflexis)However, for many years, the drug industry and the Food and Drug Administration (FDA) have coped with the inherent variability in biological products from natural sources. FDA maintains that the batch-to-batch and lot-to-lot variability that occurs for both brand-name biologics and biosimilars can be assessed and managed effectively.

The FDA regulates both biologics and chemical drugs. Before a biologic or biosimilar may be marketed in the United States, it must be licensed (i.e., approved) by FDA. To obtain licensure of a new biologic, the sponsor (generally the manufacturer of the product) submits to the agency a biologics license application (BLA) with data demonstrating that the biologic, and the facility in which it is manufactured, processed, packed, or held, meet standards to assure that the product is safe, pure, and potent. The Biologics Price Competition and Innovation Act (BPCIA)—enacted as Title VII of the Patient Protection and Affordable Care Act (ACA, P.L. 111-148)—established an abbreviated licensure pathway for biosimilar biological products or biosimilars. To obtain licensure of a biosimilar, the sponsor submits to FDA a BLA that provides information demonstrating, among other things, biosimilarity based on data from analytical studies (structural and functional tests), animal studies (toxicity tests), and/or a clinical study or studies (tests in human patients).

Since enactment of the BPCIA, as of May 29, 2019, 19 biosimilars—for nine reference products—have been licensed in the United States. However, many of these licensed biosimilars are not yet available to patients, primarily due to ongoing litigation, although various factors may impact uptake of biosimilars.

Biologics and biosimilars frequently require special handling (such as refrigeration) and processing to avoid contamination by microbes or other unwanted substances. Also, they are usually administered to patients via injection or infused directly into the bloodstream. For these reasons, biologics often are referred to as specialty drugs. The cost of specialty drugs, including biologics, can be extremely high.

The high costs of pharmaceuticals in general—and biologics in particular—has led to an increased interest in understanding the federal government's role in the development of costly new therapeutics. In the case of six of the sevenmany biosimilars approved by FDA, the associated brand-name drugbiologic was originally discovered by scientists at public-sector research institutions. Several of theseThese brand-name biologics (Remicade, Enbrel, Humira, Avastin) are among the top-selling drugs in the United States and worldwide.


Biologics and Biosimilars: Background and Key Issues

Introduction

A biologic or biological product is a preparation, such as a therapeutic drug or a vaccine, made from living organisms, either human, animal, yeast, or microorganisms. Biologics are composed of proteins (and/or their constituent amino acids), carbohydrates (such as sugars), nucleic acids (such as DNA), or combinations of these substances. Biologics may also be cells or tissues used in transplantation.

A biosimilar, sometimes referred to as a follow-on biologic, is a therapeutic drug that is highly similar but not structurally identical to the brand-name biologic made by a pharmaceutical or biotechnology company. The brand-name product is sometimesa brand-name biologic, also referred to as the innovator or reference product.

In contrast to biologics, most commonly used drugs—over-the-counter drugs and most prescription drugs—are synthesized via a chemical process. A generic drug is chemically identical to its reference brand-name drug. The molecular structure of a commonly used chemical drug is much smaller than a biologic and therefore less complicated and more easily defined. For example, Table 1 shows that the chemical drug aspirin contains nine carbon atoms, eight hydrogen atoms, and four oxygen atoms while the large biologic drug Remicade contains over 6,000 carbon atoms, almost 10,000 hydrogen atoms, and about 2,000 oxygen atoms. Inflectra, which is biosimilar to Remicade, was approved by the Food and Drug Administration (FDA) in April 2016.

Table 1. Relative Size of Chemical and Biologic Drugs

Drug (nonproprietary name)

Molecular formula

chemical drugs

aspirin

C9H8O4

Tylenol (acetaminophen)

C8H9NO2

Sovaldi (sofosbuvir)

C22H29FN3O9P

small biologic drugs

Lantus (insulin glargine)

C267H404N72O78S6

Epogen (epoetin alfa)

C809H1301N229O240S5

Neupogen, Zarxio (filgrastim)

C845H1339N223O243S9

growth hormone (somatropin)

C990H1528N262O300S7

large biologic drugs

Enbrel, Erelzi (etanercept)

C2224H3472N618O701S36

Remicade, Inflectra (infliximab)

C6428H9912N1694O1987S46

Source: Drugs@FDA, https://www.accessdata.fda.gov/scripts/cder/daf/, and Drugs.com.

Notes: The nonproprietary name of a drug product is used in drug labeling, drug regulation, and scientific literature to identify a pharmaceutical substance or active pharmaceutical ingredient. C, carbon; H, hydrogen; O, oxygen; N, nitrogen; F, fluorine; P, phosphorus; S, sulfur.

The FDA regulates both biologics and chemical drugs. The Center for Biologics Evaluation and Research (CBER) within FDA regulates what are often referred to as traditional biologics, such as vaccines, blood and blood products, allergenic extracts, and certain devices and test kits.1 CBER also regulates gene therapy products, cellular therapy products, human tissue used in transplantation, and the tissue used in xenotransplantation—the transplantation of nonhuman cells, tissues, or organs into a human.2

The FDA Center for Drug Evaluation and Research (CDER) regulates prescription brand-name and generic drugs, over-the-counter drugs, and most therapeutic biologics; this last responsibility was transferred from CBER to CDER in 2003.3 See Appendix A for further details. Examples of types of therapeutic biologics regulated by CDER are briefly described in the list below.4

  • Biologics and biosimilars frequently require special handling (such as refrigeration) and processing to avoid contamination by microbes or other unwanted substances. Also, they are usually administered to patients via injection or infused directly into the bloodstream. For these reasons, biologics often are referred to as specialty drugs.1 In the past, biologics were often dispensed by pharmacies with specialized facilities and personnel. The term specialty drugs is now often used to describe drugs that are expensive for any of several reasons, including the requirement for special handling. The cost of specialty drugs, including biologics, may be extremely high. For example, the annual cost of some biologic medications in the United States, such as Soliris (eculizumab) and Vimizim (elosulfase alfa), exceeds $250,000 per patient.2 The use of biologics and spending on these products has been increasing; see for example Appendix B. Spending on biologics in the United States totaled $120.1 billion in 2017, a 12.5% increase over 2016.3 The amount spent on "original" biologics subject to biosimilar competition in 2017 was $10.6 billion (8.8% of $120.1 billion), and the amount spent on biosimilars in 2017 was $0.9 billion (0.7% of 120.1 billion).4 Biologics spending has increased by 10% each year since 2011.5

    Biologic drugs are often more expensive in the United States than in Europe and Canada.6 In Europe, the introduction of biosimilars has reduced prices for biologics, which may be attributed to price regulation interventions and commercial decisions of manufacturers.7 For example, in October 2018, AbbVie agreed to an 80% price reduction in certain European countries on the monoclonal antibody Humira, the top selling drug in the world, after the introduction of several biosimilars there.8

    Biologics and biosimilars are larger in size than chemical drugs and their manufacturing and purification processes can be more complicated and more expensive than those used to make chemical drugs. However, information about manufacturing costs for drugs and biologics is generally not publicly available, although a few studies have attempted to estimate the cost of production of certain biologics. For example, one study examined the cost of insulin production, concluding that "it may be possible to profitably manufacture biosimilar insulins at prices of US$72 per year or less for human insulin and US$133 per year or less for insulin analogues."9 The study notes several limitations, including that expenses associated with registration, quality assurance and control, and other costs were not individually considered. Additionally, as explained later in this report, for historical reasons, insulin has been regulated by FDA as a drug rather than as a biologic; as such, there are currently no biosimilar insulins available in the United States. Another analysis looked specifically at the manufacturing processes for therapeutic monoclonal antibodies, a class of biologics that includes many cancer drugs. According to the paper, which was authored by a bioprocess engineering expert at Genentech, monoclonal antibodies "are becoming a unique class of therapeutic products… with unlimited production capacity and low production costs, whose pricing will have no direct link to drug substance product. The pricing will instead reflect the innovator companies' clinical investment in addition to costs incurred from failed pipeline products."10

    As discussed later in the report (see "Federal Research and Biologics Development"), many of the top-selling brand-name biologics—for example, Humira, Remicade, Enbrel, Avastin—were originally discovered by scientists performing basic research at public-sector institutions. However, the next phase of research—clinical testing—is often claimed to be the most expensive step in bringing a pharmaceutical product to market, although estimates for clinical trial costs vary depending on the therapeutic area and study's assumptions.

    FDA Regulation of Biologics Biological products were originally regulated by the National Institutes of Health (NIH) and its precursors. In 1972, this regulatory responsibility was transferred to FDA; see Appendix A of this report for further details.

    FDA generally regulates biologics pursuant to its authorities under the Public Health Service Act (PHSA), but regulates some biologics as drugs under authorities in the Federal Food, Drug and Cosmetic Act (FFDCA). Responsibility for regulation of biologics within FDA is shared by both the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER). CBER regulates what are often referred to as traditional biologics, such as vaccines, blood and blood products, allergenic extracts, and certain devices and test kits.11 CBER also regulates gene therapy products, cellular therapy products, human tissue used in transplantation, and the tissue used in xenotransplantation—the transplantation of nonhuman cells, tissues, or organs into a human.12

    CDER regulates—in addition to prescription brand-name and generic drugs and over-the-counter drugs—most therapeutic biologics. Responsibility for therapeutic biologics was transferred from CBER to CDER in 2003.13 See Appendix A for further details. Examples of types of therapeutic biologics regulated by CDER are briefly described in the list below.14
    Monoclonal antibodies—proteins that bind to a specific substance in the body or a specific cell. A monoclonal antibody may carry a drug or toxin. An example of a monoclonal antibody product is infliximab, used to treat Crohn's disease, ulcerative colitis, rheumatoid arthritis, and psoriasis.
  • Cytokines—proteins that control (stimulate or slow down) the immune system and are used to fight cancer, infections, and other diseases. Examples include interleukins, interferons, and colony-stimulating factors, such as filgrastim.
  • Growth factors—substances, such as hormones, made by the body that regulate cell division and cell survival, such as the human growth hormone somatropin.
  • Enzymes—proteins that speed up chemical reactions in the body. Enzymes take part in many cell functions, including cell signaling, growth, and division. In cancer treatment, enzyme inhibitors may be used to block certain enzymes that cancer cells need to grow.
  • Immunomodulators—substances, such as a vaccine, that stimulate or suppress the immune system and may help the body fight cancer, infection, or other diseases.

Biologics and biosimilars frequently require special handling (such as refrigeration) and processing to avoid contamination by microbes or other unwanted substances. Also, they are usually administered to patients via injection or infused directly into the bloodstream. For these reasons, biologics often are referred to as specialty drugs.5 In the past, biologics were often dispensed by pharmacies with specialized facilities and personnel. The term specialty drugs is now used to describe drugs that are expensive for any of several reasons, including the requirement for special handling.

The cost of specialty drugs, including biologics, may be extremely high. For example, the annual cost of some biologic medications, such as Soliris (eculizumab) and Vimizim (elosulfase alfa), exceeds $250,000 per patient.6 The use of biologics and spending on these products has been increasing; see for example Appendix C. Spending on biologics in the United States totaled $105.5 billion in 2016, a 13% increase over 2015.7 The amount spent on biologics subject to biosimilar competition in 2016 was $3.2 billion (3% of $105.5 billion), of which $2.9 billion was spent on "original" biologics and $0.3 billion was spent on biosimilars.8 Biologics spending has increased by 10% each year since 2011.9

According to a December 2016 report to Congress by the Department of Health and Human Services (HHS), "[i]ncreases in spending in the Medicare Part B program have been driven by increases in biologics. Spending on biologics between 2006 and 2014 grew by 13.3 percent annually, whereas spending on small molecule drugs grew by 0.7 percent annually during the same period. In 2014, biologics accounted for 63 percent of prescription drug spending in Part B."10

Biologic drugs are often more expensive in the United States than in Europe and Canada; see Appendix B. In Europe, the introduction of biosimilars has reduced prices for biologics, in some cases by 33% compared with the original price of the reference product; for one drug in Portugal, the price reduction was 61%.11

The next section of this report describes efforts by Congress to lower the price of commonly used chemical drugs via passage of the 1984 Hatch-Waxman Act and its use of a similar approach in 2010 to provide lower-cost alternatives for biologics.

Events Leading Up to Biosimilars Legislation

Congress passed the Drug Price Competition and Patent Term Restoration Act of 1984 (P.L. 98-417)—often called the Hatch-Waxman Act—to allow for the FDA approval ofMost biological products are regulated—licensed for marketing by FDA via a biologics license application (BLA)—under authorities in the Public Health Service Act (PHSA).15 This is in contrast to chemical drugs, which are approved for marketing by FDA via a new drug application (NDA) or abbreviated new drug application (ANDA). To obtain licensure, the sponsor (generally the manufacturer) must demonstrate in the BLA that the biological product, and that the facility in which it is manufactured, processed, packed, or held, meet standards to assure that the product is safe, pure, and potent.16 As is the case with other FDA-approved products, any subsequent change to the approved manufacturing process—such as a change in the supplier of a raw material or the replacement of a piece of equipment—requires a demonstration to FDA of the comparability of the product's quality attributes before and after the change to ensure that the safety and effectiveness of the product is maintained. For example, the brand-name biologic Remicade (infliximab) underwent 37 manufacturing changes between 1998 and October 2014; each change required a demonstration of comparability, most likely through chemical, physical, and biological assays.17

Historically, certain biological products were regulated as drugs, approved via an NDA under the FFDCA rather than as biologics by NIH under the PHSA. In 1941, Congress gave FDA authority over the marketing of insulin, a natural source biological product.18 The hormone insulin is a small protein (a short chain of 51 amino acids) and in the 1940s, it was obtained in the same way as many biologics—extraction from animals—hence the term "natural source."19 Despite this similarity with other biologics, insulin was regulated as a drug by FDA rather than as a biologic by NIH. Besides insulin, a small set of other natural source biological products have been regulated as drugs under the FFDCA rather than as biologics under the PHSA: the hormone glucagon, human growth hormone, hormones to treat infertility, hormones used to manage menopause and osteoporosis, and certain medical enzymes (hyaluronidase and urokinase).20

In the late 1970s and early 1980s, the biotechnology industry began to develop its first biologics for use as human therapeutic agents (e.g., recombinant proteins and monoclonal antibodies). Some of these products were regulated as drugs under the FFDCA (e.g., insulin and human growth hormone created using recombinant DNA technology), while others were regulated as biologics under the PHSA (e.g., cytokines, proteins involved in the immune response, and blood factors). As such, currently, while most biologics are licensed under the PHSA, some are approved as drugs under the FFDCA. This will no longer be the case on March 23, 2020, when applications for biologics approved under the FFDCA will be deemed to be licenses under the PHSA (see "New Regulatory Pathway for Biosimilars").21

In 2010, the Biologics Price Competition and Innovation Act (BPCIA)—enacted as Title VII of the Patient Protection and Affordable Care Act (ACA, P.L. 111-148), established an abbreviated pathway under the PHSA for licensure of biosimilar biologics (i.e., biosimilars, sometimes referred to as follow-on biologics). A biosimilar is a biological product that is demonstrated to be "highly similar" (i.e., biosimilar), but not identical, to an FDA-licensed biological product (i.e., the reference product). The next sections describe events leading up to the enactment of the BPCIA and provide an overview of the requirements governing the abbreviated licensure process for biosimilars.

Events Leading Up to Biosimilars Legislation In contrast to biosimilars, generic drugs have been able to be marketed in the United States since 1984 when the Drug Price Competition and Patent Term Restoration Act of 1984 (P.L. 98-417)—often called the Hatch-Waxman Act—established an abbreviated approval pathway for generic chemical drugs. generic chemical drugs.12 By offering ana lower-priced alternative to brand-name drug products, the Hatch-Waxman Act has been credited with lowering the cost of drugs to consumers, as well as allowing the U.S. generic drug industry to expand.

22 For chemical drugs, "generic medications decrease prices 60% to 90% on branded oral-solid medications," according to some experts.13 The23 Generally, generic drug industry achievesmanufacturers achieve cost savings by avoiding the expense of clinical trials, as well as the initial drug research and development costs incurred by the brand-name manufacturer. Before a generic drug is approved for marketing, the generic drug company must demonstrate to the FDA that the drug product is identical to the original product. To obtain approval of a generic drug, the manufacturer submits to FDA an ANDA demonstrating that the generic drug is the same as the brand-name drug (i.e., the reference listed drug [RLD]). To prove sameness, the generic must have the same active ingredient(s), strength, dosage form, and route of administration as the RLD; be bioequivalent to the RLD; and meet other requirements (e.g., reviews of chemistry, manufacturing, controls, labeling, and testing).24 This "sameness" allows the generic company to rely on, or "reference," the FDA's previous finding of safety and effectiveness for the already approved drug. A generic drug is generally considered to be interchangeable with its reference (brand-name) drug and with other generic products that use the same reference drug.

The Hatch-Waxman Act established a second abbreviated pathway, the so-called 505(b)(2) pathway. This pathway has been used to approve some biological products under the FFDCA, specifically follow-on natural source biologics that had received approval under the FFDCA rather than licensure under the PHSA. In contrast to an ANDA, a 505(b)(2) NDA contains full reports of investigations of safety and effectiveness, but at least some of the information relied upon for approval comes from studies that were not conducted by or for the applicant and for which the applicant has not obtained a right of reference. A 505(b)(2) NDA may rely on published literature or on FDA's finding of safety and effectiveness for the RLD.

The Hatch-Waxman Act provided a mechanism for the approval of generic drugs and certain follow-on biologics under the FFDCA, but not for follow-on biologics or biosimilars under the PHSA. As a result, after Hatch-Waxman, companies could submit so-called follow-on applications (i.e., 505(b)(2) NDAs) for FDA review only for the small number of biologics that had been approved under the FFDCA (e.g., insulin). Companies were effectively blocked from submitting follow-on applications for the much larger group of therapeutic biologics that had been licensed under the PHSA.

Insulin: Case Study of a Small Biologic

Insulin production has changed over the years as researchers have made alterations to the product that have eased its use by patients. The original insulin, also called regular insulin, is a short-acting product with a duration of action of about eight hours. In the late 1930s through the 1950s, regular insulin was altered by adding substances to gain longer action; these are called intermediate-acting insulins. In 1982, recombinant DNA technology allowed for the replacement of animal insulin by human insulin made by microorganisms in a laboratory fermentation process. Over the past few decades, slight modifications of the insulin molecule—called insulin analogs—have been developed. Long-acting insulin analogs, Lantus (insulin glargine) and Levemir (insulin detemir), entered the market in the early 2000s. Rapid-acting insulin analogs Humalog (insulin lispro) and Novolog (insulin aspart) were developed to allow for quicker absorption and shorter duration of action. As a result, there are now five types of insulin products: long-acting, rapid-acting, intermediate-acting, short-acting (regular insulin), and premixed. The price of certain insulin products has risen significantly. For example, from 2001 to 2015, the price of insulin lispro increased 585% (from $35 to $234 per vial). One vial may last a patient less than two weeks.

Currently, three firms—Eli Lilly, Novo Nordisk, Sanofi Aventis—account for over 90% of the global market and 100% of the U.S. insulin market. An FDA analysis found that a drug's price is directly affected by the number of different companies marketing the drug. Because three firms make all the insulin used in this country, the market behaves differently from the usual case in pharmaceutical markets where generic competition results in price reductions. A 1995 analysis of Eli Lilly's insulin production process found that the total cost involved in making enough insulin to treat one patient per year was $33.60. A 2018 study calculated that a year's supply of human insulin could be priced at $48 to $71 per person and analog insulins could be priced at between $78 and $133; this amount would cover production costs and still deliver a profit to the manufacturer. How much profit is fair is a large piece of the drug pricing puzzle. A 2017 Government Accountability Office (GAO) report found that the average profit margin for the largest 25 drug companies—companies with the highest pharmaceutical and biotechnology sales revenue in 2015—was 20% in 2015, compared with 6.7% for the largest 500 U.S. companies in general. The three insulin manufacturers are among the largest 25 drug companies. For further details, see CRS In Focus IF11026, Insulin Products and the Cost of Diabetes Treatment.

Even when patent protection for biological products was approaching expiration, the market competition that occurred with chemical drugs via generics could not happen with therapeutic biologics because FDA lacked clear regulatory authority to approve biosimilars. Although some entities, such as the Generic Pharmaceutical Association (GPhA, now called the Association for Accessible Medicines), advocated that the FDA establish a regulatory system for the approval of biosimilars under its existing statutory authority,25 the Biotechnology Industry Organization (BIO) filed a citizen petition with the FDA requesting a number of actions that would have inhibited the approval of biosimilars.26

In April 2006, the European Medicines Agency (EMA) authorized for marketing in Europe the first biosimilar product, Omnitrope, a human growth hormone derived from recombinant DNA processes. This was followed by the authorization of five other biosimilar products in 2007, two more in 2008, and numerous others thereafter.27

In the United States, FDA approval of Omnitrope via the 505(b)(2) pathway was announced in June 2006 following an April 10, 2006, ruling by the U.S. District Court for the District of Columbia in favor of Omnitrope's sponsor, Sandoz.28 The court ruled that the FDA must move forward with consideration of the application, submitted by Sandoz in 2003, which presented Omnitrope as "indistinguishable" from the FDA-approved Genotropin, marketed by Pfizer. Sandoz "alleged that the FDA had violated its statutory obligation to act on the Omnitrope application within 180 days, a time frame that the FDA characterized as merely a congressional aspiration."29

Omnitrope was not the first follow-on biologic approved through the abbreviated 505(b)(2) pathway.30 However, scientific and regulatory uncertainty surrounding its approval may have signaled to Congress that legislation was needed to allow for approval/licensure of follow-on biologics under the PHSA. At the time of the Omnitrope approval in 2006, FDA indicated in a document on the agency's website that this action "does not establish a pathway" for approval of other follow-on biologics. "The agency has said that Congress must change the law before it can approve copies of nearly all other biotech products, and lawmakers haven't moved on the issue."31

New Regulatory Pathway for Biosimilars In March 2010, the BPCIA—enacted as Title VII of the ACA—established a new regulatory authority for FDA by creating an abbreviated licensure pathway in Section 351(k) of the PHSA for biological products that are demonstrated to be "highly similar" (biosimilar) to or "interchangeable" with an FDA-licensed biological product. The ACA also directed FDA to develop and present to Congress recommendations for a user fee program to support review of biosimilar product applications submitted under Section 351(k) of the PHSA.32 The Biosimilar User Fee Act of 2012 (BsUFA), enacted as Title IV of Food and Drug Administration Safety and Innovation Act (FDASIA, P.L. 112-144), authorized FDA to assess and collect fees for biosimilars (for additional information about the user fee legislation, see Appendix A).

Under Section 351(k) of the PHSA, a company interested in marketing a biosimilar product in the United States must first submit to FDA an application that provides information demonstrating, among other things, biosimilarity based on data from analytical studies (structural and functional tests), animal studies (toxicity tests), and a clinical study or studies (tests in human patients). The agency may decide, at its discretion, that a certain study or studies are unnecessary in a biosimilar application.33 A biological product may be demonstrated to be "biosimilar" to the reference product if data show that the product is "highly similar" to the reference product, notwithstanding minor differences in clinically inactive components, and there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency.34

To be considered interchangeable with the reference product, the applicant must show that the biologic is biosimilar to the reference product and that it can be expected to produce the same clinical result as the reference product in any given patient. Additionally, for products administered more than once, the applicant must demonstrate that "the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch."35 Interchangeable products may be substituted for the reference product by a pharmacist without the intervention of the prescribing health care provider.36 To date, FDA has not approved any interchangeable products.

Because biologics are more complex than chemical drugs, both in composition and method of manufacture, biosimilars will not be exact replicas of the brand-name product, but may instead be shown to be highly similar. However, for many years, the drug industry and FDA have coped with the inherent variability in biological products from natural sources. FDA maintains that the batch-to-batch and lot-to-lot variability that occurs for both brand-name biologics and biosimilars can be assessed and managed effectively.

Under the BPCIA, biologics that were approved as drugs under the FFDCA will transition to biological licenses under the PHSA in March 2020—the so-called "deemed to be a license" provision.37 This BPCIA provision affects the relatively small set of biological products that were approved under the FFDCA: hormone insulin, hormone glucagon, human growth hormone, hormones to treat infertility, hormones used to manage menopause and osteoporosis, and certain medical enzymes (hyaluronidase and urokinase). While the BPCIA requires that an NDA for a biologic is deemed to be a BLA on the date that is 10 years after enactment (i.e., March 23, 2020), the statute is silent on implementation. FDA released draft guidance regarding the agency's interpretation of this BPCIA provision in March 2016 and final guidance in December 2018.38

In FDA's interpretation, as of March 23, 2020, applications for biological products that were approved under the FFDCA will no longer exist (as NDAs or ANDAs) and will be replaced by approved BLAs under the PHSA. In addition, FDA will not approve any application under the FFDCA for a biological product subject to the transition provisions that is still pending as of March 23, 2020. The FDA suggests that such applications be withdrawn and resubmitted under the PHSA, either under Section 351(a) (a full BLA) or 351(k) (a BLA for a biosimilar or interchangeable biological product).

To balance competition and innovation, the BPCIA established two periods of exclusivity applicable to a brand-name biologic (i.e., the reference product)—one with a duration of 4 years and the other with a duration of 12 years.39 Periods of regulatory exclusivity attach upon approval or licensure of a drug or biologic, respectively, if certain statutory requirements are met, limiting the ability of competitors to reference the data generated by brand-name drug manufacturers. During the four-year exclusivity period, a BLA for a biosimilar or interchangeable product referencing the brand-name biologic may not be submitted to FDA. During the 12-year exclusivity period, approval of a BLA for a biosimilar or interchangeable product referencing the brand-name biologic may not be made effective. This means that FDA may not approve a BLA for a biosimilar or interchangeable product until 12 years after the date on which the reference product was first licensed, and a BLA for a biosimilar or interchangeable product cannot be submitted to FDA until four years after the date on which the reference product was licensed. Certain biologics are not eligible for the reference product exclusivity, for example, if an application is for a minor change to a previously licensed biologic.40 A new biologic may be eligible for an additional 6-month period of exclusivity that would attach to the 12- and 4-year periods if the applicant conducts pediatric studies pursuant to a written request from FDA.41 Additionally, a biologic approved to treat a rare disease or condition may be granted seven years of orphan drug exclusivity for the protected indication, in which case FDA may not license another biologic for the protected orphan indication until after the expiration of the 7-year or 12-year exclusivity period, whichever is later.42 While the first biosimilar for a brand-name is not eligible for exclusivity, the first interchangeable product is. This means that FDA will not make an interchangeability determination for a subsequent biologic relying on the same reference product for any condition of use until such exclusivity expires.43 The periods of exclusivity available for biological products under the PHSA are generally longer than those for chemical drugs under the FFDCA (i.e., five-year new chemical entity exclusivity, three-year new clinical study exclusivity).

Transitional biological products will not be eligible for the 12-year biologics exclusivity period because they were not first licensed under the PHSA, as specified by the BPCIA. In guidance, FDA states, "[n]othing in the BPCI Act suggests that Congress intended for biological products approved under section 505 of the FD&C Act—some of which were approved decades ago—to obtain a 12-year period of reference product exclusivity upon being deemed to be licensed under section 351(a) of the PHS Act."44

Additionally, according to FDA guidance, any unexpired period of exclusivity associated with an approved NDA for a biologic subject to the transition would cease to have any effect.45 This would include the five-year new chemical entity exclusivity awarded to a drug whose active ingredient FDA has not previously approved, as well as the three-year new clinical study exclusivity, which may be awarded with respect to an NDA or supplemental NDA for a previously approved active ingredient (e.g., for a change in route of administration or new indication). For example, Sanofi, the manufacturer of the insulin Admelog, would lose almost 9 months of Hatch-Waxman exclusivity in the transition (Admelog's exclusivity expires on December 11, 2020).46 Any unexpired periods of orphan drug exclusivity would continue to apply for the protected indication after March 23, 2020, as orphan drug exclusivity can block the approval of a drug approved under the FFDCA or a biologic licensed under the PHSA. Similarly, any unexpired pediatric exclusivity associated with an approved NDA for a biologic would continue to apply to a deemed BLA after March 23, 2020.47 Approval and Marketing of Biosimilars The biosimilars market is still developing and while less than 2% of Americans use biologics, these products represent 40% of total spending on prescription drugs.48 As of May 29, 2019, FDA has approved a total of 19 biosimilars for 9 reference products as shown in Table 2. Table 2. Biosimilars Approved for Marketing in the United States by FDA

Reference Product

Nonproprietary Name

Biosimilar(Marketer, approval date)

Nonproprietary Name

Neupogen

filgrastim

Zarxio (Sandoz, March 2015)Nivestym (Pfizer, July 2018) filgrastim-sndzfilgrastim-aafi

Remicade

infliximab

Inflectra (Celltrion/Pfizer, April 2016)Renflexis (Samsung/Merck, April 2017)Ixifi (Pfizer, December 2017) infliximab-dyybinfliximab-abdainfliximab-qbtx

Enbrel

etanercept

Erelzi (Sandoz, August 2016)

Eticovo (Samsung, April 2019)

etanercept-szzs

etanercept-ykro

Humira

adalimumab

Amjevita (Amgen, September 2016)Cyltezo (Boehringer Ingelheim, August 2017)Hyrimoz (Sandoz, October 2018) adalimumab-attoadalimumab-adbmadalimumab-adaz

Avastin

bevacizumab

Mvasi (Amgen, September 2017)

bevacizumab-awwb

Herceptin

trastuzumab

Ogivri (Mylan, December 2017)Herzuma (Celltrion, December 2018)Ontruzant (Samsung, January 2019)Trazimera (Pfizer, March 2019) trastuzumab-dksttrastuzumab-pkrbtrastuzumab-dttbtrastuzumab-qyyp Epogen/Procrit

epoetin

Retacrit (Hospira/Pfizer, May 2018)

epoetin alfa-epbx

Neulasta

pegfilgrastim

Fulphila (Mylan, June 2018)

Udenyca (Coherus Bioscience, November 2018)

pegfilgrastim-jmdbpegfilgrastim-cbqv

Rituxan

rituximab

Truxima (Celltrion, November 2018)

rituximab-abbs

Sources: FDA, Biosimilar Product Information, accessed May 29, 2019 https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm580432.htm.

Although FDA has licensed 19 biosimilars for marketing in the United States, many of these products are not yet available to patients, primarily due to ongoing litigation and settlement agreements. However, even once a biosimilar is launched, additional factors have been identified as potentially limiting biosimilar competition. These factors, which are described in greater detail below, include biosimilar naming and labeling conventions; interchangeability requirements; and access to samples for biosimilars testing. FDA has attempted to address some of these factors in its Biosimilars Action Plan, which was issued in July 2018.49 Other factors, such as exclusive contracts with insurers, rebates to payors, and reimbursement policies also have been identified as impeding biosimilar uptake, but are outside the scope of this report.

Patent Litigation and Settlements The launch of several biosimilar products has been delayed due to ongoing patent litigation and settlements between brand biologic and biosimilar companies. For example, AbbVie has been the subject of Congressional inquiry for its use of a so-called "patent thicket" to protect its biologic Humira (adalimumab) from biosimilar competition.50 According to one analysis, AbbVie filed 247 patent applications with respect to Humira and was issued 132 patents.51 Humira was initially licensed in the United States in 2002. Although FDA has approved three biosimilar versions of the product—Amgen's Amjevita, Boehringer Ingelheim's Cyltezo, and Sandoz's Hyrimoz—none of these are currently available to U.S. patients. AbbVie has reportedly settled patent lawsuits with several companies to delay biosimilar versions of Humira from becoming available in the United States until 2023 (see Table 3).52 Table 3. Settlement Agreements Between AbbVie and Competitors

Settlement agreements addressing launch of Humira and biosimilar competitors

Competitor

Biosimilar licensed by FDA?

U.S. licensure date per settlement

Amgen

Yes—Amjevita on September 23, 2016

January 31, 2023

Samsung Bioepis

No

June 30, 2023

Boehringer Ingelheim

Yes—Cyltezo on August 25, 2017

July 1, 2023

Mylan

No

July 31, 2023

Sandoz

Yes—Hyrimoz on October 30, 2018

September 30, 2023

Fresenius Kabi

No

September 30, 2023

Momenta

No

November 20, 2023

Pfizer

No

November 20, 2023

Source: AbbVie, News Center, accessed May 16, 2019, https://news.abbvie.com/news/press-releases/.

Notes: Table created by CRS based on AbbVie press releases and the FDA Purple Book.

Under Title XI of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA; P.L. 108-173), certain settlement agreements between brand and generic drug companies must be filed with the Federal Trade Commission (FTC) and Department of Justice (DOJ). The Patient Right to Know Drug Prices Act (P.L. 115-263) amended MMA Title XI, expanding these reporting requirements to include agreements between biosimilar product applicants and brand biologic companies, as well as agreements between two biosimilar product applicants. Section 4004 of the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act (P.L. 115-271; the SUPPORT for Patients and Communities Act) amended MMA Title XI, further expanding reporting requirements between biologic manufacturers and biosimilar product applicants.

Some concern has been raised about a lack of transparency surrounding patents for biologics and "patent thickets that are purely designed to deter the entry of approved biosimilars."53 For drugs approved under the FFDCA, pursuant to the Hatch-Waxman Act, a drug manufacturer must list as part of its NDA any patents that claim the drug that is the subject of the NDA or the method of using that drug.54 FDA then publishes this information in the Approved Drug Products with Therapeutic Equivalence Evaluations, more commonly known as the Orange Book.55 The Orange Book satisfies the statutory requirement that FDA make publicly available, and revise every 30 days, a list of drugs that have been approved for safety and effectiveness and any patent information submitted with respect to such drugs.56 When a generic company submits an ANDA referencing a listed drug (typically the brand-name drug), it must provide a certification with respect to each patent listed in the Orange Book for that drug.57 The Orange Book also lists any unexpired periods of exclusivity covering an approved drug, in addition to other information applicants may find helpful.58

The PHSA, as amended by the BPCIA, does not require manufacturers of biologics to list patent information as part of a BLA, and the patent resolution scheme is different for biologics and biosimilars than for chemical drugs under Hatch-Waxman. The BPCIA provides for "an elaborate process for disclosure and negotiation, sometimes referred to as the 'patent dance.' The 'dance' generally involves an applicant and reference product sponsor participating in a series of informational exchanges regarding potential disputes over patent validity and infringement."59 Also in contrast to Hatch-Waxman, approval of a biosimilar under the BPCIA is not contingent upon resolution of patent disputes. As such, FDA may approve a biosimilar despite unresolved patent issues.

While FDA is not required by law to publish information about approved biologics and biosimilars, the agency does so voluntarily with the publication of the Purple Book. Unlike the Orange Book, which is available in paper form and as a searchable, electronic database, the Purple Book consists of two lists—one for biological products (including biosimilar and interchangeable products) licensed by CDER and the other for those licensed by CBER.60 For brand-name biologics, the list identifies the date the biologic was licensed (i.e., approved), and if FDA evaluated the product for reference product exclusivity, the date the exclusivity will expire. FDA has not made a determination of the date of first licensure for all biologics. According to the agency, a determination of the date of first licensure and product exclusivity expiration "will generally be made for reasons of regulatory necessity and/or at the request of the [BLA] license holder."61 The CDER and CBER lists also cross-reference the names of brand-name biologics licensed with the names of licensed biosimilar products.

In FDA's July 2018 "Biosimilars Action Plan," the agency said it would enhance the Purple Book to include more information about approved biologics.62 FDA also requested comments from the public on what steps the agency could take, within its statutory authority, related to biologics, including "additional information or features [that] could be incorporated into the Purple Book to make it more useful to stakeholders, including patients, healthcare providers, pharmacists, and manufacturers[.]"63 Commenters proposed that FDA should include more comprehensive information about biologics;64 publish prompt reference product exclusivity decisions at the time of biologic approval;65 update the Purple Book to clarify which products have been determined not to have exclusivity and those that are still subject to pending decisions;66 and to make the Purple Book into a single searchable electronic database (e.g., more like the Orange Book).67 Commenters noted that amending the Purple Book to list patent information would require a change in statute and, potentially, a change to the patent resolution scheme. In the 116th Congress, bipartisan legislation has been introduced that would codify the publication of the Purple Book as a single searchable list and would require additional information to be published, including information about patents that claim the biologic or other patentable inventions relating to the biologic, thus providing more patent transparency and potentially promoting biosimilar competition.68 Naming

Even once patent litigation is resolved and a biosimilar is marketed, one factor that has been identified as potentially impacting uptake of launched biosimilars is FDA's proposed naming scheme, specifically in regard to the nonproprietary name of the biosimilar compared to the reference product. The nonproprietary name, or proper name, is used in the product's labeling, regulation, and scientific literature to identify a pharmaceutical substance or active pharmaceutical ingredient. For chemical drugs, the nonproprietary name is also known as the generic name. This is in contrast to the proprietary name of a drug or biologic, which is the trademarked name, or brand name. It is the name a company uses to market its drug product, and it is usually capitalized, followed by a superscript R in a circle (®). For example, Neupogen® is the proprietary name for filgrastim, the nonproprietary name for the active substance.

FDA released draft guidance on the nonproprietary naming of biological products in August 2015; this guidance was finalized on January 12, 2017.69 In March 2019, FDA issued a revised draft guidance.70 The agency intends to ultimately issue a revised, final version of the 2017 naming guidance incorporating comments on the 2019 draft guidance.71 According to the naming convention outlined in the January 2017 guidance, "the nonproprietary name designated for each originator biological product [i.e., the reference product], related biological product, and biosimilar product will be a proper name that is a combination of the core name and a distinguishing suffix that is devoid of meaning and composed of four lowercase letters."72 The core name refers to the component shared among an originator biological product and any related biological, biosimilar, or interchangeable product as part of the proper name.73 An example of a core name is filgrastim. The suffix is attached to the core name with a hyphen as a unique identifier, for example, filgrastim-xzwy. This naming convention was to be applied to previously licensed and prospective biologics and biosimilars.

In the March 2019 revised draft guidance, FDA stated that it no longer intends to modify the proper names of biologics that were previously licensed under the PHSA without an FDA-designated suffix in their proper names. The agency also does not intend to apply the naming convention to transition biologics (e.g., insulin).74 Instead, FDA will apply the naming convention to biological products at the time they are licensed. This is in contrast to the approach outlined in the agency's 2017 naming guidance, which would have applied this naming convention to previously licensed biologics, as well. For interchangeable products, in the revised guidance, FDA determined that a unique suffix that distinguishes an interchangeable product from other products sharing the same core name would be appropriate.75

In general, the biosimilars industry seems to support the shared use of a nonproprietary name, whereas those advocating for the innovator companies prefer a naming scheme that distinguishes between the reference biologic product and the biosimilar.76 In its October 2015 public comments to FDA, the Federal Trade Commission (FTC) expressed concern that the FDA's naming proposal assigning unique differentiating suffixes "could result in physicians incorrectly believing that biosimilars' drug substances differ in clinically meaningful ways from their reference biologics' drug substances."77 This "misperception" could "deter physicians from prescribing biosimilars" thereby "impeding the development of biosimilar markets and competition."78 FTC reiterated these concerns in its May 2019 public comments on FDA's March 2019 draft guidance, stating that "[t]his unusual naming convention—applied exclusively to a subset of new entrants—likely would create consumer confusion and discourage use of newly introduced biosimilar and interchangeable products."79 Biosimilars Labeling

Another factor that has been identified as potentially impacting uptake of launched biosimilars is FDA's policy on biosimilar labeling, specifically the recommendation for inclusion of a biosimilarity statement. The labeling for a prescription drug product conveys information about the product's safety and effectiveness to a health care provider, allowing the provider to decide if the product is appropriate for a particular patient. In 2006, FDA issued a final rule on the content and format of labeling for prescription drug products, including biological products.80 FDA requires that labeling begin with a highlights section that includes any warnings about the drug. Other FDA-required elements of labeling include indications and usage, dosage and administration, dosage forms and strengths, contraindications, warnings and precautions, adverse reactions, drug interactions, use in specific populations, drug abuse and dependence, overdosage, clinical pharmacology, nonclinical toxicology, clinical studies, references, how supplied/storage and handling, and patient counseling information.

FDA released draft guidance on biosimilar labeling in March 2016 and final guidance in July 2018.81 FDA recommends that the highlights section of the labeling contain a "Biosimilarity Statement" describing the biosimilar product's relationship to its reference product. For example, "NIVESTYM (filgrastim-aafi) is biosimilar* to NEUPOGEN (filgrastim)," followed by the statement:

* Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. Biosimilarity of [BIOSIMILAR PRODUCT'S PROPRIETARY NAME] has been demonstrated for the condition(s) of use (e.g., indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information.

Some stakeholders have expressed opposition to the biosimilarity statement, noting that it "could create needless confusion for patients," and that this statement "does not serve a practical function."82

The biosimilar product is not required by FDA to have the same labeling as the reference product; for example, the number of approved indications for use may differ. FDA recommends that comparative data demonstrating biosimilarity not be included in biosimilar product labeling "to avoid potential confusion or misinterpretation of the comparative data."83 However, such comparative data are available to prescribers and the public on the FDA website.84 Comments on the FDA labeling guidance reflected differing views: while the generic industry wants less information in biosimilar labeling, the brand-name industry would like FDA to require more information.85 In contrast, the Biotechnology Innovation Organization (BIO), which represents makers of brand-name biologics, stated that more information is preferable to less with regard to labeling. "The prescribing physician needs to have access to all relevant information, including the relevant nonclinical and clinical data supporting the finding of biosimilarity, and the resulting labeling should be transparent to allow the prescriber to identify whether the described studies were conducted with the biosimilar or reference product."86

Interchangeability and Substitution

Another factor that may affect uptake of biosimilars is that a biosimilar generally cannot be automatically substituted for the reference product (i.e., brand-name biologic) at the pharmacy-level unless it is determined to be interchangeable with the reference product. An interchangeable product "can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product. Interchangeable products may be substituted for the reference product by a pharmacist without the intervention of the prescribing health care provider."87 In January 2017, FDA released draft guidance on interchangeability, and final guidance on May 10, 2019.88 FDA has not yet approved an interchangeable product.

As mentioned previously, a generic drug generally is considered to be interchangeable with its reference (brand-name) drug and with other generic products that use the same reference drug. All states have enacted laws that allow or require a pharmacist to substitute a generic for the reference drug. Following passage of the Hatch-Waxman Act, one major source of cost saving was the ability of a pharmacist to substitute a generic drug for a brand-name drug without the intervention of a health care provider. However, because a biosimilar is not structurally identical to its brand-name biologic, assessing interchangeability is a separate process.

In the United States, FDA regulates the drug product but the states regulate pharmacies and the practice of pharmacy. According to the National Conference of State Legislatures (NCSL), as of October 22, 2018 "at least 49 states have considered legislation establishing state standards for substitution of a biosimilar prescription product to replace an original biologic product."89 NCSL indicates that a total of 45 states and Puerto Rico have enacted legislation; the provisions of state legislation vary.90

Sample Sharing and Biosimilars Development

Another factor that may affect biosimilar competition is access to samples of the reference product for purposes of biosimilar testing and development. As aforementioned, before a company may market a biosimilar, it must demonstrate that its product is highly similar to a reference product. Such comparative testing generally necessitates access to samples of a reference product.91 FDA has reported receiving numerous inquiries from biosimilar product developers indicating that they would like to develop a biosimilar version of a marketed drug, but are unable to obtain the necessary samples of a reference product. Some brand-name companies have implicated FDA-mandated safety programs—risk evaluation and mitigation strategies or REMS—for why they are not willing to sell samples to the biosimilar product developer, including that generic product developers may not ensure the safe use of these drugs, and that the brand company could be held liable.92 A REMS-restricted distribution program controls or limits the chain of supply to ensure drug safety. For biologics not subject to a REMS, companies have implemented self-imposed restricted distribution systems. By withholding access to samples, a brand-name company is generally able to prevent or delay a biosimilar product developer from conducting the required testing and submitting an application to FDA for review.

In December 2018, FDA announced that it would start focusing on "these same potentially anticompetitive practices" as it already has with chemical drugs.93 For example, for chemical drugs, in December 2014, FDA issued draft guidance outlining the steps that a generic developer should take to obtain a letter from FDA to the brand company, indicating that its proposed testing protocol is comparably as safe as the brand company's REMS, and that it would not be a violation of the REMS to provide the product samples for such testing.94 FDA announced that it would set up a similar system for biosimilar product developers, although FDA cannot compel a company to sell samples to another sponsor. Additionally, for chemical drugs, FDA has published on its website a list of products for which it has received sample access inquiries related to limited distribution of the brand drug.95 It is not clear whether FDA will publish a similar list for biosimilar product inquiries. Out of the 76 approved REMS, 15 cover BLAs.96 However, the agency said it was evaluating how it could make it easier for biosimilar product developers to use reference products from outside the United States where they may be cheaper and more accessible.97 Additionally, legislation has been introduced that would aim to keep brand companies from using REMS and non-REMS restricted distribution systems to prevent or delay biosimilars (and generic drugs) from entering the market.98

Federal Research and Biologics Development

The high costs of pharmaceuticals in general—and biologics in particular—has led to an increased interest in understanding the federal government's role in the development of costly new therapeutics. In the case of many biosimilars approved by FDA, the associated brand-name biologic (i.e., the reference product) was originally discovered by scientists at public-sector research institutions. These brand-name biologics—for example, Remicade, Enbrel, Humira, Avastin—are among the top-selling drugs in the United States and worldwide.

In general, the federal government—through the work conducted or supported by NIH—tends to focus more on basic or preclinical research and the pharmaceutical industry concentrates more of its research funding on clinical trials rather than on discovery activity.99 When trying to assign credit for specific therapeutic advancements, drawing a line between basic and applied research can be challenging. For example, without a major underlying advance, like recombinant DNA, the development of whole new classes of drugs would not have occurred.

Various studies have attempted to quantify the contribution of publicly funded research to the discovery of new drugs. A study published in 2003 found that of the 284 new drugs approved by FDA from 1990 through 1999, 6.7% originated from sources other than private industry.100 A 1993 study found that 7.6% of new drugs approved from 1981 through 1990 originated from nonindustry sources.101 However, rather than focusing on all drug approvals—including many "me too"102 drugs—another approach is to look at the origin of truly innovative new drugs, what FDA calls new molecular entities (NMEs). NMEs are drugs that have not been approved by FDA previously and frequently provide important new therapies for patients.103 A 2010 study found that of the NMEs and new biologics that received FDA approval between 1998 and 2007, 24.1% originated from work that was publicly funded.104

A study by Stevens et al., published in 2011 claims to be more comprehensive than these earlier investigations.105 The Stevens study identified 153 FDA-approved pharmaceutical products—102 NMEs, 36 biologics, and 15 vaccines—that were discovered at least in part by public-sector research institutions (PSRIs) from 1970 through 2009. About half of these drugs fell into two therapeutic categories: oncology and infectious disease. The study also examined more broadly new drug applications (NDAs), not including biologics, approved from 1990 through 2007. The study identified 1,541 approved NDAs, which includes, but is not limited to, drugs that are NMEs; new esters, salts, or derivatives; and new formulations, combinations, and indications of previously approved drugs. Of the 1,541 NDAs approved by FDA from 1990 through 2007, 143, or 9.3%, resulted from work conducted in publicly funded labs.

The 2011 Stevens study considered a PSRI "to have participated in the applied phase of research that led to discovery of a drug if it, solely or jointly, created intellectual property specific to the drug that was subsequently transferred to a company through a commercial license." The methodology used by the Stevens study "excluded the role of PSRIs in the development of platform technologies that have contributed to the development of whole new classes of drugs." For example, the following platform technologies were all developed with public funds and were excluded from the study:

  • recombinant DNA technology (Cohen-Boyer patents);
  • bacterial production methods for recombinant DNA (Riggs-Itakura patents);
  • production and chimerization106 methods for antibodies (Cabilly patents);
  • methods to produce glycosylated recombinant proteins in mammalian cells (Axel patents); and
  • methods of gene silencing with the use of small interfering RNAs (Mello-Fire patents).

Although these platform technologies enabled the development of many of the products approved by FDA during the period evaluated in the study, they were excluded "because the PSRI scientists who developed the platforms generally did not use them to develop specific drug candidates."107 However, without these platform technologies, many new drugs would not have been developed, resulting perhaps in a vastly different economic outlook for the pharmaceutical industry.

Appendix A. Major Laws on Biologics Regulation

In general, biological products are regulated (licensed for marketing) under the Public Health Service Act—originally by the National Institutes of Health (NIH) and its precursors and later, starting in 1972, by the FDA—and chemical drugs are regulated (approved for marketing) under the Federal Food, Drug, and Cosmetic Act—by the FDA. This section provides a brief history of these two acts and other relevant laws as they relate to biologics, as well as some of the important amendments that have occurred during the past 100 years.

Relevant Laws

Biologics Control Act of 1902

The regulation of biologics by the federal government began with the Biologics Control Act of 1902, "the first enduring scheme of national regulation for any pharmaceutical product."108 The act was groundbreaking, "the very first premarket approval statute in history."109 It set new precedents, "shifting from retrospective post-market to prospective pre-market government review."110 The Biologics Control Act was passed in response to deaths (many of children) from tetanus contamination of smallpox vaccine and diphtheria antitoxin. The act focused on the manufacturing process of such biological products; it required that facilities manufacturing such biological products be inspected before a federal license was issued to market them.

Pure Food and Drugs Act and the Federal Food, Drug, and Cosmetic Act The Biologics Control Act predates the regulation of drugs under the Pure Food and Drugs Act, which was enacted in 1906. The 1906 act "did not include any form of premarket control over new drugs to ensure their safety ... [and] did not include any controls over manufacturing establishments, unlike the pre-existing Biologics Act and the later-enacted Federal Food, Drug, and Cosmetic Act (FFDCA)."111considered to be interchangeable with its reference (brand-name) drug and with other generic products that use the same reference drug. The sponsor of the generic drug must also meet manufacturing process standards and reporting requirements.

During the time that Hatch-Waxman was debated by Congress and later implemented by the FDA, the biotechnology industry was developing its first biologics for use as human therapeutic agents. In 1982, FDA allowed on the market the first human drug developed by the biotechnology industry, human insulin (Humulin-R). This was followed by human growth hormone (Protropin) in 1985, alpha interferon (Intron-A) in 1986, tissue plasminogen activator (Activase) in 1987, and erythropoietin (Epogen) in 1989.

Most biological products are regulated—licensed for marketing by FDA via a biologics license application (BLA)—under the Public Health Service Act (PHSA). Biological products were originally regulated by the National Institutes of Health (NIH) and its precursors. In 1972, this regulatory responsibility was transferred to FDA; see Appendix A of this report for further details. All chemical prescription drugs are regulated—approved for marketing by FDA via a new drug application (NDA) or abbreviated new drug application (ANDA)—under the Federal Food, Drug, and Cosmetic Act (FFDCA).

The Hatch-Waxman Act of 1984

Hatch-Waxman added two pathways to the FFDCA: Section 505(j) and Section 505(b)(2). Section 505(j) established an Abbreviated New Drug Application (ANDA) process for a generic drug that contains the same active ingredient as the brand-name drug. In the ANDA, the generic company establishes that its drug product is chemically the same as the already approved drug, and thereby relies on the FDA's previous finding of safety and effectiveness for the approved drug. The 505(j) pathway is used for the approval of most generic chemical drugs. The 505(b)(2) pathway may be used for a drug that has a significant difference from a brand-name drug but is still sufficiently similar to that drug. The company filing the 505(b)(2) application must submit additional nonclinical and clinical data to show that the proposed product is safe and effective. The application may rely on published literature or on the FDA's finding of safety and effectiveness for the already approved product to support the approval of the proposed product.

The Hatch-Waxman Act provided a mechanism for the approval of generic drugs under the FFDCA, but it did not provide a mechanism for follow-on biologics/biosimilars under the PHSA. As a result, after Hatch-Waxman, companies could submit follow-on biologics applications for FDA review only for the very small number of so-called "natural source" biologics that had been approved under the FFDCA. Companies were effectively blocked from submitting follow-on applications for the much larger group of therapeutic biologics that had been licensed under the PHSA.

Historically, certain biological products were regulated as drugs under the FFDCA rather than as biologics under the PHSA. In 1941, Congress gave the FDA authority over the marketing of insulin.14 The hormone insulin is a small protein—a short chain of 51 amino acids—that regulates carbohydrate (sugar) metabolism. In the 1940s, insulin was obtained in the same way as many biologics—extraction from animals—hence the term "natural source."15 Despite this similarity with other biologics, insulin was regulated as a drug by FDA rather than as a biologic by NIH. Besides insulin, a small set of other natural source biological products were regulated as drugs under the FFDCA rather than as biologics under the PHSA: the hormone glucagon, human growth hormone, hormones to treat infertility, hormones used to manage menopause and osteoporosis, and certain medical enzymes (hyaluronidase and urokinase).16

Even when patent protection for specialty biologic drug products was approaching expiration, the market competition that occurred with chemical drugs via generics could not happen with therapeutic biologics because FDA lacked clear regulatory authority to approve biosimilars. Although some entities, such as the Generic Pharmaceutical Association (GPhA, now called the Association for Accessible Medicines), advocated that the FDA establish a regulatory system for the approval of biosimilars under its existing statutory authority,17 the Biotechnology Industry Organization (BIO) filed a citizen petition with the FDA requesting a number of actions that would have inhibited the approval of biosimilars.18

In contrast, the pathway to marketing biosimilars in Europe seemingly had fewer barriers. In April 2006, the European Medicines Agency (EMA) authorized for marketing in Europe the first biosimilar product, Omnitrope, a human growth hormone. This was followed by the authorization of five other biosimilar products in 2007, two more in 2008, and many more thereafter (as shown in Table 2).

Table 2. Biosimilars Authorized for Marketing in Europe by the EMA

Name

Active Substance

Marketing
Authorization
Holder

Therapeutic Area

Authorization
Date

Omnitrope

somatropin

Sandoz

pituitary dwarfism, Prader-Willi Syndrome, Turner Syndrome

4/12/2006

Binocrit

epoetin alfa

Sandoz

anemia, chronic kidney failure

8/28/2007

Epoetin Alfa Hexal

epoetin alfa

Hexal

anemia, cancer, chronic kidney failure

8/28/2007

Abseamed

epoetin alfa

Sandoz

same as above

8/28/2007

Retacrit

epoetin zeta

Hospira

anemia, autologous blood transfusion, cancer, chronic kidney failure

12/18/2007

Silapo

epoetin zeta

Stada

same as above

12/18/2007

Ratiograstim

filgrastim

Ratiopharm

cancer, hematopoietic stem cell transplantation, neutropenia

9/15/2008

Tevagrastim

filgrastim

Teva

same as above

9/15/2008

Zarzio

filgrastim

Sandoz

same as above

2/6/2009

Filgrastim Hexal

filgrastim

Hexal

same as above

2/6/2009

Nivestim

filgrastim

Hospira

same as above

6/8/2010

Inflectra

infliximab

Celltrion

psoriatic arthritis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis, ankylosing spondylitis

9/10/2013

Remsima

infliximab

Hospira

same as above

9/10/2013

Ovaleap

follitropin alfa

Teva

anovulation

9/27/2013

Grastofil

filgrastim

Apotex

neutropenia

10/18/2013

Bemfola

follitropin alfa

Finox Biotech

anovulation

3/27/2014

Abasaglar (Abasria)

insulin glargine

Eli Lilly

diabetes mellitus

9/9/2014

Accofil

filgrastim

Accord

neutropenia

9/18/2014

Benepali

etanercept

Samsung

psoriatic arthritis, rheumatoid arthritis, psoriasis,

1/14/2016

Flixabi

infliximab

Samsung

psoriatic arthritis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis, ankylosing spondylitis

5/26/2016

Thorinane

enoxaparin sodium

Pharmathen

venous thromboembolism

9/15/2016

Inhixa

enoxaparin sodium

Techdow

venous thromboembolism

9/15/2016

Terrosa

teriparatide

Gedeon Richter

osteoporosis

1/4/2017

Lusduna

insulin glargine

MSD (Merck)

diabetes mellitus

1/4/2017

Movymia

teriparatide

Stada

osteoporosis

1/11/2017

Truxima

rituximab

Celltrion

rheumatoid arthritis, leukemia (chronic lymphocytic, B-cell), non-Hodgkin's lymphoma, microscopic polyangiitis, Wegener granulomatosis

2/17/2017

Solymbic

adalimumab

Amgen

psoriatic arthritis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, hidradenitis suppurativa, psoriasis, ankylosing spondylitis

3/22/2017

Amgevita

adalimumab

Amgen

juvenile rheumatoid arthritis, psoriatic arthritis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis, ankylosing spondylitis

3/22/2017

Rixathon

rituximab

Sandoz

rheumatoid arthritis, leukemia (chronic lymphocytic, B-cell), non-Hodgkin's lymphoma, microscopic polyangiitis, Wegener's granulomatosis

6/15/2017

Riximyo

rituximab

Sandoz

rheumatoid arthritis, non-Hodgkin's lymphoma, microscopic polyangiitis, Wegener granulomatosis

6/15/2017

Erelzi

etanercept

Sandoz

juvenile rheumatoid arthritis, psoriatic arthritis, rheumatoid arthritis, psoriasis, ankylosing spondylitis

6/23/2017

Blitzima

rituximab

Celltrion

leukemia (chronic lymphocytic, B-cell), non-Hodgkin's lymphoma

7/13/2017

Rituzena

rituximab

Celltrion

leukemia (chronic lymphocytic, B-cell), non-Hodgkin's lymphoma, microscopic polyangiitis, Wegener granulomatosis

7/13/2017

Ritemvia

rituximab

Celltrion

non-Hodgkin's lymphoma, microscopic polyangiitis, Wegener granulomatosis

7/13/2017

Imraldi

adalimumab

Samsung

psoriatic arthritis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, hidradenitis suppurativa, psoriasis, ankylosing spondylitis, Uveitis

8/24/2017

Source: European Medicines Agency (EMA), European public assessment reports, September 15, 2017, available http://www.ema.europa.eu/ema/index.jsp.

Notes: In addition to the products listed above, the EMA authorized three biosimilars that were later voluntarily withdrawn: Valtropin (somatropin), Filgrastim ratiopharm (filgrastim), and Biograstim (filgrastim). Two other products were refused authorization by the EMA: Alpheon (recombinant human interferon alfa-2a) and Solumarv (human insulin).

In the United States, FDA approval of Omnitrope was announced in June 2006 following an April 10, 2006, ruling by the U.S. District Court for the District of Columbia in favor of Omnitrope's sponsor, Sandoz.19 The court ruled that the FDA must move forward with consideration of the application, submitted by Sandoz in 2003, which presented Omnitrope as "indistinguishable" from the FDA-approved Genotropin, marketed by Pfizer. Sandoz "alleged that the FDA had violated its statutory obligation to act on the Omnitrope application within 180 days, a time frame that the FDA characterized as merely a congressional aspiration."20 The 505(b)(2) pathway, created by the Hatch-Waxman Act, was used to approve Omnitrope.21

At the time of the Omnitrope approval in 2006, the FDA indicated in a document on the agency's website that this action "does not establish a pathway" for approval of other follow-on biologic drugs. "The agency has said that Congress must change the law before it can approve copies of nearly all other biotech products, and lawmakers haven't moved on the issue."22

New Regulatory Pathway for Biosimilars

In March 2010, Congress established a new regulatory authority for FDA by creating an abbreviated licensure pathway in Section 351(k) of the PHSA for biological products that are demonstrated to be "highly similar" (biosimilar) to or "interchangeable" with an FDA-licensed biological product. This authority was accomplished via the Biologics Price Competition and Innovation Act (BPCIA) of 2009, enacted as Title VII of the Affordable Care Act (ACA, P.L. 111-148).23 In addition, Congress authorized FDA to collect the associated user fees from industry. FDA describes the terms biosimilar and interchangeable in the following paragraphs.

Under the BPCI Act, a sponsor may seek approval of a "biosimilar" product under new section 351(k) of the PHS Act. A biological product may be demonstrated to be "biosimilar" if data show that the product is "highly similar" to the reference product notwithstanding minor differences in clinically inactive components and there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity and potency.

In order to meet the higher standard of interchangeability, a sponsor must demonstrate that the biosimilar product can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product. Interchangeable products may be substituted for the reference product by a pharmacist without the intervention of the prescribing health care provider.24

FDA held a two-day public meeting on November 2 and 3, 2010, to obtain perspectives from industry and the general public prior to developing and releasing agency guidance on the new biosimilars pathway. Based on public input at this first meeting, FDA released three draft guidance documents in February 2012 and held another public meeting on May 11, 2012, to obtain feedback on the draft guidance.25 The FDA released final guidance on the first three draft guidance documents on April 28, 2015. The agency has also released additional guidance on a variety of other topics related to biosimilars. A list of FDA guidance documents on biosimilars is available on the agency's website.26

Under Section 351(k) of the PHSA, a company interested in marketing a biosimilar product in the United States must first submit to FDA an application that provides information demonstrating biosimilarity based on data from analytical studies (structural and functional tests), animal studies (toxicity tests), and a clinical study or studies (tests in human patients). The agency may decide, at its discretion, that a certain study or studies are unnecessary in a biosimilar application.

As is the case with other FDA-approved products, any subsequent change to the approved manufacturing process—such as a change in the supplier of a raw material or the replacement of a piece of equipment—requires a demonstration to FDA of the comparability of the product's quality attributes before and after the change to ensure that the safety and effectiveness of the product is maintained. For example, the brand-name biologic Remicade (infliximab) underwent 37 manufacturing changes between 1998 and October 2014; each change required a demonstration of comparability, most likely through chemical, physical, and biological assays.27

For many years, the drug industry and FDA have coped with the inherent variability in biological products from natural sources. FDA maintains that the batch-to-batch and lot-to-lot variability that occurs for brand-name biologics and biosimilars can be assessed and managed effectively.

FDA Approval of Biosimilars

Although FDA has approved seven biosimilars for marketing in the United States, sales of five biosimilars have been delayed, or alleged to be adversely impacted, by actions of the brand-name manufacturers.

The marketing launch of three U.S. biosimilars (see "Erelzi," "Amjevita," and "Cyltezo") is being delayed by patent infringement lawsuits filed by brand-name manufacturers. In addition, Pfizer, which has FDA approval to market biosimilar Inflectra, has sued Johnson & Johnson (J&J), maker of brand-name biologic Remicade, for allegedly using "exclusionary contracts" and other anticompetitive tactics to prevent insurers from covering Inflectra (see "Inflectra"). Such anticompetitive practices would be expected to have a negative impact on the sales of another recently approved biosimilar (see "Renflexis").

The sections below provide a brief description of the seven biosimilars approved by FDA between March 2015 and October 2017. The high costs of pharmaceuticals in general—and biologics in particular—have led to an increased interest in understanding the federal government's role in the development of costly new therapeutics. Note that for six of the seven biosimilars described below, the brand-name drug was originally discovered by scientists at public-sector research institutions (see Table 6 and "Federal Research and New Drug Development"). Several of these brand-name biologics (Remicade, Enbrel, Humira, Avastin) are among the top-selling drugs—both worldwide and in the United States (see Appendix C).

Zarxio

In March 2015, FDA announced the approval of Zarxio (filgrastim-sndz), the first biosimilar product approved for marketing in the United States (see Table 3). Zarxio, marketed by Sandoz Inc., is biosimilar to Neupogen (filgrastim), marketed by Amgen Inc.28 Neupogen (filgrastim) was originally discovered by scientists at Sloan Kettering (see Table 6). Amgen subsequently received a license from FDA in 1991 to market Neupogen (filgrastim) (see Appendix D).29 Zarxio is approved for the same indications as Neupogen.

Table 3. Biosimilars Approved for Marketing in the United States by FDA

Name

Active Substance

Manufacturer/
Marketer

Indications
(Therapeutic Area)

Approval Date

Zarxio

filgrastim-sndz

Sandoz

cancer, hematopoietic stem cell transplantation, neutropenia

3/6/2015

Inflectra

infliximab-dyyb

Celltrion/Pfizer

psoriatic arthritis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis, ankylosing spondylitis

4/5/2016

Erelzi

etanercept-szzs

Sandoz

rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis

8/30/2016

Amjevita

adalimumab-atto

Amgen

rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, polyarticular juvenile idiopathic arthritis (4 years of age and older)

9/23/2016

Renflexis

infliximab-abda

Samsung/Merck

psoriatic arthritis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis, ankylosing spondylitis

4/21/2017

Cyltezo

adalimumab-adbm

Boehringer Ingelheim

rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, polyarticular juvenile idiopathic arthritis (4 years of age and older)

8/25/2017

Mvasi

bevacizumab-awwb

Amgen

metastatic colorectal cancer, non-squamous non-small cell lung cancer, glioblastoma, metastatic renal cell carcinoma, cervical cancer

9/14/2017

Sources: FDA News Releases, and Drugs@FDA (https://www.accessdata.fda.gov/scripts/cder/daf/).

Inflectra

In April 2016, FDA approved a second biosimilar, Inflectra (infliximab-dyyb).30 Inflectra is biosimilar to the brand-name drug Remicade (infliximab), made by Janssen Biotech, Inc., which is part of J&J. Remicade (infliximab) was originally discovered by scientists at New York University (see Table 6). In 1998, FDA issued a license to market infliximab (as shown in Appendix D) to Centocor Inc., which later became Janssen Biotech Inc.31

The biosimilar Inflectra is made by Celltrion, Inc., in the Republic of Korea, for Pfizer.32 In late November 2016, Pfizer began marketing Inflectra in the United States at a price that was 15% below the price of the brand-name drug, Remicade. In the United States and globally, Remicade is one of the top-selling drugs (see Appendix C).

In September 2017, Pfizer filed a lawsuit against J&J alleging anticompetitive practices due to J&J's "exclusionary contracts" with health insurers.33 Specifically, Pfizer charged that J&J "threatened to withhold significant rebates [from insurers] unless the insurers agreed to 'biosimilar-exclusion' contracts that effectively block coverage for Inflectra and other infliximab biosimilars."34 Another infliximab biosimilar was approved by FDA in April 2017 (see "Renflexis" below).

Because of the large base of patients who are already taking J&J's brand-name drug, Remicade, and are unlikely to switch to Pfizer's new biosimilar, the rebate is a powerful financial incentive for an insurer to prefer the higher-priced brand-name biologic over the biosimilar. The alleged mechanism used by the brand-name manufacturer against the biosimilar manufacturer is explained in a June 2017 JAMA article:

If a biosimilar manufacturer intends to upend the preferred position of the brand by offering a substantial price discount to the [insurer], the branded manufacturer can respond by withdrawing the rebate on the [branded] biologic, creating a "rebate trap." For any patient continuing the [branded] biologic, a payer's cost for that patient will double once the rebate is withdrawn . . . . Even in [an] optimistic scenario, in which the price of the biosimilar is 60% less than the price of the brand after rebates and discounts, if the payer is only able to convert 50% of its patient users to the biosimilar [because existing patients will tend to stay on the original branded product], the rebate trap ensures that payer total costs actually increase relative to costs prior to biosimilar availability.

To avoid the rebate trap, any strategy to reduce spending on biologics through adoption of biosimilars requires a near-complete switch of patient users from the branded biologic to the biosimilar. However, for many chronic diseases, the proportion of patients new to a given biological therapy is less than 20% of the total patients taking that drug in a given year. The remainder represents a stable base of patients whose disease is well-maintained while they are using current therapy and thus are unlikely to switch [to the biosimilar].35

According to Pfizer's lawsuit, "providers have declined to purchase Inflectra across the board, even for patients covered by insurance plans that do cover the product."36 The lawsuit states that as of September 1, 2017, about 90% of health care providers using infliximab had purchased no Inflectra at all, almost no national commercial health insurer provided coverage for Inflectra, and Inflectra had secured less than 4% of total infliximab unit sales in the United States.37 Since FDA approved Inflectra in April 2016, "J&J has raised the list price of Remicade by close to 9% and increased the amount the U.S. government reimburses for Remicade by more than $190 per infused dose."38 Pfizer states in the lawsuit that if J&J's anticompetitive practices are allowed to continue, these tactics "will become the playbook for biologic originator firms seeking to preserve their dominance in the face of biosimilar competition—thus subverting the competition-enhancing objectives of the BPCIA."39

The president of J&J's Janssen Biotech, Scott White, said the following in a statement regarding the Pfizer lawsuit: "We are effectively competing on value and price, and to date Pfizer has failed to demonstrate sufficient value to patients, providers, payers and employers. Competition is bringing down the overall cost of Remicade and will continue to bring down costs in the future. There is no merit to this lawsuit."40

Erelzi

In August 2016, FDA approved a third biosimilar, Erelzi (etanercept-szzs), manufactured by Sandoz.41 Erelzi is biosimilar to the brand-name drug Enbrel (etanercept) which is manufactured by Amgen. Enbrel (etanercept) was originally discovered by scientists at Massachusetts General Hospital (see Table 6). In 1998, as shown in Appendix D, Immunex received a license from FDA to market Enbrel (etanercept).42 Immunex was acquired by Amgen in July 2002.43 Enbrel (etanercept) is one of the top-selling drugs in the world and in the United States (see Appendix C).

Erelzi is approved for all indications included on the label for Enbrel. According to a Sandoz press release, "the approval is based on a comprehensive package of analytical, nonclinical, and clinical data confirming that Erelzi is highly similar to the US-licensed reference product. Clinical studies included four comparative pharmacokinetic (PK) studies in 216 healthy volunteers and a confirmatory effectiveness and safety similarity study in 531 patients with chronic plaque psoriasis. Extrapolation to all indications approved for use on the reference product label is on the basis that the Sandoz biosimilar etanercept and the reference product are essentially the same."44 A release date for marketing of Erelzi has not yet been set due to a lawsuit filed by Amgen against Sandoz and its parent company Novartis; a trial is scheduled for April 2018.45

Amjevita

In September 2016, FDA approved a fourth biosimilar, Amjevita (adalimumab-atto), manufactured by Amgen.46 Amjevita is biosimilar to Humira (adalimumab), which is currently manufactured by AbbVie (formerly a part of Abbott Laboratories). Humira (adalimumab) was originally discovered by scientists at Rockefeller University and Scripps (see Table 6). In 2002, Abbott Laboratories was licensed by FDA to market Humira (as shown in Appendix D).47

Amjevita was approved for 7 indications (see Table 3); in contrast, Humira is approved for 10 indications.48 Humira (adalimumab) is one of the top-selling drugs, both worldwide and in the United States (see Appendix C). Due to patent infringement litigation between Amgen and AbbVie, it is unlikely that Amjevita will be commercially available until at least 2018.49

Renflexis

In April 2017, FDA approved a fifth biosimilar, Renflexis, (infliximab-abda), made by Samsung Bioepsis in the Republic of Korea. Renflexis is biosimilar to the brand-name drug Remicade (infliximab) made by Janssen Biotech, Inc., which is part of J&J. Remicade (infliximab) was originally discovered by scientists at New York University (see Table 6). In 1998 FDA issued a license to market infliximab (as shown in Appendix D) to Centocor Inc., which later became Janssen Biotech Inc.50 In the United States and globally, Remicade is one of the top-selling drugs (see Appendix C).

Samsung has partnered with Merck to launch Renflexis in the United States; sales of the drug began at the end of July 2017 at a price that is 35% below the price of Remicade.51 (See also the discussion of another biosimilar to Remicade [infliximab], "Inflectra" above.)

Cyltezo

In August 2017, FDA approved a sixth biosimilar, Cyltezo (adalimumab-adbm), manufactured by Boehringer Ingelheim (BI). Cyltezo is biosimilar to Humira (adalimumab), which is currently manufactured by AbbVie. Humira (adalimumab) was originally discovered by scientists at Rockefeller University and Scripps (see Table 6).

In 2002, Abbott Laboratories was licensed by FDA to market Humira (as shown in Appendix D).52 Humira (adalimumab) is one of the top-selling drugs, both globally and in the United States (see Appendix C). AbbVie filed a lawsuit against BI on August 2, 2017, alleging infringement of eight Humira patents, and therefore a launch date for Cyltezo remains unclear.53

Mvasi

In September 2017, FDA approved Mvasi (bevacizumab-awwb), manufactured by Amgen. Mvasi is biosimilar to Avastin (bevacizumab), which is made by Genentech. In 2004, as shown in Appendix D, Genentech received a license from FDA to market Avastin (bevacizumab).54 Avastin (bevacizumab) is one of the top-selling drugs in the United States (see Appendix C).

FDA Issues Related to Biosimilars

Naming

The proprietary name of a drug product is the trademarked name, or brand name, for the product. It is the name a company uses to market its drug product, and it is usually capitalized, followed by a superscript R in a circle (®). For example, Neupogen® is the proprietary name for filgrastim, the nonproprietary name for the active substance.

The Purple Book lists biological products, including any biosimilar and interchangeable biological products, licensed by FDA under the PHS Act, as well as the date the product was licensed. Appendix D provides CDER and CBER licensed biological products, listed by year of licensure, and has further examples of proprietary names and nonproprietary names.

The nonproprietary name of a drug product is used in drug labeling, drug regulation, and scientific literature to identify a pharmaceutical substance or active pharmaceutical ingredient. For chemical drugs, the nonproprietary name is also known as the generic name.

FDA released draft guidance on the nonproprietary naming of biological products in August 2015; this guidance was finalized on January 12, 2017.55 The guidance provides the FDA's rationale regarding its naming convention for biosimilars. Throughout the guidance, FDA uses the term "proper name" instead of "nonproprietary name" due to the nomenclature used in the PHSA.56

"Under this naming convention, the nonproprietary name designated for each originator biological product, related biological product, and biosimilar product will be a proper name that is a combination of the core name and a distinguishing suffix that is devoid of meaning and composed of four lowercase letters."57 An example of a core name is filgrastim. The suffix is attached to the core name with a hyphen as a unique identifier, for example, filgrastim-xzwy. "FDA is continuing to consider the appropriate suffix format for interchangeable products."58

For originator biological products59—the reference product—FDA intends to use a core name that is the name adopted by the United States Adopted Name (USAN) Council.60 Nonproprietary names are selected by the USAN Council according to principles developed to ensure safety, consistency, and logic in the choice of names.61

In Europe, reference drugs and biosimilars use the identical International Nonproprietary Name (INN), a World Health Organization (WHO) drug-naming system that has been in place since 1953. The WHO selects INNs based on the advice of experts on a WHO advisory panel.62 In January 2016, the WHO released its voluntary Biological Qualifier (BQ) proposal for biosimilar naming.63 "The BQ is an additional and independent element used in conjunction with the INN to uniquely identify a biological substance to aid in the prescription and dispensing of medicines, pharmacovigilance, and the global transfer of prescriptions. The BQ is a code formed of four random consonants in two 2-letter blocks separated by a 2-digit checksum."64

In general, biosimilar industry groups support the shared use of a nonproprietary name, whereas those advocating for the innovator companies prefer a naming scheme that distinguishes between the reference biologic product and the biosimilar.65

In its October 2015 public comments to FDA, the Federal Trade Commission expressed concern that the FDA's naming proposal "could result in physicians incorrectly believing that biosimilars' drug substances differ in clinically meaningful ways from their reference biologics' drug substances."66 This "misperception" could "deter physicians from prescribing biosimilars" thereby "impeding the development of biosimilar markets and competition."67 The FTC comment provides further explanation:

Historically, all originator biologics that met the same identification tests and other aspects of identity ... received the same nonproprietary name." [For example, there] are eight different manufacturers of human growth hormone (recombinant) and all of their products carry the same nonproprietary name—somatropin. ... [A]ny differences in nonproprietary names generally signal pharmacological and chemical relationship differences between the products. Although the FDA's proposal will use the same USAN as the core name for each biosimilar and its reference biologic, based on historical practice, the addition of unique differentiating suffixes may lead physicians to believe mistakenly that the products necessarily have clinically meaningful differences. ... Differences in the nonproprietary names of biosimilars could contribute to misperceptions that the drug substance of a biosimilar should be identical, not "highly similar" to that of its reference biologic. [Participants at an FTC workshop on biosimilars contend that] the term identical is abused to instill fear and foster misunderstanding. Because biosimilars are new in the U.S., many physicians do not yet fully understand that a lack of identicality is inherent in biologics. Every biologic displays a certain degree of variability, even between different batches of the same product.68

Labeling

The labeling for a prescription drug product conveys information about the product's safety and effectiveness to a health care provider, allowing the provider to decide if the product is appropriate for a particular patient. In 2006, FDA issued a final rule on the content and format of labeling for prescription drug products, including biological products, and provided the following description:69

A prescription drug product's FDA approved labeling (also known as "professional labeling," "package insert," "direction circular," or "package circular") is a compilation of information about the product, approved by FDA, based on the agency's thorough analysis of the new drug application (NDA) or biologics license application (BLA) submitted by the applicant. This labeling contains information necessary for safe and effective use. It is written for the health care practitioner audience, because prescription drugs require "professional supervision of a practitioner licensed by law to administer such drug" (section 503(b) of the act (21 U.S.C. 353(b))).

FDA requires that labeling begin with a highlights section that includes any warnings about the drug. Other FDA-required elements of labeling include indications and usage, dosage and administration, dosage forms and strengths, contraindications, warnings and precautions, adverse reactions, drug interactions, use in specific populations, drug abuse and dependence, overdosage, clinical pharmacology, nonclinical toxicology, clinical studies, references, how supplied/storage and handling, and patient counseling information.

FDA released draft guidance on biosimilar labeling in March 2016.70 FDA recommends that the highlights section of the labeling contain a "Biosimilarity Statement" describing the biosimilar product's relationship to its reference product. The biosimilar product is not required by FDA to have the same labeling as the reference product; for example, the number of approved indications for use may differ. FDA recommends that comparative data demonstrating biosimilarity not be included in biosimilar product labeling "to avoid potential confusion or misinterpretation of the comparative data."71 However, such comparative data are available to prescribers and the public on the FDA website.72

Comments on the FDA labeling guidance reflected differing views: while the generic industry wants less information in biosimilar labeling, the brand-name industry would like FDA to require more information.73 For example, the Generic Pharmaceutical Association (GPhA, now called the Association for Accessible Medicines) said that the Biosimilarity Statement "not only is unnecessary but also may be confusing to patients and healthcare providers."74 In contrast, BIO, which represents makers of brand-name pharmaceuticals among other companies, stated that more information is preferable to less with regard to labeling. "The prescribing physician needs to have access to all relevant information, including the relevant nonclinical and clinical data supporting the finding of biosimilarity, and the resulting labeling should be transparent to allow the prescriber to identify whether the described studies were conducted with the biosimilar or reference product."75

Transition

Under the BPCIA, biologics that were approved as drugs under the FFDCA will transition to biological licenses under the PHSA in March 2020. This BPCIA provision affects the relatively small set of biological products mentioned above: hormone insulin, hormone glucagon, human growth hormone, hormones to treat infertility, hormones used to manage menopause and osteoporosis, and certain medical enzymes (hyaluronidase and urokinase).

FDA released draft guidance regarding the agency's interpretation of this BPCIA provision in March 2016.76 The FDA describes the BPCIA provision as follows:

Section 7002(e) of the BPCI Act provides that a marketing application for a "biological product" must be submitted under section 351 of the PHS Act, subject to the following exception during a transition period ending on March 23, 2020:

• An application for a biological product may be submitted under section 505 of the FD&C Act not later than March 23, 2020, if the biological product is in a product class for which a biological product in such product class was approved under section 505 of the FD&C Act not later than March 23, 2010.

—However, an application for a biological product may not be submitted under section 505 of the FD&C Act if there is another biological product approved under section 351(a) of the PHS Act that could be a "reference product" if such application were submitted under section 351(k) of the PHS Act.

An approved application for a biological product under section 505 of the FD&C Act shall be deemed to be a license for a biological product under section 351 of the PHS Act on March 23, 2020.77

In FDA's interpretation, as of March 23, 2020, applications for biological products that were approved under the FFDCA will no longer exist (as NDAs or ANDAs) and will be replaced by approved BLAs under the PHSA. In addition, FDA will not approve any application under the FFDCA for a biological product subject to the transition provisions that is still pending as of March 23, 2020. The FDA suggests that such applications be withdrawn and resubmitted under the PHSA, either Section 351(a) or 351(k). Some industry representatives, such as the Generic Pharmaceutical Association's Biosimilars Council, have commented that the FDA's proposed policy will significantly delay "the review, approval and availability of biological products that compete with expensive brand name biologics."78

Perhaps most importantly, under the FDA's interpretation

any unexpired period of exclusivity associated with an approved NDA for a biological product subject to section 7002(e) of the BPCI Act (e.g., 5-year exclusivity, 3-year exclusivity, or pediatric exclusivity) would cease to have any effect.... However, any unexpired period of orphan drug exclusivity would continue to apply to the drug for the protected use after March 23, 2020, because orphan drug exclusivity can be granted to and can block the approval of a drug approved under section 505 of the FD&C Act or a biological product licensed under section 351 of the PHS Act.79

Industry groups, such as the Pharmaceutical Research and Manufacturers of America, have commented that the FDA policy on exclusivity raises significant legal and trade issues.80

Lastly, the transitional biological products will not be eligible for the 12-year biologics exclusivity period because they were not first licensed under the PHSA, as specified by the BPCIA. FDA states, "[n]othing in the BPCI Act suggests that Congress intended to grant biological products approved under section 505 of the FD&C Act—some of which were approved decades ago—a period of exclusivity upon being deemed to have a license under the PHS Act that would impede biosimilar or interchangeable product competition in several product classes until the year 2032."81

Interchangeability and Substitution

An interchangeable product "can be expected to produce the same clinical result as the reference product in any given patient and, for a biological product that is administered more than once, that the risk of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of maintaining the patient on the reference product. Interchangeable products may be substituted for the reference product by a pharmacist without the intervention of the prescribing health care provider."82

As mentioned previously, a generic drug is considered to be interchangeable with its reference (brand-name) drug and with other generic products that use the same reference drug. Following passage of the Hatch-Waxman Act, one major source of cost saving was the ability of a pharmacist to substitute a generic drug for a brand-name drug without the intervention of a health care provider. However, because a biosimilar is not structurally identical to its brand-name biologic, assessing interchangeability is a separate process. In January 2017, FDA released draft guidance on interchangeability.83 The comment period on the interchangeability guidance was extended to May 19, 2017.84 FDA has not yet approved an interchangeable product.

In Europe, the EMA does not make a determination on interchangeability. "The EMA evaluates biosimilar medicines for authorization purposes. The Agency's evaluations do not include recommendations on whether a biosimilar should be used interchangeably with its reference medicine. For questions related to switching from one biological medicine to another, patients should speak to their doctor and pharmacist."85 Individual member states decide their own policy on interchangeability. Some countries, such as Denmark, "have concluded that all originators [reference products] and biosimilars are interchangeable unless proven not to be"; in contrast, Ireland allows a single switch but multiple switches are not allowed.86

In the United States, FDA regulates the drug product but the states regulate pharmacies and the practice of pharmacy. According to the National Conference of State Legislatures (NCSL), as of March 31, 2017 "at least 37 states have considered legislation establishing state standards for substitution of a biosimilar prescription product to replace an original biologic product."87 NCSL indicates that a total of 27 states and Puerto Rico have enacted legislation; the provisions of state legislation vary.88

Reauthorization of the Biosimilar User Fee Act (BsUFA)

FDA first gained the authority to collect user fees from the manufacturers of brand-name prescription drugs and biological products in 1992, when Congress passed the Prescription Drug User Fee Act (PDUFA).89 With PDUFA, FDA, industry, and Congress reached an agreement on two concepts: (1) performance goals—FDA would negotiate with industry on target completion times for various review processes, and (2) use of fees—the revenue from prescription drug user fees would be used only for activities to support the review of new product applications and would supplement—rather than supplant—congressional appropriations to FDA. The added resources from user fees allowed FDA to increase staff available to review applications and to reduce the median review time for standard applications. Over the years, Congress has added similar authority regarding medical devices, animal drugs, and generic human drugs.90 User fees made up 43% of the FY2016 FDA budget.

The FFDCA was amended by the Biosimilar User Fee Act of 2012 (BsUFA I), which authorizes FDA to collect fees for agency activities associated with the review of biosimilars from October 2012 through September 2017.91 Under BsUFA I, FDA collected six different types of fees from industry; fee amounts were based on inflation-adjusted PDUFA human drug application fee amounts for each fiscal year. Because no marketed biosimilar biological products existed when the BsUFA I program started, it included fees for products in the development phase—what FDA calls the Biosimilar Product Development (BPD) program—to generate fee revenue for the new program and to enable companies to meet with FDA in the early development of biosimilar biological products.92 The BPD program provides assistance to industry sponsors in the early stages of developing a new biosimilar product. As of February 2017, there were 64 BPD programs (each developing a separate biosimilar product) to 23 different reference products.93 A company can choose to discontinue participation in the biosimilar biological product development program but would have to pay a reactivation fee to resume further product development with FDA. The biosimilar biological product application fee could be waived for the first such application from a small business.94 FY2017 fee rates under BsUFA I are shown in Table 4. The FDA provides information on the amount of BsUFA fees collected each fiscal year and how the fees are spent in an annual financial report.95

Table 4. FY2017 Fee Rates Under BsUFA I

Fee Category

Fee Rate for FY2017

Initial BPD [10% of the PDUFA human drug application fee]

$203,810

Annual BPD [10% of the human drug application fee]

$203,810

Reactivation BPD [20% of the human drug application fee]

$407,620

Applications requiring clinical data [100% of the human drug application fee minus the cumulative amount paid for product development program fees]

$2,038,100

Applications not requiring clinical data

$1,019,050

Supplement requiring clinical data

$1,019,050

Establishment [100% of the PDUFA prescription drug establishment fee]

$512,200

Product [100% of the PDUFA prescription drug product fee]

$97,750

Source: Federal Register, July 28, 2016.

The five-year biosimilars user fee authority was scheduled to sunset on October 1, 2017. FDA held a public meeting on the reauthorization of the program—BsUFA II—on December 18, 2015.96 From March 2016 through May 2016, the agency held negotiation sessions with industry on the reauthorization agreement.97 In September 2016, the agency posted on its website the draft BsUFA II agreement on FDA performance goals and procedures for FY2018 through FY2022.98 A second BsUFA II public meeting was held on October 20, 2016.99 Following a 30-day comment period on the draft, a final BsUFA recommendation was submitted to Congress. Congress reauthorized the biosimilar user fee program via the Food and Drug Administration Reauthorization Act of 2017 (FDARA, P.L. 115-52), which was signed into law by President Donald J. Trump on August 18, 2017.100

According to March 2017 congressional testimony, FDA faced challenges in achieving the BsUFA I goals for advisory meetings with industry. The situation was due to the lack of additional staff "to handle the increased workload for biosimilar review."101 FDA anticipates that the new hiring authorities in the recently enacted 21st Century Cures Act (P.L. 114-255) will be used to "strengthen staff capacity; modernize the hiring system and infrastructure; augment human resources capacity through the use of dedicated expert contractors; establish a dedicated function for the recruitment and retention of scientific staffing; set clear goals for hiring; and conduct a comprehensive and continuous assessment of hiring and retention practices."102 These enhancements are designed to allow FDA to meet performance goals and help save "the applicant time and resources and ultimately encourage price competition and lower healthcare costs."103

Under BsUFA II, the supplement fee and the establishment fee have been dropped and the initial, annual, and reactivation BPD fees have been retained. The product fee is renamed the BsUFA Program fee, "with a new provision that sponsors shall not be assessed more than five BsUFA Program fees for a fiscal year per application."104 The application fee will no longer be reduced by the cumulative amount of BPD fees paid by the sponsor for that product. FDA and industry estimate that the agency will need approximately $45 million in FY2018 to cover the BsUFA program costs. This amount may be adjusted to reflect workload and costs estimates for FY2018, but the adjustment may not exceed an increase of $9 million.105

Table 5. FY2018 Fee Rates Under BsUFA II

Fee Category

Fee Rate for FY2018

BPD Initial

$227,213

BPD Annual

$227,213

BPD Reactivation

$454,426

Application w/Clinical data

$1,746,745

Application w/o Clinical data

$873,373

Program

$304,162

Source: Federal Register, September 14, 2017.

Federal Research and New Drug Development

In general, the federal government—such as the work conducted or supported by NIH—tends to focus more on basic or preclinical research and the pharmaceutical industry concentrates more of its research funding on clinical trials rather than on discovery activity.106 When trying to assign credit for specific therapeutic advancements, drawing a line between basic and applied research can be challenging. For example, without a major underlying advance, like recombinant DNA, the development of whole new classes of drugs would not have occurred. Concern over the high costs of pharmaceuticals in general and biologics in particular has led some to look more carefully at the federal role in the development of costly new therapeutics.

Various studies have attempted to quantify the contribution of publicly funded research to the discovery of new drugs. A study published in 2003 found that of the 284 new drugs approved by FDA from 1990 through 1999, 6.7% originated from sources other than private industry.107 A 1993 study found that 7.6% of new drugs approved from 1981 through 1990 originated from nonindustry sources.108 However, rather than focusing on all drug approvals—including many "me too"109 drugs—another way to answer this question is to look at the origin of truly innovative new drugs, what FDA calls new molecular entities (NMEs). NMEs are drugs that have not been approved by FDA previously and frequently provide important new therapies for patients.110 A 2010 study found that of the NMEs and new biologics that received FDA approval between 1998 and 2007, 24.1% originated from work that was publicly funded.111

A study by Stevens et al. published in 2011 claims to be more comprehensive than these earlier investigations.112 The Stevens study found that of the 1,541 drugs approved by FDA from 1990 through 2007, 143, or 9.3%, resulted from work conducted in publicly funded labs. Of the total 1,541 drug applications, FDA granted priority review to 348 applications, and 66 of these (19%) resulted from publicly funded research. The authors state that "viewed from another perspective, 46.2% of the new-drug applications from PSRIs [public-sector research institutions] received priority reviews, as compared with 20.0% of applications that were based purely on private-sector research, an increase by a factor of 2.3."113 An FDA designation of priority review is for "the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications."114 According to the authors, their data "suggest that PSRIs tend to discover drugs that are expected to have a disproportionately important clinical effect."115

The 2011 Stevens study considered a PSRI "to have participated in the applied phase of research that led to discovery of a drug if it, solely or jointly, created intellectual property specific to the drug that was subsequently transferred to a company through a commercial license." It is important to understand that the methodology used by the Stevens study "excluded the role of PSRIs in the development of platform technologies that have contributed to the development of whole new classes of drugs." For example, the following platform technologies were all developed with public funds and were excluded from the study:

  • recombinant DNA technology (Cohen-Boyer patents);
  • bacterial production methods for recombinant DNA (Riggs-Itakura patents);
  • production and chimerization116 methods for antibodies (Cabilly patents);
  • methods to produce glycosylated recombinant proteins in mammalian cells (Axel patents); and
  • methods of gene silencing with the use of small interfering RNAs (Mello-Fire patents).

Although these platform technologies enabled the development of many of the products approved by FDA during the period evaluated in the study, they were excluded "because the PSRI scientists who developed the platforms generally did not use them to develop specific drug candidates."117 However, without these platform technologies, many new drugs would not have been developed, resulting perhaps in a vastly different economic outlook for the pharmaceutical industry.

According to the Stevens et al., 2011 publication, the 36 biologic drugs listed in Table 6 were "discovered at least in part by PSRIs during the past 40 years."118

Table 6. Biologic Drugs Discovered by Public-Sector Research Institutions

Nonproprietary
Name

Brand Name

Originating Institution(s)

Marketer
(in February 2011)

abatacept

Orencia

U. of Michigan & Department of the Navy

Bristol-Myers Squibb

abciximab

ReoPro

State University of New York

Eli Lilly

adalimumab

Humira

Rockefeller University & Scripps

Abbott

agalsidase beta

Fabrazyme

Mt. Sinai School of Medicine

Genzyme

aldesleukin

Proleukin

Sloan-Kettering

Novartis

alefacept

Amevive

U. of Michigan & Dana-Farber Cancer Institute

Astellas Pharma Inc.

alglucosidase alfa

Myozyme

Duke University

Genzyme

anakinra

Kineret

U. of Colorado

BioVitrium

antihemophilic factor (human)

Monoclate-P

Scripps CSL

Behring

bivalirudin

AngioMax

Health Research, Inc. (Wadsworth Center)

The Medicines Company

botulinum toxin type A

Botox (Hyperhydrosis)

Mt. Sinai School of Medicine

Allergan

cetrorelix

Cetrotide

Tulane University

Merck Serono

cetuximab

Erbitux

U. of California

Bristol-Myers Squibb

coagulation factor IX

BeneFIX

U. of Washington

Wyeth

daclizumab

Zenapax

National Institutes of Health

Roche

denileukin diftitox

ONTAK

Harvard, Boston Medical Center, & Boston Univ.

Eisai

drotrecogin alfa

Xigris

Oklahoma Medical Research Foundation

Eli Lilly

eculizumab

Soliris

Oklahoma Medical Research Foundation & Yale University

Alexion

enfuvirtide

Fuzeon

Duke University

Roche

etanercept

Enbrel

Massachusetts General Hospital

Amgen

filgrastim

Neupogen

Sloan Kettering

Amgen

ibritumomab (Intravenous route)

Zevalin

National Institutes of Health

BiogenIdec

infliximab

Remicade

New York University

Johnson & Johnson

interferon beta-1A

Avonex

Stanford University

BiogenIdec

laronidase

Aldurazyme

Los Angeles Biomedical Research Institute

Genzyme

natalizumab

Tysabri

Fred Hutchinson Cancer Center

BiogenIdec

orelvekin

Neumega

Children's Hospital, Boston

Wyeth

palivisumab

Synagis

National Institutes of Health

AstraZeneca

pegfilgrastim

Neulasta

Sloan Kettering

Amgen

pegvisomant

Somavert

Ohio University

Pfizer

protein C concentrate (Human)

Ceprotin

Oklahoma Medical Research Foundation

Baxter Healthcare

respiratory syncytial virus immune globulin

Respigam

U. of Massachusetts

AstraZeneca

sermorelin acetate

Geref (Discontinued)

Salk Institute

Merck Serono

somatropin

Nutropin &
Protropin (Discontinued)

U. of California

Genentech

somatropin recombinant

Humatrope

U. of California

Eli Lilly

tositumomab

Bexxar

U. of Michigan & Dana-Farber Cancer Institute

GlaxoSmithKline

Source: Supplementary Appendix to Stevens, Jensen, Wyller, et al., "The Role of Public-Sector Research in the Discovery of Drugs and Vaccines," The New England Journal of Medicine, February 10, 2011.

Notes: Marketer may have changed since original publication date; current marketer may be identified via Drugs@FDA. Drugs in italics were not found in the CDER or CBER Purple Book but were found in Drugs@FDA, except Respigam which was not found in either Purple Book or in Drugs@FDA. Geref and Protropin have been discontinued.

Appendix A. Major Laws on Biologics Regulation

In general, biological products are regulated (licensed for marketing) under the Public Health Service Act—originally by the National Institutes of Health (NIH) and its precursors and later, starting in 1972, by the FDA—and chemical drugs are regulated (approved for marketing) under the Federal Food, Drug, and Cosmetic Act—by the FDA. This section provides a brief history of these two acts and other relevant laws as they relate to biologics, as well as some of the important amendments that have occurred during the past 100 years.

Relevant Laws

Biologics Control Act of 1902

The regulation of biologics by the federal government began with the Biologics Control Act of 1902, "the first enduring scheme of national regulation for any pharmaceutical product."119 The act was groundbreaking, "the very first premarket approval statute in history."120 It set new precedents, "shifting from retrospective post-market to prospective pre-market government review."121 The Biologics Control Act was passed in response to deaths (many of children) from tetanus contamination of smallpox vaccine and diphtheria antitoxin. The act focused on the manufacturing process of such biological products; it required that facilities manufacturing such biological products be inspected before a federal license was issued to market them.

Pure Food and Drugs Act and the Federal Food, Drug, and Cosmetic Act

The Biologics Control Act predates the regulation of drugs under the Pure Food and Drugs Act, which was enacted in 1906. The 1906 act "did not include any form of premarket control over new drugs to ensure their safety ... [and] did not include any controls over manufacturing establishments, unlike the pre-existing Biologics Act and the later-enacted Federal Food, Drug, and Cosmetic Act (FFDCA)."122 The Pure Food and Drugs Act was replaced by the FFDCA in 1938. The FFDCA required that drug manufacturers submit, prior to marketing, a new drug application (NDA) demonstrating, among other things, that the product was safe.

The Public Health Service Act

The Biologics Control Act was revised and recodified (42 U.S.C. 262) when the Public Health Service Act (PHSA) was passed in 1944. The 1944 act specified that a biological product that has been licensed for marketing under the PHSA is also subject to regulation (though not approval) under the FFDCA. A biological product is defined under Section 351(i) of the PHSA, as

a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product ... applicable to the prevention, treatment or cure of a disease or condition of human beings.

Section 351(j) of the PHSA states that the FFDCA "applies to a biological product subject to regulation under this section, except that a product for which a license has been approved under subsection (a) shall not be required to have an approved application under section 505 of such Act." Most biological products regulated under the PHSA also meet the definition of a drug under Section 201(g) of the FFDCA:

articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or animals; and articles (other than food) intended to affect the structure or any function of the body of man or other animals.

The PHSA was amended by the FDA Modernization Act of 1997 (FDAMA, P.L. 105-115) to require a single biological license application (BLA) for a biological product, rather than the two licenses—Establishment License Application (ELA) and Product License Application (PLA)—that had been required between 1944 and 1997. The PHSA provides authority to suspend a license immediately if there is a danger to public health.

The PHSA was amended by the Biologics Price Competition and Innovation Act (BPCIA) of 2009, enacted as Title VII of the Affordable Care Act (ACA, P.L. 111-148). The BPCIA created a licensure pathway for biological products demonstrated to be "highly similar" (biosimilar) to or "interchangeable" with an FDA-approved biological product, and it authorized the agency to collect associated fees. The BPCIA also created FDA-administered periods of regulatory exclusivity for certain brand-name biologics and biosimilar products, as well as procedures for brand-name and biosimilar manufacturers to resolve patent disputes.

History of Regulation of Biologics by Federal Agencies

Following enactment of the 1902 Biologics Act, regulatory responsibility for biologics was first delegated to the Hygienic Laboratory, a precursor of NIH.123112 In 1972, regulatory authority for biologics was transferred from the NIH Division of Biological Standards to the Bureau of Biologics at the FDA.124

113

In 1982, the FDA's Bureau of Drugs and Bureau of Biologics merged to form the National Center for Drugs and Biologics.125114 In 1988, the Center for Drugs and Biologics was split into the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).126115 CBER continued to use NIH facilities and buildings until it moved in October 2014 to the new FDA headquarters in White Oak, MD.127

116

Because biotechnology products frequently cross the conventional boundaries between biologics, drugs, and devices, determining the jurisdictional status of these products has been difficult for both the FDA and industry. Some products have had characteristics that met multiple statutory and scientific definitions.128117 In 1991, FDA published an Intercenter Agreement between CBER and CDER.129118 In general, the agreement stated that traditional biologics (vaccines, blood, blood products, antitoxins, allergenic products), as well as most biotechnology products, would be regulated by CBER. The small set of biologics regulated as drugs under the FFDCA (mentioned above) would continue to be regulated by CDER, regardless of the method of manufacture.

In 2002, however, the FDA announced its intention to reorganize review responsibilities, consolidating review of new pharmaceutical products under CDER, thereby letting CBER to concentrate on vaccines, blood safety, gene therapy, and tissue transplantation.130119 On June 30, 2003, responsibility for most therapeutic biologics was transferred from CBER to CDER.131120 Under this structure, biological products transferred to CDER are regulated as licensed biologics under Section 351 of the PHSA. Examples of products transferred to CDER include monoclonal antibodies, immunomodulators (other than vaccines and allergenic products), growth factors, and cytokines.132121 Remaining at CBER are traditional biologics such as vaccines, allergenic products, antitoxins, antivenins, venoms, and blood and blood products, including recombinant versions of plasma derivatives (clotting factors produced via biotechnology).

User Fee Legislation

FDA first gained the authority to collect user fees from the manufacturers of brand-name prescription drugs and biological products in 1992, when Congress passed the Prescription Drug User Fee Act (PDUFA).122 With PDUFA, FDA, industry, and Congress reached an agreement on two concepts: (1) performance goals—FDA would negotiate with industry on target completion times for various review processes, and (2) use of fees—the revenue from prescription drug user fees would be used only for activities to support the review of new product applications and would supplement—rather than supplant—congressional appropriations to FDA. The added resources from user fees allowed FDA to increase staff available to review applications and to reduce the median review time for standard applications. Over the years, Congress has added similar authority regarding medical devices, animal drugs, and generic human drugs.123 User fees made up almost 50% of the FY2019 FDA budget.

The BPCIA, enacted as Title VII of the ACA, directed FDA to develop and present to Congress recommendations for a user fee program to support review of biosimilar product applications submitted under Section 351(k) of the PHSA.124 The Biosimilar User Fee Act of 2012 (BsUFA or BsUFA I), enacted as Title IV of Food and Drug Administration Safety and Innovation Act (FDASIA, P.L. 112-144), authorized FDA to assess and collect fees for agency activities associated with the review of biosimilars from October 2012 through September 2017.125 Under BsUFA I, FDA collected six different types of fees from industry;126 fee amounts were based on inflation-adjusted PDUFA human drug application fee amounts for each fiscal year. Because no marketed biosimilar biological products existed when the BsUFA I program started, it included fees for products in the development phase—what FDA calls the Biosimilar Product Development (BPD) program—to generate fee revenue for the new program and to enable companies to meet with FDA in the early development of biosimilar biological products.127 The BPD program provides assistance to industry sponsors in the early stages of developing a new biosimilar product. As of May 1, 2018, "67 programs were enrolled in the BPD Program to discuss development of proposed biosimilar products or proposed interchangeable products. CDER has received meeting requests to discuss the development of biosimilar or interchangeable products for 31 different reference products."128

The biosimilar user fee program was reauthorized through FY2022 via the Food and Drug Administration Reauthorization Act of 2017 (FDARA, P.L. 115-52), which was signed into law by President Donald J. Trump on August 18, 2017.129 Under BsUFA II, the supplement fee and the establishment fee have been dropped and the initial, annual, and reactivation BPD fees have been retained. The product fee is renamed the BsUFA Program fee, "with a new provision that sponsors shall not be assessed more than five BsUFA Program fees for a fiscal year per application."130 The application fee will no longer be reduced by the cumulative amount of BPD fees paid by the sponsor for that product.

Appendix B. Top-Selling Drugs Table B-1. Top 15 Best-Selling Drugs of 2018

Biologics in bold; dollars in billions

Brand Name

Nonproprietary Name

Sponsor Companies

2018 Sales

Humira

adalimumab

AbbVie

$19.936

Eliquis

apixaban

Bristol-Myers Squibb and Pfizer

$9.872

Revlimid

lenalidomide

Celgene

$9.685

Opdivo

nivolumab

Bristol-Myers Squibb and Ono Pharmaceutical

$7.570

Keytruda

pembrolizumab

Merck

$7.171

Enbrel

etanercept

Amgen and Pfizer

$7.126

Herceptin

trastuzumab

Roche (Genentech)

$6.981

Avastin

bevacizumab

Roche (Genentech)

$6.847

Rituxan

rituximab

Roche (Genentech) and Biogen

$6.750

Xarelto

rivaroxaban

Bayer and Johnson & Johnson

$6.589

Eylea

aflibercept

Bayer and Regeneron Pharmaceuticals

$6.551

Remicade

infliximab

Johnson & Johnson and Merck & Co.

$5.908

Prevnar13

pneumococcal vaccine

Pfizer

Remaining at CBER are traditional biologics such as vaccines, allergenic products, antitoxins, antivenins, venoms, and blood and blood products, including recombinant versions of plasma derivatives (clotting factors produced via biotechnology).

Appendix B. Comparison of Biologic Drug Prices

Table B-1. Comparison of Biologic Drug Prices

Drug

Package Size

Medicare

Norway

England

Ontario, Canada

Indication

Lucentis

0.5 mg syringe/vial

$1,936

$894

$1,159

$1,254

Macular degeneration

Eylea

2 mg/0.05 ml vial

$1,930

$919

$1,274

$1,129

Macular degeneration

Rituxan

500 mg vial

$3,678

$1,527

$1,364

$1,820

Rheumatoid arthritis

Avastin

100 mg vial

$685

$399

$379

$398

Cancer

Prolia

60 mg syringe

$893

$260

$286

$285

Osteoporosis

Herceptin

Per 100 mg

$858

$483

$424

$493

Breast cancer

Orencia

250 mg vial

$881

$437

$472

$390

Rheumatoid arthritis

Aranesp

500 mcg syringe

$1,995

$663

$1,146

$1,227

Anemia

Botox

100 unit vial

$563

$178

$216

$284

Overactive bladder, chronic migraine

Erbitux

100 mg

$527

$270

$278

$302

Colorectal cancer

Tysabri

300 mg vial

$4,842

$1,870

N/A

$2,573

Multiple sclerosis

Actemra

80 mg vial

$305

$168

$160

$144

Rheumatoid arthritis

Yervoy

50 mg vial

$6,738

$4,362

$5,856

$4,618

Skin cancer

Xolair

150 mg syringe/vial

$852

$463

$400

$487

Asthma

Nplate

250 mcg vial

$1,399

$836

$753

$754

Autoimmune disease

Cimzia

Two 200 mg syringes

$2,357

$803

$1,117

$1,058

Crohn's Disease

Soliris

300 mg/30 ml vial

$6,315

$5,730

$4,919

$5,368

Rare diseases

Benefix

1000 unit vial

$1,451

$936

$948

N/A

Hemophilia

Neupogen

Ten 300 mcg vials

$2,943

N/A

N/A

$1,532

White blood cell deficiency

Vectibix

100 mg vial

$987

$472

$592

$498

Colorectal cancer

Benlysta

120 mg vial

$479

$189

N/A

N/A

Lupus

Xiaflex

0.9 mg vial

$3,370

$1,094

$1,015

N/A

Peyronie's disease

Pulmozyme

30 2.5 mg ampules

$2,845

$886

$775

N/A

Cystic fibrosis

Adcetris

50 mg vial

$5,894

$3,887

$3,904

$3,854

Hodgkin lymphoma

Arzerra

1,000 mg vial

$4,819

N/A

$2,842

N/A

Chronic lymphocytic leukemia

Xyntha

250 unit vial kit

$293

$226

$196

N/A

Hemophilia

Source: Jeanne Whalen, "Why the U.S. Pays More than Other Countries for Drugs," The Wall Street Journal, December 1, 2015.

Notes: Medicare beneficiaries are responsible for paying 20% of prices listed here. Medicare [Part B] itself covers 80%. Prices listed reflect a temporary 2% discount imposed by federal spending cuts known as budget sequestration. Foreign prices were converted to U.S. dollars at July 1, 2015, exchange rates. Rankings were determined by Medicare Part B payments to doctors' offices and medical practices in 2013, the latest year for which data were available. Norwegian prices include 25% Value Added Tax levied on pharmaceuticals. England's National Health Service says prices listed here are "indicative" and may vary in some circumstances. Source: WSJ analysis of data from CMS; the Norwegian Medicines Agency and the Norwegian Drug Procurement Cooperation; the National Health Service Business Services Authority; and Ontario's Ministry of Health and Long-Term Care.

Table B-2. Examples of Average Biologic Drug Prices for Top-Selling Drugs in 2015

Monthly price, U.S. dollars

Drug

U.S. nondiscounted

U.S. estimated discounted

Canada

France

Germany

Humira (adalimumab),
40 mg biweekly

$3,430.82

$2,504.50

$1,164.32

$981.79

$1,749.26

Lantus (insulin glargine),
50 insulin units daily

372.75

186.38

67.00

46.60

60.90

Herceptin (trastuzumab),
450 mg every 3 weeks

5,593.47

4,754.45

 

2,527.97

3,185.87

Source: Aaron S. Kesselheim and Jerry Avorn, "The High Cost of Prescription Drugs in the United States: Origins and Prospects for Reform," JAMA, vol. 316, no. 8 (August 23/30, 2016), p. 859.

Note: The "nondiscounted" price is the list price. The "estimated discounted" price accounts for undisclosed discounts ("rebates") that manufacturers offer to U.S. payers.

Appendix C. Top-Selling Drugs

Table C-1. The Top Three Selling Drugs, Global Sales, 1996-2015

Biologics in bold; dollars in billions

Year

Number 1 selling drug

Number 2 selling drug

Number 3 selling drug

1996

Norvasc $1.8

Zoloft $1.3

Epogen $1.1

1997

Prozac $2.6

Norvasc $2.2

Zoloft $1.5

1998

Prilosec $4.8

Prozac $2.8

Norvasc $2.5

1999

Prilosec $5.9

Norvasc $3.0

Claritin $2.67

2000

Prilosec $6.26

Lipitor $5.0

Norvasc $3.36

2001

Lipitor $6.45

Prilosec $5.7

Epogen $5.5

2002

Lipitor $7.97

Epogen $6.5

Zocor $5.4

2003

Lipitor $9.9

Epogen $6.4

Zocor $5.0

2004

Lipitor $11.7

Epogen $6.2

Plavix $5.4

2005

Lipitor $13.1

Plavix $6.3

Epogen $5.8

2006

Lipitor $13.8

Advair Diskus $6.18

Plavix $6.1

2007

Lipitor $13.6

Plavix $8.1

Advair Diskus $7.1

2008

Lipitor $13.5

Plavix $9.5

Advair Diskus $7.7

2009

Lipitor $12.65

Plavix $9.8

Advair Diskus $7.88

2010

Lipitor $11.9

Plavix $9.4

Advair Diskus $8.0

2011

Lipitor $10.87

Plavix $9.9

Remicade $8.9

2012

Humira $9.6

Remicade $9.1

Enbrel $8.5

2013

Humira $11.0

Remicade $9.8

Enbrel $8.78

2014

Humira $12.9

Solvaldi $10.3

Remicade $9.9

2015*

Harvoni $10.5

Humira $10.3

Enbrel $6.57

Source: Nature Biotechnology, v. 34 (3), March 2016, pp. 276-283, Supplementary Table 4.

Note: *Data from the first three quarters of 2015.


Table C-2. Top 10 Selling Drugs, U.S. Sales, 2015

Biologics in bold; dollars in millions

Source: Genetic Engineering & Biotechnology News, March 11, 2019.

Brand name

Nonproprietary name

Company

2015 sales

Harvoni

sofosbuvir

Valeant Pharmaceuticals International

$10,090

Humira

adalimumab

AbbVie

$8,405

Enbrel

etanercept

Amgen

$5,099

$5.802

Remicade

Stelara

infliximab

ustekinumab

Janssen Biotech (Johnson & Johnson

)

$4,453

5.156

Prevnar 13

Lyrica

pneumococcal vaccine

pregabalin

Pfizer

$4.970

Pfizer

$4,026

Neulasta

pegfilgrastim

Amgen

$3,891

Revlimid

lenalidomide

Celgene

$3,535

Avastin

bevacizumab

Roche

$3,178

Tecfidera

dimethyl fumarate

Biogen

$2,908

Eylea

aflibercept

Regeneron Pharmaceuticals

$2,676

Source: EvaluatePharma, World Preview2016, Outlook to 2022, 9th Edition, September 2016, http://www.evaluate.com/PharmaWorldPreview2016.

Notes: Genetic Engineering & Biotechnology News indicate in the Notes for this article that the above amounts include U.S. sales and, where applicable, sales elsewhere in the world. According to the text of the article, the "drugs are ranked based on sales or revenue reported for 2018 by biopharma companies in press announcements, annual reports, investor materials, and/or conference calls."

Author Contact Information

Agata Dabrowska, Analyst in Health Policy ([email address scrubbed], [phone number scrubbed])

Acknowledgments

Judith Johnson, retired CRS Specialist in Biomedical Policy, had authored previous versions of this report.

Footnotes

1.

For further information, see CRS Report R44132, Specialty Drugs: Background and Policy Concerns.

2.

Aaron S. Kesselheim and Jerry Avorn, "The High Cost of Prescription Drugs in the United States: Origins and Prospects for Reform," JAMA, vol. 316, no. 8 (August 23/30, 2016), pp. 858-871.

3.

QuintilesIMS Institute, Medicine use and spending in the U.S.: A review of 2017 and Outlook to 2022, April 2018, p. 11.

4.

Ibid.

5.

Ibid.

6.

Jeanne Whalen, "Why the U.S. Pays More than Other Countries for Drugs," The Wall Street Journal, December 1, 2015.

7.

IMS Health, The Impact of Biosimilar Competition, June 2016, p. 4, http://ec.europa.eu/growth/tools-databases/newsroom/cf/itemdetail.cfm?item_id=8854.

8.

Ed Silverman, "AbbVie offers a 'huge' discount on Humira to fend off European rivals," STAT+ Pharmalot, November 1, 2018. Zachary Brennan, "AbbVie Sees 80% Discounts in Nordic Market With New Humira Biosimilars," RAPS Regulatory Focus, November 2, 2018, at https://www.raps.org/news-and-articles/news-articles/2018/11/abbvie-sees-80-discounts-in-nordic-market-with-ne.

9.

D. Gotham, M. Barber, & A. Hill, "Production costs and potential prices for biosimilars of human insulin and insulin analogues," BMJ Global Health, 2018, doi:10.1136/bmjgh-2018-000850.

10.

Brian Kelley, "Industrialization of mAb production technology: The bioprocessing industry at a crossroads," mAbs, vol. 1, no. 5 (2009), pp. 443-452. https://doi.org/10.4161/mabs.1.5.9448.

11.

FDA, http://www.fda.gov/BiologicsBloodVaccines/default.htm.

12.

CBER does not regulate the transplantation of vascularized human organ transplants such as kidney, liver, heart, lung, or pancreas. The Health Resources Services Administration (HRSA) oversees the transplantation of vascularized human organs.

13.

Federal Register, vol. 68, no. 123, June 26, 2003, pp. 38067-38068. CDER's work covers more than just medicines. For example, fluoride toothpaste, antiperspirants, dandruff shampoos, and sunscreens are all considered "drugs." FDA, About the Center for Drug Evaluation and Research, http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/default.htm.

14.

Definitions from NCI Dictionary of Cancer Terms http://www.cancer.gov/publications/dictionaries/cancer-terms.

15.

PHSA Section 351(a).

16.

Ibid. While FDA approves drugs that are "safe and effective" the equivalent terminology for biologics is "safe, pure and potent." In an April 2015 FDA guidance document, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, the agency states that "[t]he standard for licensure of a biological product as potent under section 351(a) of the PHS Act has long been interpreted to include effectiveness (see 21 CFR 600.3(s) and the guidance for industry on Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products). In this guidance, we use the terms safety and effectiveness and safety, purity, and potency interchangeably in the discussions pertaining to biosimilar products."

17. Comments by Brian Lehman, Manager of Pharmacy Benefits and Policy, Ohio Public Employees Retirement System (OPERS), at the June 20, 2016, Alliance for Health Reform briefing, "The Emerging Biosimilars Market," webcast at https://www.youtube.com/watch?v=XZvhLYZ_TZg; and, FDA, CDERLearn website, FDA Overview of Biosimilar Products, slide 13 in Module 4 "Complexity of Biological Product Manufacturing," http://fdabiosimilars.e-paga.com/course/framework/. 18.

David M. Dudzinski, "Reflections on Historical, Scientific, and Legal Issues Relevant to Designing Approval Pathways for Generic Versions of Recombinant Protein-Based Therapeutics and Monoclonal Antibodies," Food and Drug Law Journal, (2005) vol. 60, p. 153. The Insulin Amendments, P.L. 77-366, codified at 21 U.S.C. 356, were repealed by P.L. 105-115, the Food and Drug Administration Modernization Act (FDAMA).

19.

Ibid., p. 154.

20.

Janet Woodcock, Deputy Commissioner, Chief Medical Officer, FDA, testimony before the House Committee on Oversight and Government Reform, March 26, 2007, at http://www.fda.gov/newsevents/testimony/ucm154070.htm; and BIO Citizen Petition, Follow-on Therapeutic Proteins, April 23, 2003, http://www.fda.gov/OHRMS/DOCKETS/DOCKETS/03p0176/03p-0176-cp00001-01-vol11.pdf.

21.

BPCIA §7002(e).

22.

For additional information, see CRS Report R44643, The Hatch-Waxman Act: A Primer.

23.

Jonah Houts, Express Scripts, Inc., testimony before the House Committee on Oversight and Government Reform, Hearing on "Safe and Affordable Biotech Drugs: The Need for a Generic Pathway," March 26, 2007.

24.

FFDCA §505(j).

25.

Bill Nixon, President and CEO, Generic Pharmaceutical Association, letter to Daniel Troy, Chief Counsel, FDA, January 18, 2002, http://www.fda.gov/cder/ogd/GPHA_jan_21.htm.

26.

BIO Citizen Petition, Follow-on Therapeutic Proteins, April 23, 2003, http://www.fda.gov/OHRMS/DOCKETS/DOCKETS/03p0176/03p-0176-cp00001-01-vol11.pdf.

27.

European Medicines Agency (EMA), European public assessment reports, available at https://www.ema.europa.eu/en/human-regulatory/overview/biosimilar-medicines-overview.

28.

Anna Wilde Mathews and Jeanne Whalen, "FDA Clears Copycat Version Of Human Growth Hormone," The Wall Street Journal, June 1, 2006, and Anna Wilde Mathews, "FDA Is Ordered to Rule on Generic Biotech Drug," The Wall Street Journal, April 15, 2006.

29.

"Europe approves two follow-on human growth hormones," Nature Biotechnology, vol. 24 (June 2006), p. 601.

30.

FDA had approved via the 505(b)(2) pathways several other follow-on biologics: Fortical (calcitonin-salmon) nasal spray, for treatment of postmenopausal osteoporosis, approved in August 2005; Hylenex (hyaluronidase-human), for increasing absorption of an injected drug, approved in December 2005; and GlucaGen (glucagon recombinant for injection), for recovery from insulin induced hypoglycemia, approved in June 1998. More recently, in December 2015, FDA approved Basaglar under a 505(b)(2) NDA, relying in part, on FDA's finding of safety and effectiveness for Lantus (insulin glargine injection) to support approval. In its press release, FDA makes clear that Basaglar is not approved as a generic. Basaglar also is not approved as a biosimilar, as there are no insulin glargine products that are currently licensed under the PHSA, so there is no "reference product" for a proposed biosimilar product. See "Follow-on Protein Products," Testimony of Dr. Janet Woodcock before the House Committee on Oversight and Government Reform, March 26, 2007, and "FDA approves Basaglar, the first 'follow-on' insulin glargine product to treat diabetes," December 16, 2015.

31.

Anna Wilde Mathews and Jeanne Whalen, "FDA Clears Copycat Version Of Human Growth Hormone," The Wall Street Journal, June 1, 2006.

32.

ACA §7002(f).

33.

PHSA §351(k)(2)(A).

34.

PHSA §351(i)(2).

35.

PHSA §351(k)(4).

36.

FDA, Implementation of the Biologics Price Competition and Innovation Act of 2009, http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm215089.htm.

37.

BPCIA §7002(e).

38.

FDA, Interpretation of the "Deemed to be a License" Provision of the Biologics Price Competition and Innovation Act of 2009 Guidance for Industry, December 2018, https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM490264.pdf.

39.

PHSA §351(k)(7).

40.

PHSA §351(k)(7)(C).

41.

PHSA §351(m).

42.

FFDCA §527(a). See also FDA, "Guidance for Industry Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act," August 2014, https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm407844.pdf.

43.

PHSA §351(k)(6).

44.

FDA, Interpretation of the "Deemed to be a License" Provision of the Biologics Price Competition and Innovation Act of 2009 Guidance for Industry, December 2018, pp. 9-10, https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM490264.pdf.

45.

Ibid.

46.

Sue Sutter, "Sanofi's Admelog, a Humalog Follow-On, Approved in US As 'Black Hole' for Insulin Looms," Pink Sheet, December 18, 2017.

47.

FDA, Interpretation of the "Deemed to be a License" Provision of the Biologics Price Competition and Innovation Act of 2009 Guidance for Industry, December 2018, p. 7, https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM490264.pdf.

48.

FDA Statement, "Remarks from FDA Commissioner Scott Gottlieb, M.D., as prepared for delivery at the Brookings Institution on the release of the FDA's Biosimilars Action Plan," July 18, 2018, https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm613881.htm.

49.

FDA, "Biosimilar Action Plan: Balancing Innovation and Competition," July 2018, https://www.fda.gov/media/114574/download.

50.

"This term is used in two slightly different ways, both relating to products with a high number of patents. First, a patent thicket may describe the situation where multiple parties have overlapping patent rights on one product, such that a 'potential manufacturer must negotiate licenses with each patent owner in order to bring a product to market without infringing.' Patent thickets, in this sense, raise concerns about inefficient exploitation of a technology because the multiplicity of owners increases transaction costs and creates coordination challenges. Second, the term may be used in a looser sense to describe an incumbent manufacturer's practice of amassing of a large volume of patents relating to a single product, with the intent to intimidate follow-on competitors from entering the market (or to make it too costly and risky to do so). AbbVie's Humira patent portfolio has been alleged to be an example of this sort of patent thicket," see CRS Report R45666, Drug Pricing and Intellectual Property Law: A Legal Overview for the 116th Congress.

51.

Initiative for Medicines, Access, and Knowledge (I-MAK), "Overpatented, Overpriced: How Excessive Pharmaceutical Patenting is Extending Monopolies and Driving up Drug Prices," p. 7, see https://www.i-mak.org/wp-content/uploads/2018/08/I-MAK-Overpatented-Overpriced-Report.pdf.

52. Ed Silverman, "Behind the patent thicket: tactics AbbVie allegedly used to thwart biosimilar versions of Humira, STAT, November 7, 2018, https://www.statnews.com/pharmalot/2018/11/07/abbvie-biosimilars-humira-patents/. 53
Sales represent company-reported sales where available, otherwise based on an average of equity analyst estimates.

Appendix D. The Purple Book

Table D-1. CDER Purple Book: Licensed Biological Products

Listed by year of licensure, including biosimilars

Year

Brand name (nonproprietary name)

1965

Santyl (collagenase)

1978

Elspar (asparaginase)

1986

Intron A (interferon alfa-2b)

1987

Activase (alteplase, cathflo activase)

1989

Epogen/Procrit (epoetin alfa), Alferon N Injection (interferon alfa-n3), Botox (onabotulinumtoxinA)

1991

Neupogen (filgrastim), Leukine (sargramostim)

1992

Proleukin (aldesleukin)

1993

Betaseron (interferon beta-1b), Pulmozyme (dornase alfa)

1994

Oncaspar (pegaspargase), ReoPro (abciximab)

1996

Avonex (interferon beta-1a), ProstaScint (capromab pendetide), Retavase (reteplase)

1997

Neumega (oprelvekin), Rituxan (rituximab), Zenapax (daclizumab), Regranex (becaplermin)

1998

Simulect (basiliximab), Synagis (palivizumab), Remicade (infliximab), Herceptin (trastuzumab), Enbrel (etanercept)

1999

Ontak (denileukin diftitox), Actimmune (interferon gamma-1b)

2000

TNKase (tenecteplase), Myobloc (rimabotulinumtoxinB)

2001

Campath, Lemtrada (alemtuzumab), Aranesp (darbepoetin alfa), Kineret (anakinra)

2002

Zevalin (ibritumomab tiuxetan), Rebif (interferon beta-1a), Elitek (rasburicase), Pegasys (peginterferon alfa-2a), Humira (adalimumab)

2003

Fabrazyme (agalsidase beta), Aldurazyme (laronidase), Xolair (omalizumab)

2004

Erbitux (cetuximab), Avastin (bevacizumab), Tysabri (natalizumab), Kepivance (palifermin), Pegasys Copegus Combination Pack (peginterferon alfa-2a co-packaged with ribavirin)

2005

Naglazyme (galsulfase), Orencia (abatacept)

2006

Myozyme (alglucosidase alfa), Lucentis (ranibizumab), Elaprase (idursulfase), Vectibix (panitumumab)

2007

Soliris (eculizumab), Mircera (methoxy polyethylene glycol-epoetin beta)

2008

Arcalyst (rilonacept), Cimzia (certolizumab pegol), Nplate (romiplostim)

2009

Simponi (golimumab), Dysport (abobotulinumtoxinA), Ilaris (canakinumab), Extavia (interferon beta-1b), Stelara (ustekinumab), Arzerra (ofatumumab), Kalbitor (ecallantide)

2010

Actemra (tocilizumab), Xiaflex (collagenase clostridium histolyticum), Lumizyme (alglucosidase alfa), Prolia, Xgeva (denosumab), Xeomin (incobotulinumtoxinA), Krystexxa (pegloticase)

2011

Benlysta (belimumab), Yervoy (ipilimumab), Nulojix (belatacept), Adcetris (brentuximab vedotin), Eylea (aflibercept), Erwinaze (asparaginase erwinia chrysanthemi)

2012

Voraxaze (glucarpidase), Perjeta (pertuzumab), Zaltrap (ziv-aflibercept), Granix (tbo-filgrastim), Jetrea (ocriplasmin), raxibacumab (raxibacumab)

2013

Kadcyla (ado-trastuzumab emtansine), Simponi Aria (golimumab injection, for IV use), Actemra (tocilizumab), Gazyva (obinutuzumab)

2014

Vimizim (elosulfase alfa), Myalept (metreleptin), Tanzeum (albiglutide), Cyramza (ramucirumab), Sylvant (siltuximab), Entyvio (vedolizumab), Plegridy (peginterferon beta-1a), Keytruda (pembrolizumab), Trulicity (dulaglutide), Blincyto (blinatumomab), Opdivo (nivolumab)

2015

Cosentyx (secukinumab), Natpara (parathyroid hormone), Zarxio (filgrastim-sndz), Unituxin (dinutuximab), Praluent (alirocumab), Repatha (evolocumab), Praxbind (idarucizumab), Strensiq (asfotase alfa), Nucala (mepolizumab), Darzalex (daratumumab), Portrazza (necitumumab), Empliciti (elotuzumab), Kanuma (sebelipase alfa)

2016

Anthim (obiltoxaximab), Taltz (ixekizumab), Cinqair (reslizumab), Inflectra (infliximab-dyyb), Tecentriq (atezolizumab), Zinbryta (daclizumab), Erelzi (etanercept-szzs), Amjevita (adalimumab-atto), Stelara (ustekinumab), Lartruvo (olaratumab), Zinplava (bezlotoxumab)

2017

Siliq (brodalumab), Bavencio (avelumab), Dupixent (dupilumab), Ocrevus (ocrelizumab), Renflexis (infliximab-abda), Brineura (cerliponase alfa), Imfinzi (durvalumab), Kevzara (sarilumab), Rituxan Hycela, (rituximab and hyaluronidase human), Tremfya (guselkumab), Benlysta (belimumab), Besponsa (inotuzumab ozogamicin), Cyltezo (adalimumab-adbm), Mylotarg (gemtuzumab ozogamicin), Mvasi (bevacizumab-awwb)

Source: Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER) Purple Book, accessed on September 15, 2017, https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm.

Notes: Table includes BLAs only; it does not include biological products that were regulated as drugs via a New Drug Application (NDA) under the Federal Food, Drug and Cosmetic Act (FFDCA).

Table D-2. CBER Purple Book: Licensed Biological Products

Recombinant products, listed by year of licensure

Year

Brand name (nonproprietary name)

1997

Benefix (coagulation factor IX)

1999

NovoSeven (coagulation factor VIIa)

2000

Refacto (antihemophilic factor)

2003

Advate (antihemophilic factor, plasma/albumin free)

2008

Recothrom (thrombin topical), Xyntha (antihemophilic factor, plasma/albumin free)

2009

Atryn (antithrombin)

2010

Provenge (sipuleucel-T)

2011

LaViv (azficel-T)

2013

Rixubis (coagulation factor IX), NovoEight (antihemophilic factor), Tretten (coagulation factor XIII A subunit)

2014

Alprolix (coagulation factor IX, Fc fusion protein), Eloctate (antihemophilic factor, Fc fusion protein), Ruconest (C1 esterase inhibitor), Obizur (antihemophilic factor, porcine sequence)

2015

Ixinity (coagulation factor IX), Nuwiq (antihemophilic factor), Imlygic (talimogene laherparepvec), Adynovate (antihemophilic factor, PEGylated), Vonvendi (von Willebrand factor)

2016

Kovaltry (antihemophilic factor, full length), Idelvion (coagulation factor IX, albumin fusion protein), Solchayn (antihemophilic factor, single chain)

2017

Rebinyn (coagulation factor IX, GlycoPEGylated)

Source: FDA, Center for Biologics Evaluation and Research (CBER) Purple Book, accessed on September 15, 2017, https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm; and, Nature Biotechnology, v. 34 (3), March 2016, pp. 276-283, Supplementary Table 3.

Notes: Table includes recombinant products only; it does not include most biological products listed in the CBER Purple Book.

Author Contact Information

[author name scrubbed], Specialist in Biomedical Policy ([email address scrubbed], [phone number scrubbed])

Footnotes

77. 87. 99. 107. FDA, Biosimilar User Fee Act (BsUFA II) Reauthorization Public Meeting, October 20, 2016, slide 31, https://www.fda.gov/downloads/ForIndustry/UserFees/BiosimilarUserFeeActBsUFA/UCM526071.pdf.

1.

FDA, http://www.fda.gov/BiologicsBloodVaccines/default.htm.

2.

CBER does not regulate the transplantation of vascularized human organ transplants such as kidney, liver, heart, lung, or pancreas. The Health Resources Services Administration (HRSA) oversees the transplantation of vascularized human organs.

3.

Federal Register, vol. 68, no. 123, June 26, 2003, pp. 38067-38068. CDER's work covers more than just medicines. For example, fluoride toothpaste, antiperspirants, dandruff shampoos, and sunscreens are all considered "drugs." FDA, About the Center for Drug Evaluation and Research, http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/default.htm.

4.

Definitions from NCI Dictionary of Cancer Terms http://www.cancer.gov/publications/dictionaries/cancer-terms.

5.

For further information, see CRS Report R44132, Specialty Drugs: Background and Policy Concerns.

6.

Aaron S. Kesselheim and Jerry Avorn, "The High Cost of Prescription Drugs in the United States: Origins and Prospects for Reform," JAMA, vol. 316, no. 8 (August 23/30, 2016), pp. 858-871.

7.

QuintilesIMS Institute, Medicine use and spending in the U.S.: A review of 2016 and Outlook to 2021, May 2017, p. 11.

8.

Ibid.

9.

Ibid.

10.

HHS, Office of the Assistant Secretary for Planning and Evaluation (ASPE), "Report to Congress: Prescription Drugs: Innovation, Spending, and Patient Access," December 7, 2016, pp. 5-6.

11.

IMS Health, The Impact of Biosimilar Competition, June 2016, p. 4, http://ec.europa.eu/growth/tools-databases/newsroom/cf/itemdetail.cfm?item_id=8854.

12.

To balance the establishment of the generic drug industry, the Hatch-Waxman Act provided the sponsor of a brand-name drug a period of market exclusivity (apart from its patent protection) to allow the sponsor of an innovator drug time to recoup its research investment, or earn more profit, before the market entry of the lower-priced generic product. For more information, see CRS Report R41114, The Hatch-Waxman Act: Over a Quarter Century Later.

13.

Jonah Houts, Express Scripts, Inc., testimony before the House Committee on Oversight and Government Reform, Hearing on "Safe and Affordable Biotech Drugs: The Need for a Generic Pathway," March 26, 2007.

14.

David M. Dudzinski, "Reflections on Historical, Scientific, and Legal Issues Relevant to Designing Approval Pathways for Generic Versions of Recombinant Protein-Based Therapeutics and Monoclonal Antibodies," Food and Drug Law Journal, (2005) vol. 60, p. 153. The Insulin Amendments, P.L. 77-366, codified at 21 U.S.C. 356, were repealed by P.L. 105-115, the Food and Drug Administration Modernization Act (FDAMA).

15.

Ibid., p. 154.

16.

Janet Woodcock, Deputy Commissioner, Chief Medical Officer, FDA, testimony before the House Committee on Oversight and Government Reform, March 26, 2007, at http://www.fda.gov/newsevents/testimony/ucm154070.htm; and BIO Citizen Petition, Follow-on Therapeutic Proteins, April 23, 2003, http://www.fda.gov/OHRMS/DOCKETS/DOCKETS/03p0176/03p-0176-cp00001-01-vol11.pdf.

17.

Bill Nixon, President and CEO, Generic Pharmaceutical Association, letter to Daniel Troy, Chief Counsel, FDA, January 18, 2002, http://www.fda.gov/cder/ogd/GPHA_jan_21.htm.

18.

BIO Citizen Petition, Follow-on Therapeutic Proteins, April 23, 2003, http://www.fda.gov/OHRMS/DOCKETS/DOCKETS/03p0176/03p-0176-cp00001-01-vol11.pdf.

19.

Anna Wilde Mathews and Jeanne Whalen, "FDA Clears Copycat Version Of Human Growth Hormone," The Wall Street Journal, June 1, 2006, and Anna Wilde Mathews, "FDA Is Ordered to Rule on Generic Biotech Drug," The Wall Street Journal, April 15, 2006.

20.

"Europe approves two follow-on human growth hormones," Nature Biotechnology, vol. 24 (June 2006), p. 601.

21.

Other follow-on products have used the 505(b)(2) pathway: Fortical (calcitonin-salmon) nasal spray, for treatment of postmenopausal osteoporosis, approved in August 2005; Hylenex (hyaluronidase-human), for increasing absorption of an injected drug, approved in December 2005; and Basaglar (insulin glargine injection), for treatment of diabetes, approved in December 2015. All are follow-ons of biologics that were regulated as drugs under the FFDCA.

22.

Anna Wilde Mathews and Jeanne Whalen, "FDA Clears Copycat Version Of Human Growth Hormone," The Wall Street Journal, June 1, 2006.

23.

The BPCIA also created FDA-administered periods of regulatory exclusivity for certain brand-name biologics and biosimilar products, as well as procedures for brand-name and biosimilar manufacturers to resolve patent disputes. For further information, see CRS Report R44173, Follow-On Biologics: Intellectual Property Issues.

24.

FDA, Implementation of the Biologics Price Competition and Innovation Act of 2009, http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm215089.htm.

25.

The three draft guidances were published in the Federal Register on February 15, 2012: (1) Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, (2) Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009, and (3) Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product.

26.

FDA, Guidances (Drugs), Biosimilars, http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm.

27.

Comments by Brian Lehman, Manager of Pharmacy Benefits and Policy, Ohio Public Employees Retirement System (OPERS), at the June 20, 2016, Alliance for Health Reform briefing, "The Emerging Biosimilars Market," webcast at https://www.youtube.com/watch?v=XZvhLYZ_TZg; and, FDA, CDERLearn website, FDA Overview of Biosimilar Products, slide 13 in Module 4 "Complexity of Biological Product Manufacturing," http://fdabiosimilars.e-paga.com/course/framework/.

28.

FDA News Release, "FDA approves first biosimilar product Zarxio," March 6, 2015, http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm436648.htm.

29.

See Drugs@FDA https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm, for license information on Neupogen (filgrastim) https://www.accessdata.fda.gov/drugsatfda_docs/bla/pre96/103353Orig1s000.pdf.

30.

FDA News Release, "FDA approves Inflectra, a biosimilar to Remicade," April 5, 2016, http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm494227.htm.

31.

See Drugs@FDA https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm, for license information on Remicade (infliximab) https://www.accessdata.fda.gov/drugsatfda_docs/appletter/1998/inflcen082498L.htm. In 2008, Centocor merged with Ortho Biotech. In June 2011, Centocor Ortho Biotech Inc. changed its name to Janssen Biotech Inc. Reid Kanaley, McClatchy-Tribune Business News, June 22, 2011.

32.

Pfizer acquired Inflectra from Hospira in 2015.

33.

Jonathan D. Rockoff, "Pfizer Alleges J&J Thwarted Competition to Remicade, in Legal Test of Biotech-Drug Copies; the lawsuit alleges J&J's 'exclusionary contracts' hurt Pfizer's copy of arthritis drug Remicade," The Wall Street Journal, September 20, 2017.

34.

Pfizer, "Pfizer Goes to Court to Allow Competition for Biologics and Expand Options for Patients," September 20, 2017, https://investors.pfizer.com/investor-news/press-release-details/2017/Pfizer-Goes-to-Court-to-Allow-Competition-for-Biologics-and-Expand-Options-for-Patients/default.aspx.

35.

Aaron Hakim and Joseph S. Ross, "Obstacles to the Adoption of Biosimilars for Chronic Diseases," JAMA, vol. 317, no. 21 (June 6, 2017), pp. 2163-2164, http://jamanetwork.com/journals/jama/fullarticle/2625049.

36.

Pfizer v. Johnson & Johnson and Janssen Biotech, Inc., p. 6 (U.S. District Court, Eastern District of Pennsylvania), http://freepdfhosting.com/db2fe78c75.pdf.

37.

Ibid., p. 7.

38.

Ibid.

39.

Ibid., p. 9.

40.

Ed Silverman, "Pfizer accuses J&J of illegally stifling insurance coverage for its biosimilar," Pharmalot, September 20, 2017, https://www.statnews.com/pharmalot/2017/09/20/pfizer-jnj-biosimilars-insurance/

41.

FDA News Release, "FDA approves Erelzi, a biosimilar to Enbrel," August 30, 2016, http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm518639.htm.

42.

See Drugs@FDA https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm, for license information on Enbrel (etanercept) https://www.accessdata.fda.gov/drugsatfda_docs/appletter/1998/etanimm110298L.htm.

43.

Carey Krause, "The marriage of Amgen and Immunex," Chemical Market Reporter, August 12, 2002.

44.

Sandoz, "FDA approves Sandoz Erelzi™ to treat multiple inflammatory diseases," press release, August 30, 2016, http://www.sandoz.com/media_center/press_releases_news/global_news/2016-08-30-fda-approves-sandoz-erelzi.shtml.

45.

"FDA approves third biosimilar for sale in US," American Health Line, September 6, 2016.

46.

FDA News Release, "FDA approves Amjevita, a biosimilar to Humira," September 23, 2016, http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm522243.htm.

47.

See Drugs@FDA https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm, for license information on Humira (adalimumab) https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/adalabb123102L.htm.

48.

The current Humira label can be found via Drugs@FDA. The Humira label as of June 30, 2016, is available http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125057s397lbl.pdf. In addition to the indications listed for Amjevita, Humira is also approved to treat hidradenitis suppurativa, uveitis, and pediatric Crohn's disease, as well as polyarticular juvenile idiopathic arthritis in patients as young as two years of age.

49.

Nicholas Florko, "FDA Approves Second Humira Biosimilar," InsideHealthPolicy.com's FDA Week, September 1, 2017.

50.

See Drugs@FDA https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm, for license information on Remicade (infliximab) https://www.accessdata.fda.gov/drugsatfda_docs/appletter/1998/inflcen082498L.htm. In 2008, Centocor merged with Ortho Biotech. In June 2011 Centocor Ortho Biotech Inc. changed its name to Janssen Biotech Inc. Reid Kanaley, McClatchy-Tribune Business News, June 22, 2011.

51.

Timothy Martin and John D. Rockoff, "Samsung Releases Arthritis Drug in First Foray Into U.S. Pharmaceuticals; Samsung Bioepis's biosimilar drug for rheumatoid arthritis to be marketed by Merck in U.S.," Wall Street Journal, July 24, 2017.

52.

See Drugs@FDA https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm, for license information on Humira (adalimumab) https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/adalabb123102L.htm.

53.

Nicholas Florko, "FDA Approves Second Humira Biosimilar," InsideHealthPolicy.com's FDA Week, September 1, 2017.

54.

See Drugs@FDA https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm, for license information on Avastin (bevacizumab) https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2004/125085ltr.pdf.

55.

FDA, Nonproprietary Naming of Biological Products: Guidance for Industry, January 2017, https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM459987.pdf.

56.

Section 351(a)(1)(B)(i) of the PHSA (42 U.S.C. 262(a)(1)(B)(i) and §600.3(k) of Title 21 of the Code of Federal Regulations (21 C.F.R. 600.3(k)).

57.

FDA, Nonproprietary Naming of Biological Products: Guidance for Industry, January 2017, p. 1, at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM459987.pdf.

58.

Ibid.

59.

FDA defines as follows: "Originator biological product" means a biological product submitted in a BLA under Section 351(a) of the PHS Act (i.e., a stand-alone BLA) for which there is no previously licensed biological product submitted under Section 351(a) that is a related biological product. BLA is a biologics license application.

60.

FDA, Nonproprietary Naming of Biological Products: Guidance for Industry, January 2017, p. 7, at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM459987.pdf.

61.

For information on the USAN Council, see http://www.ama-assn.org/ama/pub/physician-resources/medical-science/united-states-adopted-names-council.page.

62.

WHO, Essential medicines and health products, Guidance on INN, at http://www.who.int/medicines/services/inn/innguidance/en/.

63.

WHO, Biological Qualifier: An INN Proposal, Programme on International Nonproprietary Names (INN), http://www.who.int/medicines/services/inn/WHO_INN_BQ_proposal_2015.pdf.

64.

Ibid. As explained in the WHO document, the BQ code "will consist of four random consonants and an optional two digits as a checksum. The WHO INN will issue the BQ letters with a checksum, but it is at the discretion of the individual regulatory authority whether the checksum is used as part of the BQ. The form of the BQ may take: (1) four letters; (2) four letters followed by the checksum; or (3) two letters, two digits and two letters, thus mimicking car registration plates to be more memorable. For instance, TRADENAME INN BQ: GROKINO anonutropin alfa bxsh; or GROKINO anonutropin alfa bxsh08; or GROKINO anonutropin alfa bx08sh."

65.

Erin Durkin, "WHO Unveils Final Biological Naming Plan That Differs From FDA's," InsideHealthPolicy's FDA Week, January 29, 2016.

66.

FDA Statement, "Remarks from FDA Commissioner Scott Gottlieb, M.D., as prepared for delivery at the Brookings Institution on the release of the FDA's Biosimilars Action Plan," July 18, 2018, https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm613881.htm.

54.

FFDCA §505(b)(1).

55.

FDA, Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations, https://www.accessdata.fda.gov/Scripts/cder/ob/index.cfm.

56.

FFDCA §505(j)(7)(A). See also the Orange Book Preface, available at https://www.fda.gov/Drugs/DevelopmentApprovalProcess/ucm079068.htm.

57.

FFDCA §505(j)(2)(A)(vii). For additional information about the patent certification procedures, see CRS Report R44643, The Hatch-Waxman Act: A Primer.

58.

FDA, Orange Book Preface, available at https://www.fda.gov/Drugs/DevelopmentApprovalProcess/ucm079068.htm.

59.

CRS Legal Sidebar WSLG1796, UPDATE: Battle Over Biosimilars: The Supreme Court Considers Dueling Interpretations of the ACA's Biologics Price Competition and Innovation Act Provisions. For additional information about the biologics patent dance, see CRS Report R45666, Drug Pricing and Intellectual Property Law: A Legal Overview for the 116th Congress.

60.

FDA, "Purple Book: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations," https://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/therapeuticbiologicapplications/biosimilars/ucm411418.htm.

61.

FDA, "Background Information: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations (Purple Book)," https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411424.htm.

62.

FDA, "Biosimilars Action Plan: Balancing Innovation and Competition," July 2018, https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM613761.pdf.

63.

FDA, "Facilitating Competition and Innovation in the Biological Products Marketplace; Public Hearing; Request for Comments," FDA-2018-N-2689 https://www.regulations.gov/docketBrowser?rpp=25&so=DESC&sb=commentDueDate&po=25&dct=PS&D=FDA-2018-N-2689.

64.

The Academy of Managed Care Pharmacy, Re: Facilitating Competition and Innovation in the Biological Products Marketplace; Public Hearing; Request for Comments, September 21, 2018.

65.

The Pharmaceutical Research and Manufacturers of America (PhRMA), Re: Docket No. FDA-2018-N-2689: Facilitating Competition and Innovation in the Biological Products Marketplace; Public Hearing; Request for Comments, September 21, 2018.

66.

Comments from The Association for Accessible Medicines (AAM) and the Biosimilars Council on behalf of our member companies, regarding Docket FDA-2018-N-2689, Facilitating Competition and Innovation in the Biological Products Marketplace, Public Hearing; Request for Comments, September 21, 2018.

67.

Ibid. The Academy of Managed Care Pharmacy, Re: Facilitating Competition and Innovation in the Biological Products Marketplace; Public Hearing; Request for Comments, September 21, 2018.

68.

For example, S. 659 in the 116th Congress.

69.

FDA, Nonproprietary Naming of Biological Products: Guidance for Industry, January 2017, https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM459987.pdf.

70.

FDA, Nonproprietary Naming of Biological Products: Update, Draft Guidance, March 2019, https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM632806.pdf.

71.

FDA, "Statement from FDA Commissioner Scott Gottlieb, M.D., on FDA's steps on naming of biological medicines to balance competition and safety for patients receiving these products," March 7, 2019, https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm632870.htm.

72.

FDA, Nonproprietary Naming of Biological Products: Guidance for Industry, January 2017, p. 1, at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM459987.pdf

73.

Nonproprietary names are selected by the USAN Council according to principles developed to ensure safety, consistency, and logic in the choice of names. For information on the USAN Council, see http://www.ama-assn.org/ama/pub/physician-resources/medical-science/united-states-adopted-names-council.page.

74.

FDA, Nonproprietary Naming of Biological Products: Update, Draft Guidance, March 2019, p. 5, https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM632806.pdf.

75.

FDA, Nonproprietary Naming of Biological Products: Update, Draft Guidance, March 2019, https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM632806.pdf.

76.

Erin Durkin, "WHO Unveils Final Biological Naming Plan That Differs From FDA's," InsideHealthPolicy's FDA Week, January 29, 2016.

Comment of the Staff of the Federal Trade Commission, Submitted to the Food and Drug Administration, In Response to a Request for Comments on Its Guidance for Industry on the "Nonproprietary Naming of Biological Products; Draft Guidance for Industry; Availability" [Docket No. FDA-2013-D-1543] Submitted on October 27, 2015, p. 2, https://www.ftc.gov/system/files/documents/advocacy_documents/ftc-staff-comment-submitted-food-drug-administration-response-fdas-request-comments-its-guidance/151028fdabiosimilar.pdf.

6778.

Ibid.

6879.

Ibid., p. 9.

69Comment of the Staff of the Federal Trade Commission, In Response to a Request for Comments on FDA's Guidance for Industry on the "Nonproprietary Naming of Biological Products; Draft Guidance for Industry; Update" [Docket No. FDA-2013-D-1543] 84 Fed Reg. 8534 (Mar. 8, 2019) Submitted on May 6, 2019, https://www.ftc.gov/system/files/documents/advocacy_documents/ftc-staff-comment-fda-department-health-human-services-its-updated-guidance-industry-nonproprietary/ftc_comment_to_fda_2019_biologics_naming_guidance_5-6-19.pdf. 80.

FDA, "[Docket No. 2000N–1269] (formerly Docket No. 00N–1269) RIN 0910–AA94, Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products," Federal Register, vol. 71, no. 15, January 24, 2006, pp. 3922-3997, http://www.gpo.gov/fdsys/pkg/FR-2006-01-24/pdf/06-545.pdf.

7081.

FDA, Labeling for Biosimilar Products: Guidance for Industry, Draft Industry, Guidance, March 2016July 2018, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM493439.pdf.

7182.

American Pharmacists Association (APhA), Re: Labeling for Biosimilar Products; Draft Guidance for Industry [Docket No. FDA2016-D-0643-0001], August 2, 2016.

83.

FDA, Drugs, From our perspective: Biosimilar product labeling, http://www.fda.gov/Drugs/NewsEvents/ucm493240.htm.

84.

Ibid.

85.

Bronwyn Mixter, "Brand, Generic Groups Differ on Biosimilar Labeling," Bloomberg BNA Health Care Daily Report, June 7, 2016.

86.

Ibid.

FDA, Drugs, From our perspective: Biosimilar product labeling, http://www.fda.gov/Drugs/NewsEvents/ucm493240.htm.

72.

Ibid.

73.

Bronwyn Mixter, "Brand, Generic Groups Differ on Biosimilar Labeling," Bloomberg BNA Health Care Daily Report, June 7, 2016.

74.

Ibid.

75.

Ibid.

76.

FDA, Implementation of the "Deemed to be a License" Provision of the Biologics Price Competition and Innovation Act of 2009, Draft Guidance, March 2016, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM490264.pdf.

77.

Ibid., p. 4.

78.

Erin Durkin, "Drug Lobbyists: FDA's BPCIA Transition Guide Hurts Access, Competition," InsideHealthPolicy, June 1, 2016.

79.

FDA, Implementation of the "Deemed to be a License" Provision of the Biologics Price Competition and Innovation Act of 2009, Draft Guidance, March 2016, p. 6, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM490264.pdf.

80.

Erin Durkin, "Industry: Axing Exclusivity As Biologics Shift To Licenses Unconstitutional," InsideHealthPolicy, May 27, 2016.

81.

FDA, Implementation of the "Deemed to be a License" Provision of the Biologics Price Competition and Innovation Act of 2009, Draft Guidance, March 2016, p. 7, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM490264.pdf.

82.

FDA, Implementation of the Biologics Price Competition and Innovation Act of 2009, http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm215089.htm.

8388.

FDA, Considerations in Demonstrating Interchangeability With a Reference Product, Draft Guidance, January 2017May 2019, https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf.

84.

FDA, "Considerations in Demonstrating Interchangeability With a Reference Product; Draft Guidance for Industry; Availability; Extension of Comment Period," 82 Federal Register 13819-13820, March 15, 2017.

85.

EMA, "Questions and answers on biosimilar medicines (similar biological medicinal products)," September 27, 2012, http://www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2009/12/WC500020062.pdf.

86.

IMS Institute for Healthcare Informatics, Delivering on the Potential of Biosimilar Medicines: The role of functioning competitive markets, March 2016, p. 26.

8789.

Richard Cauchi, "State Laws and Legislation Related to Biologic Medications and Substitution of Biosimilars," NCSL, March 31, 2017October 22, 2018, http://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx.

88.

Ibid. The 27 states (and the year a law was enacted) are Arizona (2016), California (2015), Colorado (2015), Delaware (2014), Florida (2013), Georgia (2015), Hawaii (2016), Idaho (2016), Illinois (2015), Indiana (2014), Iowa (2017), Kentucky (2016), Louisiana (2015), Massachusetts (2014), Missouri (2016), Montana (2017), New Jersey (2015), North Carolina (2015), North Dakota (2013), Oregon (2013 and 2016), Pennsylvania (2016), Rhode Island (2016), Tennessee (2015), Texas (2015), Utah (2013 and 2015), Virginia (2013), and Washington (2015). Puerto Rico enacted a law in 2015. Ten states filed legislation but failed to enact: Arkansas, Connecticut, Maryland, Michigan, Mississippi, Nebraska, Nevada, New York, Oklahoma, and Vermont90. Ibid. Alabama, Arkansas, Maine, Mississippi, Oklahoma, and the District of Columbia have not enacted such legislation.

8991.

See CRS Report R44864, Prescription Drug User Fee Act (PDUFA): 2017 Reauthorization as PDUFA VI.

90.

See CRS Report R44517, The FDA Medical Device User Fee Program: MDUFA IV Reauthorization, and CRS Report RL34459, Animal Drug User Fee Programs.

91.

Title IV of the Food and Drug Administration Safety and Innovation Act (FDASIA, P.L. 112-144).

R44810, FDA Risk Evaluation and Mitigation Strategies (REMS): Description and Effect on Generic Drug Development.
92.

U.S. Congress, House Committee on Energy and Commerce, Subcommittee on Health, Review of the Proposed Generic Drug and Biosimilars User Fees and Further Examination of Drug Shortages, Statement of Janet Woodcock, CDER Director, FDA, 112th Cong., 2nd sess., February 9, 2012.

93.

Biosimilar User Fee Act Reauthorization (BsUFA II), testimony of Janet Woodcock, M.D., FDA/CDER Director, before the U.S. House of Representatives, Committee on Energy and Commerce, Subcommittee on Health, March 2, 2017, http://docs.house.gov/meetings/IF/IF14/20170302/105631/HHRG-115-IF14-Wstate-WoodcockJ-20170302.PDF.

94.

A "small business" was defined under BsUFA I as an entity, including affiliates, with fewer than 500 employees that does not have a drug product that has been approved under a human drug, biologics, or biosimilar biological application and introduced or delivered for introduction into commerce.

95.

FY2013 through FY2016 BsUFA Financial Reports are http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/UserFeeReports/FinancialReports/BsUFA/default.htm.

96.

FDA, BsUFA Meetings, http://www.fda.gov/ForIndustry/UserFees/BiosimilarUserFeeActBsUFA/ucm461774.htm.

97.

Ibid.

98.

FDA, Biosimilar Biological Product Reauthorization Performance Goals and Procedures Fiscal Years 2018 Through 2022, http://www.fda.gov/downloads/ForIndustry/UserFees/BiosimilarUserFeeActBsUFA/UCM521121.pdf.

99.

FDA, BsUFA Meetings http://www.fda.gov/ForIndustry/UserFees/BiosimilarUserFeeActBsUFA/ucm461774.htm.

100.

For further information, see CRS Report R44961, FDA Reauthorization Act of 2017 (FDARA, P.L. 115-52).

101.

Biosimilar User Fee Act Reauthorization (BsUFA II), testimony of Janet Woodcock, M.D., CDER Director, FDA, before the U.S. House of Representatives, Committee on Energy and Commerce, Subcommittee on Health, March 2, 2017, p. 18, http://docs.house.gov/meetings/IF/IF14/20170302/105631/HHRG-115-IF14-Wstate-WoodcockJ-20170302.PDF.

102.

Ibid., pp. 22-23.

103.

Ibid., p. 23.

104.

FDA, Biosimilar User Fee Act (BsUFA II) Reauthorization Public Meeting, October 20, 2016, slide 31, https://www.fda.gov/downloads/ForIndustry/UserFees/BiosimilarUserFeeActBsUFA/UCM526071.pdf.

105.

For further details, see slide 34 of the October 20, 2016, Biosimilar User Fee Act (BsUFA II) Reauthorization Public Meeting https://www.fda.gov/downloads/ForIndustry/UserFees/BiosimilarUserFeeActBsUFA/UCM526071.pdf.

106D. Tucker, G. Wells, & M Sheer, "REMS: The Next Pharmaceutical Enforcement Priority?" Antitrust, Vol. 28, No. 2, Spring 2014. © 2014 by the American Bar Association, https://www.morganlewis.com/news/2014/03/~/media/files/docs/2014/rems-the-next-pharmaceutical-enforcement-priority.ashx.
93.

FDA, "Statement from FDA Commissioner Scott Gottlieb, M.D., on new actions advancing the agency's biosimilars policy framework," December 11, 2018, see https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm628121.htm.

94.

FDA "How to Obtain a Letter from FDA Stating that Bioequivalence Study Protocols Contain Safety Protections Comparable to Applicable REMS for RLD Guidance for Industry," Draft Guidance, December 2014, https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm425662.pdf.

95.

FDA, "Reference Listed Drug (RLD) Access Inquiries," https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/ucm607738.htm.

96.

FDA, "Approved Risk Evaluation and Mitigation Strategies (REMS)," accessed March 15, 2019, https://www.accessdata.fda.gov/Scripts/Cder/Rems/index.cfm.

97.

FDA, "Statement from FDA Commissioner Scott Gottlieb, M.D., on new actions advancing the agency's biosimilars policy framework," December 11, 2018, see https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm628121.htm. See also, FDA, "Biosimilars Action Plan: Balancing Innovation and Competition," July 2018, https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM613761.pdf.

98.

See, for example, the Creating and Restoring Equal Access to Equivalent Samples (CREATES) Act of 2019 (S. 340, H.R. 965). For additional information about the CREATES Act, see CRS Legal Sidebar LSB10272, The CREATES Act of 2019 and Lowering Drug Prices: Legal Background & Overview.

Hamilton Moses, David H.M. Matheson, Sarah Cairns-Smith, et al., "The Anatomy of Medical Research: U.S. and International Comparisons," JAMA, vol. 313, no. 2 (January 13, 2015), pp. 174-189.

107100.

Joseph A. DiMasi, Ronald W. Hansen, and Henry G. Grabowski, "The Price of Innovation: New Estimates of Drug Development Costs," Journal of Health Economics, vol. 22 (2003), pp. 151-185.

108101.

Kenneth I. Kaitin, Natalie R. Bryant, Louis Lasagna, "The Role of the Research-Based Pharmaceutical Industry in Medical Progress in the United States," Journal of Clinical Pharmacology, vol. 33, no. 5 (May 1993), pp. 412-417.

109102.

"Me too" drugs are structurally similar to drugs already available on the market. Critics fault industry for developing these duplicative products rather than investing in research on innovative drugs. Me too drugs are often heavily promoted by the pharmaceutical industry in order to gain a foothold on the market. See the January 7, 2015, ProPublica study by Charles Ornstein and Ryann Grochowski Jones https://www.propublica.org/article/vying-for-market-share-companies-heavily-promote-me-too-drugs.

110103.

According to FDA, "[s]omec]ertain drugs are classified as new molecular entities ("NMEs") for purposes of FDA review. Many of these products contain active moieties that have not been approved by FDA previously, either as a single ingredient drug or as part of a combination product; these products frequently provide important new therapies for patients. Some drugs are characterized as NMEs for administrative purposes, but nonetheless contain active moieties [i.e., parts] that are closely related to active moieties in products that have previously been approved by FDA. For example, CDER classifies biological products submitted in an application under section 351(a) of the Public Health Service Act as NMEs for purposes of FDA review, regardless of whether the Agency previously has approved a related active moiety in a different product." FDA, New Drugs at FDA: CDER's New Molecular Entities and New Therapeutic Biological Products, http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm20025676.htmhttps://www.fda.gov/drugs/development-approval-process-drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products.

111104.

Robert Kneller, "The Importance of New Companies for Drug Discovery: Origins of a Decade of New Drugs," Nature Review Drug Discovery, vol. 9, 2010, pp. 867-882.

112105.

Ashley J. Stevens, Jonathan J. Jensen, Katrine Wyller, et al., "The Role of Public-Sector Research in the Discovery of Drugs and Vaccines," The New England Journal of Medicine, vol. 364, no. 6 (February 10, 2011), pp. 535-541.

113106.

A chimeric antibody may have portions of the antibody molecule that were developed in an animal combined with human portions to avoid an immune reaction when administered to a patient.

Ibid., p. 539.

114.

FDA, Priority Review, http://www.fda.gov/ForPatients/Approvals/Fast/ucm405405.htm. A Priority Review designation means FDA's goal is to take action on an application within 6 months (compared to 10 months under standard review).

115.

Ashley J. Stevens, Jonathan J. Jensen, Katrine Wyller, et al., "The Role of Public-Sector Research in the Discovery of Drugs and Vaccines," The New England Journal of Medicine, vol. 364, no. 6 (February 10, 2011), p. 541.

116.

A chimeric antibody may have portions of the antibody molecule that were developed in an animal combined with human portions to avoid an immune reaction when administered to a patient.

117.

Ibid., p. 537.

118.

Ibid., p. 538.

119537. 108.

David M. Dudzinski, "Reflections on Historical, Scientific, and Legal Issues Relevant to Designing Approval Pathways for Generic Versions of Recombinant Protein-Based Therapeutics and Monoclonal Antibodies," Food and Drug Law Journal, 2005, vol. 60, pp. 143-260.

120109.

Ibid, p. 147.

121110.

Ibid.

122111.

Gary E. Gamerman, "Regulation of Biologics Manufacturing: Questioning the Premise," Food and Drug Law Journal, vol. 49, 1994, pp. 213-235.

123112.

The NIH Almanac—Historical Data: Chronology of Events, at http://www.nih.gov/about/almanac/historical/chronology_of_events.htm. In 1937, the biologics control program, previously the responsibility of the Division of Pathology and Bacteriology, NIH, was assigned to the newly established NIH Division of Biologics Control (redesignated Biologics Control Laboratory, 1944). In 1955, the biologics control function was placed in the newly formed NIH Division of Biologics Standards.

124113.

About FDA, "Significant Dates in U.S. Food and Drug Law History" http://www.fda.gov/AboutFDA/WhatWeDo/History/Milestones/ucm128305.htm.

125114.

FDA, Science and the Regulation of Biological Products, "From the Laboratory of Hygiene to CBER" p. 7, http://www.fda.gov/downloads/AboutFDA/WhatWeDo/History/ProductRegulation/100YearsofBiologicsRegulation/UCM070313.pdf.

126115.

Ibid.

127116.

See http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CBER/ucm385240.htm.

128117.

See, for example, "Assignment of Agency Component for Review of Premarket Applications," Final Rule, Federal Register, vol. 56, no. 225, November 21, 1991, pp. 58754-58758.

129118.

The Intercenter Agreement, http://www.fda.gov/oc/ombudsman/drug-bio.htm.

130119.

FDA Press Release, "FDA to Consolidate Review Responsibilities for New Pharmaceutical Products," September 6, 2002.

131120.

Federal Register, vol. 68, no. 123, June 26, 2003, pp. 38067-38068.

132121.

Transfer of Therapeutic Products to the Center for Drug Evaluation and Research, http://www.fda.gov/cber/transfer/transfer.htm. Also of interest is Approved Products Transferring to CDER, http://www.fda.gov/cber/transfer/transfprods.htm, and Therapeutic Biological Products, http://www.fda.gov/cder/biologics/default.htm.

122.

See CRS Report R44864, Prescription Drug User Fee Act (PDUFA): 2017 Reauthorization as PDUFA VI.

123.

See CRS Report R44517, The FDA Medical Device User Fee Program: MDUFA IV Reauthorization, and CRS Report RL34459, Animal Drug User Fee Programs.

124.

ACA §7002(f).

125.

Title IV of the Food and Drug Administration Safety and Innovation Act (FDASIA, P.L. 112-144).

126.

The following fee types were required under BsUFA I: an initial Biosimilar Product Development (BPD) fee; an annual BPD fee; reactivation BPD; an application fee (with a fee differential depending on whether the application contains clinical data or is a supplemental application); an establishment fee; and a product fee.

127.

U.S. Congress, House Committee on Energy and Commerce, Subcommittee on Health, Review of the Proposed Generic Drug and Biosimilars User Fees and Further Examination of Drug Shortages, Statement of Janet Woodcock, CDER Director, FDA, 112th Cong., 2nd sess., February 9, 2012.

128.

Joe Franklin, "Biosimilar and Interchangeable Products: Brief Update from FDA," FDLI Annual Conference, May 3, 2018, slide 3, at https://www.fdli.org/wp-content/uploads/2018/05/Biosimilars-New-Developments-and-Updates-3.pdf.

129.

For further information, see CRS Report R44961, FDA Reauthorization Act of 2017 (FDARA, P.L. 115-52).

130.