UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

 

Form 10-K

 

Commission file number 000-12477

Amgen Inc.

(Exact name of registrant as specified in its charter)

(805) 447-1000

(Registrant’s telephone number, including area code)

 

Securities registered pursuant to Section 12(b) of the Act:

 

 

Securities registered pursuant to Section 12(g) of the Act: None

Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes x No o

 

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes o No x

 

Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or Section 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes x No o

 

Indicate by check mark whether the registrant has submitted electronically and posted on its corporate Web site, if any, every Interactive Data File required to be submitted and posted pursuant to Rule 405 of Regulation S-T (§ 232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit and post such files). Yes x No o

 

Indicate by check mark if disclosure of delinquent filers pursuant to Item 405 of Regulation S-K is not contained herein, and will not be contained, to the best of registrant’s knowledge, in definitive proxy or information statements incorporated by reference in Part III of this Form 10-K or any amendment to this Form 10-K. o

 

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, or a smaller reporting company. See definitions of “large accelerated filer,” “accelerated filer” and “smaller reporting company” in Rule 12b-2 of the Exchange Act. (Check one):

 

Large accelerated filer x  Accelerated filer o  Non-accelerated filer o  Smaller reporting company o

(Do not check if a smaller reporting company)

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act) Yes o No x

 

The approximate aggregate market value of voting and non-voting stock held by non-affiliates of the registrant was $50,355,022,164 as of June 30, 2010(A)

 

932,452,902

(Number of shares of common stock outstanding as of February 11, 2011)

 

DOCUMENTS INCORPORATED BY REFERENCE

 

Specified portions of the registrant’s Proxy Statement with respect to the 2011 Annual Meeting of stockholders to be held May 20, 2011 are incorporated by reference into Part III of this annual report.

 

 

INDEX

 

PART I

 

 

Overview

 

Amgen Inc. (including its subsidiaries, referred to as “Amgen,” “the Company,” “we,” “our” or “us”) is the world’s largest independent biotechnology medicines company. We discover, develop, manufacture and market medicines for grievous illnesses. We focus solely on human therapeutics and concentrate on innovating novel medicines based on advances in cellular and molecular biology. Our mission is to serve patients.

 

We were incorporated in 1980 and organized as a Delaware corporation in 1987. Our public website is www.amgen.com. On our website, investors can find press releases, financial filings and other information about the Company. The U.S. Securities and Exchange Commission (“SEC”) website, www.sec.gov, also offers access to reports and documents we have electronically filed with or furnished to the SEC. These website addresses are not intended to function as hyperlinks, and the information contained in our website and in the SEC’s website is not intended to be a part of this filing.

 

As of December 31, 2010, we had 17,400 staff members worldwide. Approximately 6,700 of our staff members work in our research and development (“R&D”) function, approximately 4,600 work in manufacturing, approximately 4,200 work in our commercial operations and the rest are in general and administrative functions.

 

Currently, we market primarily recombinant protein therapeutics in supportive cancer care, nephrology and inflammation. Our principal products are: Aranesp^® (darbepoetin alfa) and EPOGEN^® (Epoetin alfa), erythropoiesis-stimulating agents (“ESAs”) that stimulate the production of red blood cells; Neulasta^® (pegfilgrastim), a pegylated protein, based on the Filgrastim molecule, and NEUPOGEN^® (Filgrastim), a recombinant-methionyl human granulocyte colony-stimulating factor (“G-CSF”), both of which selectively stimulate the production of neutrophils (a type of white blood cell that helps the body fight infection); and Enbrel^® (etanercept), an inhibitor of tumor necrosis factor (“TNF”), a substance that plays a role in the body’s response to inflammatory diseases. Our principal products represented 91%, 93% and 94% of our sales in 2010, 2009 and 2008, respectively. Our other marketed products include: Sensipar^®/Mimpara^® (cinacalcet), a small molecule calcimimetic that lowers serum calcium levels; Vectibix^® (panitumumab), a monoclonal antibody that binds specifically to the epidermal growth factor receptor (“EGFr”); and Nplate^® (romiplostim), a thrombopoietin (“TPO”) receptor agonist that mimics endogenous TPO, the primary driver of platelet production. In addition, in 2010 we launched Prolia^® (denosumab) and XGEVA^tm (denosumab) both of which contain the same active ingredient but which are approved for different indications, patient populations, doses and frequencies of administration. Denosumab is a fully human monoclonal antibody that specifically targets RANKL, an essential regulator of osteoclasts (the cells that break down bone).

 

We maintain sales and marketing forces primarily in the United States, Europe and Canada. We have also entered into agreements with third parties to assist in the commercialization and marketing of certain of our products in specified geographic areas. (See Business Relationships.) Together with our partners, we market our products to healthcare providers, including physicians or their clinics, dialysis centers, hospitals and pharmacies. Most patients receiving our principal products for approved indications are covered by either government or private payer healthcare programs, which influence demand. The reimbursement environment continues to evolve with greater emphasis on both cost containment and demonstration of the economic value of products.

 

In addition to our marketed products, we have various product candidates in mid-to-late stage development in a variety of therapeutic areas, including oncology, hematology, inflammation, bone, nephrology, cardiovascular and general medicine, which includes neurology. Our R&D organization has expertise in multiple treatment modalities, including large molecules (such as proteins, antibodies and peptibodies) and small molecules.

 

Our manufacturing operations consist of bulk manufacturing, formulation, fill and finish and distribution activities for all of our principal products as well as most of our product candidates. We operate commercial and/or clinical manufacturing facilities in the United States, Puerto Rico and the Netherlands. (See Item 2. Properties.)

Drug development in our industry is complex, challenging and risky; and failure rates are high. Product development cycles are very long — approximately 10 to 15 years from discovery to market. A new medicine must undergo many years of preclinical and clinical testing to establish its safety and efficacy for use in humans at appropriate dosing levels and with an acceptable benefit-risk profile. Biological products, which are produced in living systems, are inherently complex due to naturally occurring molecular variations. Highly specialized knowledge and extensive process and product characterization are required to transform laboratory-scale processes into reproducible commercial manufacturing processes. Upon approval, marketed products in our industry generally face substantial competition.

 

Our industry is also highly regulated, and various U.S. and foreign regulatory bodies have substantial authority over how we conduct our business. Government authorities in the United States and other countries regulate the manufacturing and marketing of our products as well as our ongoing R&D activities. In recent years, regulators have placed a greater scrutiny on drug safety. This has led to, and may in the future lead to: fewer products being approved by the U.S. Food and Drug Administration (“FDA”) or other regulatory bodies; delays in receiving approvals; additional safety-related requirements; restrictions on the use of products, including expanded safety labeling, or required risk management activities.

 

Significant Developments

 

Following is a summary of significant developments that occurred in 2010 and early 2011 affecting our business. A more detailed discussion of each development follows in the appropriate section.

 

Denosumab

 

 

Healthcare Reform

 

 

ESAs

 

 

Vectibix^®

 

 

Other Developments

 

 

Marketed Products

 

We market our principal products, Aranesp^®, EPOGEN^®, Neulasta^®, NEUPOGEN^® and ENBREL in supportive cancer care, nephrology and inflammation. Certain of our marketed products face, and our product candidates, if approved, are also expected to face, substantial competition, including from products marketed by large pharmaceutical corporations, which may have greater clinical, research, regulatory, manufacturing, marketing, financial and human resources than we do. Our products’ competitive position among other biological and

pharmaceutical products may be based on, among other things, safety, efficacy, reliability, availability, patient convenience/delivery devices, price, reimbursement and patent position and expirations.

 

Over the next several years, the existing patents on our principal products will begin to expire, and we expect to face increasing competition thereafter, including from biosimilar products. A “biosimilar” product is a follow-on version of another biological product for which marketing approval is sought or has been obtained based on a demonstration that it is “highly similar” to the original reference product. This demonstration will typically consist of comparative analytical, preclinical and clinical data from the biosimilar product to show that it has similar safety and efficacy as the reference product. The 2010 U.S. healthcare reform legislation authorized the FDA to approve biosimilar products under a new, abbreviated pathway. Consequently, we expect to face greater competition, including from manufacturers with biosimilar products approved in Europe that may seek to quickly obtain U.S. approval, subject to our ability to enforce our patents. In the European Union (“EU”), we are already facing increasing competition from biosimilars given an established regulatory pathway for biosimilars in the EU.

 

Further, the introduction of new products or the development of new processes or technologies by competitors or new information about existing products may result in increased competition for our marketed products, even for those protected by patents, or in a reduction of price that we receive from selling our products. In addition, the development of new treatment options or standards of care may reduce the use of our products, particularly in supportive cancer care, or may limit the utility and application of ongoing clinical trials for our product candidates.

 

In addition to the challenges presented by competition, our existing products and product candidates are also subject to increasing regulatory compliance requirements that could be imposed as conditions of approval or after a product has been approved. This is increasingly true of new therapies with novel mechanisms of action. While such therapies may offer important benefits and/or better treatment alternatives, they may also involve relatively new or higher levels of scientific complexity and may therefore generate increased safety concerns. As a condition of approval or due to safety concerns after a product has been approved, we may be required to perform additional clinical trials or studies. A postmarketing requirement (“PMR”) is a trial or study that a sponsor company is required by statute or regulation to conduct. A postmarketing commitment (“PMC”) is a trial or study that a sponsor company agrees to in writing, but is not required by law, to conduct. We currently have PMRs or PMCs for a number of our marketed products. In addition, we may be required to implement risk management plans for our products in the various regions in which they are approved. For example, in 2008 the FDA began requiring REMS for various approved products to ensure that the benefits of the drugs outweigh the risks. A REMS may also be imposed as a condition of approval or after a product has been on the market. A REMS may include a medication guide or a patient package insert, a healthcare provider communication plan or elements to assure safe use that the FDA deems necessary. While the elements of REMS may vary, all REMS require the sponsor company to submit periodic assessment reports to the FDA to demonstrate that the goals of the REMS are being met. The FDA evaluates such assessments and may require additional modifications to the REMS elements. REMS may also be modified as the FDA and companies gain more experience with REMS and how they are implemented, operated and monitored. We currently have REMS for a number of our marketed products. (See discussion on PMRs, PMCs and REMS in Government Regulation.)

 

ESAs

 

Aranesp^® and EPOGEN^® are our registered trademarks for darbepoetin alfa and Epoetin alfa, respectively, both of which are ESAs, proteins that stimulate red blood cell production. Red blood cells transport oxygen to all cells of the body. Without adequate amounts of erythropoietin, the red blood cell count is reduced. A deficient red blood cell count can result in anemia, a condition in which insufficient oxygen is delivered to the body’s organs and tissues. Anemia can be associated with chronic renal failure (“CRF”) in patients either on or not on dialysis. Individuals with CRF suffer from anemia because they do not produce sufficient amounts of erythropoietin, which is normally produced in healthy kidneys. Anemia can also result from chemotherapy treatments for patients with non-myeloid malignancies.

 

ESA products, including ours, have faced and continue to face challenges. For example, based on adverse safety results observed beginning in late 2006 in various ESA studies, performed by us and by others, that explored

the use of ESAs in settings different from those outlined in the FDA approved label, the product labeling of our ESA products in the United States and the EU has been updated several times to reflect those safety concerns. In addition, due in part to certain of these developments, reimbursement of our ESA products in the United States was also revised resulting in changes in the way ESAs are used in clinical practice, including by decreasing the number of treated patients, average dose and duration of ESA therapy. Certain of these developments have had a material adverse impact on sales of our ESA products, in particular Aranesp^® sales in the U.S. supportive cancer care setting, reflecting an overall decline in the segment.

 

Further, we believe that the following recent and pending developments could also have a material adverse impact on future sales of Aranesp^® and/or EPOGEN^®:

 

 

 

In addition to the above, following the FDA’s Oncologic Drugs Advisory Committee (“ODAC”) meeting in May 2004, we proposed a pharmacovigilance program for Aranesp^® comprised of five studies to explore the use of ESAs in settings different from those outlined in the FDA approved label. The studies were subsequently designated by the FDA as PMCs. Of the five studies, one was sponsored by Amgen while the other four were investigator-sponsored. Results of certain of those studies contributed to safety-related product labeling changes for our ESA products and changes in reimbursement, as noted above. Of the five studies, three are complete with final results of the remaining studies expected in 2011. In addition, Johnson and Johnson Pharmaceutical Research & Development (“J&JPRD”), a subsidiary of J&J, and/or its investigators have conducted numerous studies proposed at the 2004 ODAC meeting. All of these studies are closed to enrollment and summary results were submitted to the FDA.

 

Based on our discussions with the FDA in response to the May 2007 ODAC meeting, we and J&JPRD have carefully considered potential new study designs to determine the effects of ESAs on survival and tumor outcomes in anemic patients with metastatic cancer receiving concomitant myelosuppressive chemotherapy. Based on those discussions, we have initiated a randomized, double-blind, placebo-controlled, phase 3 non-inferiority study evaluating overall survival when comparing advanced NSCLC patients on Aranesp^® to patients receiving placebo (“Study’782”) as part of our Aranesp^® pharmacovigilance program. In addition, J&JPRD’s EPO-ANE-3010 study in breast cancer is also ongoing. Both studies are designated by the FDA as PMR clinical trials.

 

Adverse events or results of any of these studies could further affect product safety labeling, healthcare provider prescribing behavior, regulatory or private healthcare organization medical guidelines and/or reimbursement practices related to Aranesp^®.

 

Aranesp^® (darbepoetin alfa)

 

We were granted an exclusive license by Kirin-Amgen, Inc. (“KA”), a joint venture between Kirin Holdings Company, Limited (“Kirin”) and Amgen (see Business Relationships — Kirin Holdings Company, Limited), to manufacture and market Aranesp^® in the United States, all European countries, Canada, Australia, New Zealand, Mexico, all Central and South American countries and certain countries in Central Asia, Africa and the Middle East.

 

We market Aranesp^® primarily in the United States and Europe. Aranesp^® was launched in 2001 in the United States and Europe for the treatment of anemia associated with CRF (both in patients on dialysis and patients not on dialysis) and is also indicated for the treatment of anemia due to concomitant chemotherapy in patients with non-myeloid malignancies.

 

Worldwide Aranesp^® sales for the years ended December 31, 2010, 2009 and 2008 were $2.5 billion, $2.7 billion and $3.14 billion, respectively. For the years ended December 31, 2010, 2009 and 2008, U.S. Aranesp^® sales were $1.1 billion, $1.3 billion and $1.65 billion, respectively, and international Aranesp^® sales were $1.4 billion, $1.4 billion and $1.49 billion, respectively.

Our outstanding material patents for darbepoetin alfa are described in the following table.

 

 

 

Our principal European patent relating to Epoetin alfa expired in December 2004. Although we do not market EPOGEN^® in Europe, upon expiration of this patent, some companies received approval to market products, including biosimilars, that compete with Aranesp^® in Europe, as further discussed below.

 

Any products or technologies that are directly or indirectly successful in addressing anemia associated with chemotherapy and/or renal failure negatively impact Aranesp^® sales. In the United States, Aranesp^® competes with EPOGEN^®, primarily in the U.S. hospital dialysis clinic setting. The following table reflects companies and their currently marketed products that compete with Aranesp^® in the United States and Europe in the supportive cancer care and nephrology segments, unless otherwise indicated. The table and the following discussion of competitor marketed products and products in development may not be exhaustive.

 

 

 

In addition to competition from these marketed products, the following products in development could compete with Aranesp^® in the future:

 

EPOGEN^® (Epoetin alfa)

 

We were granted an exclusive license to manufacture and market EPOGEN^® in the United States under a licensing agreement with KA. We have retained exclusive rights to market EPOGEN^® in the United States for dialysis patients. We granted Ortho Pharmaceutical Corporation, a subsidiary of J&J (which has assigned its rights under the Product License Agreement to Centocor), a license to commercialize recombinant human erythropoietin as a human therapeutic in the United States in all indications other than dialysis. (See Business Relationships — Johnson & Johnson.)

 

We launched EPOGEN^® in the United States in 1989 for the treatment of anemia associated with CRF in patients who are on dialysis. We market EPOGEN^® in the United States for the treatment of anemic adult and pediatric patients with CRF who are on dialysis. EPOGEN^® is indicated for elevating or maintaining the red blood cell level (as determined by hematocrit or Hb measurements) and decreasing the need for blood transfusions in these patients.

 

EPOGEN^® sales in the United States for the years ended December 31, 2010, 2009 and 2008 were $2.5 billion, $2.6 billion and $2.5 billion, respectively.

 

Our outstanding material patents for Epoetin alfa are described in the following table.

 

 

Any products or technologies that are directly or indirectly successful in addressing anemia associated with renal failure negatively impact EPOGEN^® sales. In the United States, as noted above, EPOGEN^® and Aranesp^® compete with each other, primarily in the U.S. hospital dialysis clinic setting. In addition, EPOGEN^® could face additional competition from those products in development noted in the Aranesp^® section above that may be used in dialysis in the United States.

 

Neulasta^® (pegfilgrastim)/NEUPOGEN^® (Filgrastim)

 

We were granted an exclusive license to manufacture and market Neulasta^® and NEUPOGEN^® in the United States, Europe, Canada, Australia and New Zealand under a licensing agreement with KA. (See Business Relationships — Kirin Holdings Company, Limited.)

 

Neulasta^® and NEUPOGEN^® stimulate production of certain white blood cells known as neutrophils. Neutrophils defend against infection. Treatments for various diseases and diseases themselves can result in extremely low numbers of neutrophils, a condition called neutropenia. Myelosuppressive chemotherapy, one treatment option for individuals with certain types of cancers, targets cell types that grow rapidly, such as tumor cells. Normal cells that divide rapidly, such as those in the bone marrow that become neutrophils, are also vulnerable to the cytotoxic effects of myelosuppressive chemotherapy, resulting in neutropenia with an increased risk of severe infection. NEUPOGEN^® is our registered trademark for Filgrastim, our recombinant-methionyl human G-CSF. Neulasta^® is our registered trademark for pegfilgrastim, a pegylated protein based on the Filgrastim molecule. A polyethylene glycol molecule (“PEG”) is added to enlarge the Filgrastim molecule, thereby extending its half-life and causing it to be removed more slowly from the body. Because pegfilgrastim is eliminated through binding to its receptor on neutrophils and their precursors, pegfilgrastim remains in the circulation until neutrophil recovery has occurred. This neutrophil-mediated clearance allows for administration as a single dose per chemotherapy cycle, compared with NEUPOGEN^®, which requires more frequent dosing. Neulasta^® and NEUPOGEN^® are prescribed more frequently in the curative setting, in which myelosuppressive chemotherapy is administered with the intent to cure cancer, rather than in the palliative setting, in which myelosuppressive chemotherapy is administered to treat other complications of cancer by managing tumor growth.

 

We market Neulasta^® and NEUPOGEN^® primarily in the United States and Europe. Filgrastim is also marketed under the brand name GRANULOKINE^® in Italy. Neulasta^® was launched in the United States and

Europe in 2002 and is indicated to decrease the incidence of infection associated with chemotherapy-induced febrile neutropenia in cancer patients with non-myeloid malignancies. Administration of Neulasta^® in all cycles of chemotherapy is approved for patients receiving myelosuppressive chemotherapy associated with a clinically significant risk of febrile neutropenia. NEUPOGEN^® was launched in the United States and Europe in 1991. NEUPOGEN^® is indicated for reducing the incidence of infection as manifested by febrile neutropenia for patients with non-myeloid malignancies undergoing myelosuppressive chemotherapy; reducing the duration of neutropenia and neutropenia-related consequences for patients with non-myeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation; reducing the incidence and duration of neutropenia-related consequences in symptomatic patients with congenital neutropenia, cyclic neutropenia or idiopathic neutropenia (collectively, severe chronic neutropenia); mobilizing peripheral blood progenitor cells (“PBPC”) in cancer patients who have undergone myeloablative chemotherapy for stem cell transplantation; and reducing the recovery time of neutrophils and the duration of fever following induction or consolidation chemotherapy treatment in adult patients with acute myeloid leukemia (“AML”).

 

Worldwide Neulasta^®/NEUPOGEN^® sales for the years ended December 31, 2010, 2009 and 2008 were $4.8 billion, $4.6 billion and $4.7 billion, respectively. U.S. Neulasta^®/NEUPOGEN^® sales for the years ended December 31, 2010, 2009 and 2008 were $3.6 billion, $3.4 billion and $3.4 billion, respectively. International Neulasta^®/NEUPOGEN^® sales for the years ended December 31, 2010, 2009 and 2008 were $1.2 billion, $1.2 billion and $1.3 billion, respectively.

 

Our outstanding material patents for pegfilgrastim are described in the following table.

 

 

 

Our outstanding material patents for Filgrastim are described in the following table.

 

 

Our principal European patent relating to G-CSF expired in August 2006. Upon expiration of that patent, some companies received approval to market products, including biosimilars, that compete with NEUPOGEN^® and Neulasta^® in Europe, as further discussed below.

 

Neulasta^® and/or NEUPOGEN^® also face competition in some circumstances from companies marketing or developing treatments for neutropenia associated with chemotherapy, for bone marrow and PBPC transplant patients, severe chronic neutropenia and AML. Further, NEUPOGEN^® competes with Neulasta^® in the United States and Europe, and NEUPOGEN^® sales have been adversely impacted by conversion to Neulasta^®. However, we believe the conversion in the United States is substantially complete and that a significant amount of the conversion in Europe has already occurred.

The following table reflects companies and their currently marketed products that compete with Neulasta^® and/or NEUPOGEN^® in the United States and Europe in the supportive cancer care setting. The table and the following discussion of competitor marketed products and products in development may not be exhaustive.

 

 

 

In February 2010, Teva Pharmaceutical announced that the FDA had accepted for review its BLA seeking U.S. approval to market XM02 to boost white blood cells under the brand name Neutroval^tm. On September 30, 2010, the FDA issued a Complete Response Letter requesting additional information from Teva Pharmaceutical to complete the review of its applications for approval of Neutroval^tm. Neutroval^tm is currently sold under the brand name Tevagrastim^® in several European countries. If approved in the United States, this drug would compete with NEUPOGEN^® and Neulasta^®. On November 30, 2009, Teva Pharmaceutical filed a declaratory judgment action against us alleging that certain of our NEUPOGEN^® patents are invalid and not infringed by Neutroval^tm, and on January 15, 2010, we filed an answer and counterclaims seeking a declaratory judgment that our patents are valid and infringed. Pretrial proceedings are ongoing and no trial date has yet been set. (See Note 19, Contingencies and commitments to the Consolidated Financial Statements.)

 

Other companies with short-acting filgrastims in phase 3 clinical development for Europe are:

 

 

In addition, Teva Pharmaceutical has two long-acting filgrastims in phase 3 clinical development for Europe (XM-22 and Neugranin).

 

Enbrel^® (etanercept)

 

ENBREL is our registered trademark for etanercept, our TNF receptor fusion protein that inhibits the binding of TNF to its receptors, which can result in a significant reduction in inflammatory activity. TNF is one of the chemical messengers that help regulate the inflammatory process. When the body produces too much TNF, it overwhelms the immune system’s ability to control inflammation of the joints or of psoriasis-affected skin areas. ENBREL is similar to a protein that the body produces naturally, and like this protein, it binds certain TNF molecules before they can trigger inflammation.

 

We acquired the rights to ENBREL in July 2002 with our acquisition of Immunex Corporation (“Immunex”). ENBREL was launched in November 1998 for the treatment of rheumatoid arthritis (“RA”). In addition, ENBREL is now indicated for the treatment of adult patients with the following conditions: moderately to severely active RA; chronic moderate to severe plaque psoriasis patients who are candidates for systemic therapy or phototherapy; active psoriatic arthritis; and active ankylosing spondylitis. ENBREL is also approved for the treatment of moderately to severely active polyarticular juvenile idopathic arthritis in patients ages 2 and older.

We market ENBREL under a collaboration agreement with Pfizer Inc. (“Pfizer”) in the United States and Canada, which expires in the fourth quarter of 2013. (See Business Relationships — Pfizer Inc.) The rights to market and sell ENBREL outside the United States and Canada are reserved to Pfizer.

 

ENBREL sales for the years ended December 31, 2010, 2009 and 2008 were $3.5 billion, $3.5 billion and $3.6 billion, respectively.

 

Our outstanding material patents for etanercept are described in the following table.

 

 

 

Any products or technologies that are directly or indirectly successful in treating rheumatologic conditions, which includes moderate to severe RA; moderate to severe polyarticular juvenile idiopathic arthritis; ankylosing spondylitis and psoriatic arthritis; and dermatologic conditions, which includes moderate to severe plaque psoriasis, could negatively impact ENBREL sales. Certain of the treatments for these indications include generic methotrexate and other products.

 

The following table reflects companies and their currently marketed products that primarily compete with ENBREL in the United States and Canada in the inflammatory disease setting. The table and the following discussion of competitor marketed products and products in development may not be exhaustive.

 

 

 

In addition to competition from the above-noted marketed products, various competitors are developing products that may compete with ENBREL in the future, as discussed below:

 

In addition, several pharmaceutical companies announced their intent to produce biosimilars that may compete with ENBREL.

 

Other

 

Our other marketed products are Sensipar^®/Mimpara^® (cinacalcet), Vectibix^® (panitumumab), Nplate^® (romiplostim), Prolia^® (denosumab) and XGEVA^tm (denosumab).

 

Sensipar^®/Mimpara^® (cinacalcet)

 

Sensipar^® is our registered trademark in the United States and Mimpara^® is our registered trademark in Europe for cinacalcet, our small molecule medicine used in treating CKD patients on dialysis who produce too much parathyroid hormone (“PTH”), a condition known as secondary hyperparathyroidism. In 2004, Sensipar^®/Mimpara^® was approved in the United States and Europe for the treatment of secondary hyperparathyroidism in CKD patients on dialysis and for the treatment of hypercalcemia in patients with parathyroid carcinoma. In 2008, Mimpara^® was approved in Europe for the reduction of hypercalcemia in patients with primary hyperparathyroidism where a parathyroidectomy is not clinically appropriate or is contraindicated. We market Sensipar^® primarily in the United States and Mimpara^® primarily in Europe.

 

In addition, as previously discussed, CMS released the Final Rule on Bundling in Dialysis, effective January 1, 2011, resulting in a bundled payment system for dialysis facilities. Oral drugs without intravenous equivalents, such as Sensipar^® and phosphate binders, will continue to be reimbursed separately under the Medicare Part D benefit until 2014 when they will be reimbursed under the bundled payment system. Inclusion in the bundled payment system may reduce utilization of these oral drugs and have a material adverse impact on Sensipar^® sales. (See Reimbursement.)

 

Worldwide Sensipar^®/Mimpara^® sales for the years ended December 31, 2010, 2009 and 2008 were $714 million, $651 million and $597 million, respectively.

 

Our outstanding material patents for cinacalcet are described in the following table.

 

 

 

Any products or technologies that are directly or indirectly successful in treating secondary hyperparathyroidism in patients with CKD on dialysis and/or hypercalcemia in patients with parathyroid carcinoma negatively impact Sensipar^®/Mimpara^® sales.

The following table reflects companies and their currently marketed products that compete with Sensipar^® in the United States and with Mimpara^® in Europe in the nephrology segment for patients with CKD on dialysis. The table and discussion below of competitor marketed products and products in development may not be exhaustive.

 

 

On July 25, 2008, we filed a lawsuit against Teva Pharmaceuticals USA, Inc. and Teva Pharmaceutical (together defined as “Teva”) and Barr Pharmaceuticals Inc. (“Barr”) for infringement of four Sensipar^® patents. The lawsuit was based on Abbreviated New Drug Applications filed by Teva and Barr that sought approval to market generic versions of Sensipar^®. Following trial, on January 7, 2011, the U.S. District Court for the District of Delaware granted an injunction prohibiting Teva and Barr from commercializing generic versions of Sensipar^® in the United States until expiration of three of those patents. (See Note 19, Contingencies and commitments to the Consolidated Financial Statements.) These generic versions could compete with Sensipar^® in the future.

 

Vectibix^® (panitumumab)

 

Vectibix^® is our registered trademark for panitumumab, our monoclonal antibody for the treatment of patients with EGFr expressing mCRC after disease progression on, or following fluoropyrimidine-, oxaliplatin- and irinotecan- containing chemotherapy regimens. EGFr is a protein that plays an important role in cancer cell signaling and is over-expressed in many human cancers. Vectibix^® binds with high affinity to EGFrs and interferes with signals that might otherwise stimulate growth and survival of the cancer cell. We acquired full ownership of Vectibix^® with our acquisition of Abgenix, Inc. (“Abgenix”) in April 2006. In September 2006, Vectibix^® received FDA accelerated approval in the United States, based upon clinical trial data from a study demonstrating a statistically significant improvement in progression-free survival and with the condition that Amgen conduct a confirmatory trial to verify the clinical benefit of panitumumab through demonstration of an improvement in overall survival. In the EU, the conditional approval of Vectibix^® as monotherapy, for the treatment of patients with EGFr expressing metastatic colorectal carcinoma with non-mutated (wild-type) KRAS genes after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens, was received in December 2007 and is reviewed annually by the Committee for Medicinal Products for Human Use (“CHMP”). In December 2008, 2009 and 2010, the EU conditional marketing authorization was renewed with an additional specific obligation to conduct a clinical trial in the existing approved indication. In 2010, we began enrollment for this additional clinical trial which compares the effect of Vectibix^® versus Erbitux^® (cetuximab) on overall survival for chemorefractory mCRC patients with wild-type KRAS genes. KRAS is a protein found in all human cells. Some colorectal cancers have mutations in the KRAS gene. Vectibix^® has been shown to be ineffective in people whose tumors had KRAS mutations in codon 12 or 13.

 

In 2009, we announced results from the ’203 and ’181 pivotal phase 3 trials evaluating Vectibix^® in combination with chemotherapy (FOLFOX or FOLFIRI) as a first- and second-line treatment for mCRC, respectively. Both studies demonstrated that Vectibix^® administered with chemotherapy significantly improved progression-free survival in patients with wild-type KRAS mCRC. Additionally, both studies showed numeric improvements in median overall survival in the same patient population. The numeric improvements in median overall survival failed to achieve statistical significance. It was previously agreed with the FDA that the ’181 study would serve as the confirmatory trial for establishing full approval for the mCRC indication.

On April 16, 2010, our application for marketing authorization for the use of Vectibix^® in first- and second-line treatment of mCRC in patients whose tumors contain wild-type KRAS genes was submitted to the EMA. In the United States, we filed supplemental BLA submissions for first- and second-line mCRC with the FDA on October 29, 2010 and November 4, 2010. Both the EMA and FDA filings included the data from the ’203 and ’181 clinical trials. In addition, the FDA has indicated that in order for Vectibix^® to be approved for these indications, there must be a commercially available, FDA-approved KRAS test kit. We continue to work with our partner QIAGEN N.V. to support their submission of a Premarket Application for approval of this test kit.

 

On February 8, 2011, we and four other sponsor companies met with the FDA and the ODAC to discuss the status of our respective PMCs for product indications that had been granted accelerated approval by the FDA prior to 2009, including Vectibix^®. At that meeting, we updated the Committee on the completion and submission of the main PMC for Vectibix^®, the confirmatory ’181 study, and participated in an open discussion with the ODAC on the accelerated approval process.

 

Worldwide Vectibix^® sales for the years ended December 31, 2010, 2009 and 2008 were $288 million, $233 million and $153 million, respectively.

 

Our outstanding material patents for panitumumab are described in the following table.

 

 

 

Any products or technologies that are directly or indirectly successful in treating mCRC after disease progression on, or following fluoropyrimidine-, oxaliplatin- and irinotecan- containing chemotherapy regimens negatively impact Vectibix^® sales. The following table reflects companies and their currently marketed products that compete with Vectibix^® in the United States and Europe. The table may not be exhaustive.

 

 

Nplate^® (romiplostim)

 

In August 2008, the FDA approved Nplate^®, our platelet producer for the treatment of thrombocytopenia in splenectomized (spleen removed) and non-splenectomized adults with chronic immune thrombocytopenic purpura (“ITP”). Nplate^® works by raising and sustaining platelet counts. We were granted an exclusive license by KA to manufacture and market Nplate^® in the United States, all European countries, Canada, Australia, New Zealand, Mexico, all Central and South American countries and certain countries in Central Asia, Africa and the Middle East. In February 2009, we announced that the EC had granted marketing authorization for Nplate^® for the treatment of splenectomized adult chronic ITP patients who are refractory to other treatments (eg, corticosteroids, immunoglobulins). In the EU, Nplate^® may also be considered as second-line treatment for adult non-splenectomized ITP patients where surgery is contraindicated.

 

We currently have an approved REMS for Nplate^®, which includes a medication guide, a healthcare provider communication plan and certain elements to assure safe use (including restricted distribution, registry, healthcare provider, institution and patient enrollment). As required, we have submitted REMS assessment reports to the FDA and are working with the FDA to determine any additional modifications to the REMS that will be needed.

Worldwide Nplate^® sales for the years ended December 31, 2010, 2009 and 2008 were $229 million, $110 million and $17 million, respectively.

 

Our outstanding material patents for romiplostim are described in the following table.

 

 

 

Any products or technologies that are directly or indirectly successful in treating thrombocytopenia in splenectomized and non-splenectomized adults with chronic ITP negatively impact Nplate^® sales. The following table reflects currently marketed products that compete with Nplate^® in the United States and Europe. The table may not be exhaustive.

 

 

Prolia^®/XGEVA^tm (denosumab)

 

In 2010, we launched Prolia^® and XGEVA^tm, both of which contain the same active ingredient but which are approved for different indications, patient populations, doses and frequencies of administration. We have a collaboration agreement with Glaxo Group Limited (“Glaxo”), a wholly owned subsidiary of GSK, for the commercialization of denosumab in certain countries. (See Business Relationships — Glaxo Group Limited.)

 

Prolia^®

 

On June 1, 2010, the FDA approved Prolia^® for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. We estimate that the majority of potential U.S. Prolia^® patients are covered under Medicare and the remaining patients under commercial plans. (See Reimbursement.) Future U.S. product sales for Prolia^® will depend on the willingness of primary care physicians to prescribe, the availability of reimbursement for and patient acceptance of the product.

 

On May 25, 2010, the EC granted marketing authorization for Prolia^® for the treatment of osteoporosis in postmenopausal women at increased risk of fractures and for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures. The timing of reimbursement authority approval of pricing in individual EU countries will vary by country, which could follow the EC approval by many months. For example, on July 1, 2010, Prolia^® received reimbursement authority in Germany. On October 27, 2010, the National Institute for Health and Clinical Excellence (“NICE”) in the United Kingdom (“UK”) recommended Prolia^® for National Health Service (“NHS”) reimbursement as a treatment option for certain postmenopausal women who are at increased risk of primary and secondary osteoporotic fractures if other treatments available on the publicly-funded NHS are unsuitable.

 

Worldwide Prolia^® sales for the year ended December 31, 2010 were $33 million.

The following table and discussion reflect other companies and their currently marketed products that compete with Prolia^®. The table and the discussion of competitor marketed products and product in development may not be exhaustive.

 

 

 

Over the next several years, we expect certain additional marketed products noted above to lose patent protection, at which time we expect that generic versions of these products would become commercially available and compete with Prolia^®.

 

In addition to competition from the above-noted marketed products, Merck has a new cathepsin-K inhibitor, odanacatib, in phase 3 clinical trials that could compete with Prolia^® in the future.

 

XGEVA^tm

 

On November 18, 2010, the FDA approved XGEVA^tm for the prevention of SREs in patients with bone metastases from solid tumors. XGEVA^tm is not indicated for the prevention of SREs in patients with multiple myeloma.

 

We also submitted a marketing authorization application to the EMA on June 4, 2010 for denosumab for the reduction of SREs in cancer patients.

 

On December 12, 2010, we announced top-line results from a phase 3 trial evaluating XGEVA^tm versus placebo in men with castrate-resistant prostate cancer. The trial, known as the ’147 study, demonstrated that XGEVA^tm significantly improved median bone metastasis-free survival by 4.2 months compared to placebo (primary endpoint) and significantly improved time to first occurrence of bone metastases (secondary endpoint). Overall survival was similar between the XGEVA^tm and placebo groups (secondary endpoint). This study will form the basis of planned marketing applications, which we expect to submit to regulatory authorities beginning in the first half of 2011, for the prevention of bone metastasis in prostate cancer. (See Research and Development and Selected Product Candidates.)

 

U.S. XGEVA^tm sales for the year ended December 31, 2010 were $8 million.

The following table reflects currently marketed products that compete with XGEVA^tm. The table may not be exhaustive.

 

 

 

Our outstanding material patents for denosumab are described in the following table.

 

 

 

Marketing and Distribution

 

We maintain sales and marketing forces primarily in the United States, Europe and Canada to support our currently marketed products. We have also entered into agreements with third parties to assist in the commercialization and marketing of certain of our products in specified geographic areas. (See Business Relationships.) Together with our partners, we market our products to healthcare providers, including physicians or their clinics, dialysis centers, hospitals and pharmacies. We also market certain products directly to consumers through direct-to-consumer print and television advertising, and also through the Internet. In addition, for certain of our products, we promote programs to increase public awareness of the health risks associated with the diseases these products treat, as well as providing support to various patient education and support programs in the related therapeutic areas. (See Government Regulation — FDA Regulation of Product Marketing and Promotion for a discussion of the government regulation over product marketing and promotion.)

 

In the United States, we sell primarily to wholesale distributors of pharmaceutical products. We utilize those wholesale distributors as the principal means of distributing our products to healthcare providers. In Europe, we sell principally to healthcare providers and/or wholesalers depending on the distribution practice in each country. We monitor the financial condition of our larger customers and limit our credit exposure by setting credit limits, requiring letters of credit and obtaining credit insurance, as we deem appropriate.

 

We had product sales to three large wholesaler customers each accounting for more than 10% of total revenues for the years ended December 31, 2010, 2009 and 2008. On a combined basis, these distributors accounted for 71% and 88% for 2010 of worldwide gross revenues and U.S. gross product sales, respectively, as noted in the table

below. Certain information with respect to these distributors for the years ended December 31, 2010, 2009 and 2008 is as follows (dollar amounts in millions):

 

 

Reimbursement

 

Sales of all of our principal products are dependent in large part on the availability and extent of coverage and reimbursement from third-party payers, including government and private insurance plans. Most patients receiving our products are covered by government healthcare programs or private insurers. Governments may regulate coverage, reimbursement and/or pricing of our products to control costs or to affect levels of use of our products, and private insurers may adopt or be influenced by government coverage and reimbursement methodologies. Worldwide use of our products may be affected by cost containment pressures and cost shifting from governments and private insurers to healthcare providers or patients in response to ongoing initiatives to reduce or reallocate healthcare expenditures. An increasing worldwide focus on patient access controls and cost containment by public and private insurers has resulted, and may continue to result, in reduced reimbursement rates for our products. In addition, recent healthcare reform efforts enacted in the United States have made substantial long-term changes to the reimbursement of our products, and those changes have had, and are expected to continue to have, a significant impact on our business.

 

U.S. Reimbursement System

 

Our principal products are sold primarily in the United States and healthcare providers, including doctors, hospitals and other healthcare professionals and providers, are reimbursed for their services by the government through Medicare, Medicaid and other government healthcare programs as well as through private payers. Government healthcare programs are funded primarily through the payment of taxes by individuals and businesses. The public and private components of this multi-payer system are described below.

 

Medicare and Other Forms of Public Health Insurance

 

Medicare is a federal program administered by the federal government that covers individuals age 65 and over as well as those with certain disabilities and end stage renal disease (“ESRD”), regardless of their age. The primary Medicare programs that affect reimbursement for our products are Medicare Part B, which covers physician services and outpatient care, and Medicare Part D, which provides a voluntary outpatient prescription drug benefit. CMS is the federal agency responsible for administering Medicare (as well as Medicaid, described below) and, among its responsibilities, has authority to issue Medicare NCDs which are national policy statements granting, limiting or excluding Medicare coverage for specific medical items or services. In addition, CMS has authority to issue manual policy issuances and updates as well as reimbursement codes for drugs and other items, which determine how products and services are reimbursed. Medicare Administrative Contractors have authority to issue local coverage determinations. CMS sometimes uses advisory committees of external experts in order to obtain

independent expert advice on scientific, technical and policy matters. For example, the MEDCAC was established to provide independent guidance and expert advice to CMS on specific clinical topics. The MEDCAC reviews and evaluates medical literature, technology assessments, and examines data and information on the effectiveness and appropriateness of medical items and services that are covered under Medicare, or that may be eligible for coverage under Medicare.

 

Medicare Part B Coverage of Drugs and ESRD. Medicare Part B provides limited coverage of outpatient drugs and biologicals that are furnished “incident to” a physician’s services. Generally, “incident to” drugs and biologicals are covered if they satisfy certain criteria, including that they are of the type that are not usually self-administered by the patient and are reasonable and necessary for a medically accepted diagnosis or treatment. Medicare Part B also covers certain drugs pursuant to a specific statutory directive, such as blood-clotting factors and certain immunosuppressive drugs, erythropoietin and certain oral cancer drugs, if they fall under a specific statutory benefit category and they are “safe and effective” as established by FDA approval. Many of our principal products are currently covered under Medicare Part B (as well as other government healthcare programs). In addition, most patients with ESRD, regardless of age, are eligible for coverage of dialysis treatment through the ESRD Program under Medicare Part B, the primary payer for dialysis treatment. Because Medicare Part B is the primary payer for dialysis treatment, reimbursement for products, such as EPOGEN^®, that are typically administered in dialysis centers and other settings is particularly sensitive to changes in Medicare coverage and reimbursement policy. Beginning January 1, 2011, dialysis treatment is reimbursed by Medicare under a bundled payment system described in more detail below. (See Dialysis Reimbursement.)

 

Medicare Part D. Medicare Part D provides a voluntary prescription drug benefit for Medicare eligible beneficiaries. The coverage is available through various private plans that provide insurance coverage for prescription drugs for a monthly premium. The list of prescription drugs covered by Medicare Part D plans varies by plan, but drug lists maintained by individual plans must cover certain classes of drugs and biologicals; specifically the statute stipulates that Medicare Part D plans have at least two drugs in each unique therapeutic category or class, subject to certain exceptions. Medicare patients who obtain ENBREL and Sensipar^® under retail coverage, where they are primarily provided, are typically covered by Medicare Part D.

 

Medicaid. Medicaid is a joint federal and state program administered by individual states for low-income and disabled eligible beneficiaries. CMS also has responsibility for federal administration of the Medicaid program. Under federal law, states must cover low-income adults and children, pregnant women, disabled individuals and seniors, and states have the option of expanding eligibility beyond those groups of beneficiaries. Medicaid is financed jointly by the states and federal government through taxes. Medicaid offers a broad set of benefits, including prescription drugs. Medicaid includes the Drug Rebate Program which requires manufacturers to provide rebates to the states for products covered and reimbursed by state Medicaid programs.

 

See Item 1A. Risk Factors — Our sales depend on coverage and reimbursement from third-party payers.

 

Private Health Insurance

 

Employer-sponsored insurance. Employer-sponsored insurance currently represents the main pathway by which Americans receive private health insurance. Many employers provide health insurance as part of employees’ benefit packages. Insurance plans are administered by private companies, both for-profit and not-for-profit, and some companies are “self-insured” (i.e., they pay for all healthcare costs incurred by employees directly through a plan administered by a third party). Generally, employer-sponsored insurance premiums are paid primarily by employers and secondarily by employees.

 

Individual market. The individual market covers part of the population that is self-employed or retired. In addition, it covers some people who are unable to obtain insurance through their employers. The plans are administered by private insurance companies. Individuals pay out-of-pocket insurance premiums for coverage, and the benefits vary widely according to plan specifications.

Reimbursement of Our Principal Products

 

Aranesp^®, Neulasta^® and NEUPOGEN^®. Medicare and Medicaid payment policies for drugs and biologicals are subject to various laws and regulations. The Medicare program covers our principal products Aranesp^®, Neulasta^® and NEUPOGEN^® (as well as certain of our other products including Vectibix^®, Nplate^®, Prolia^® and XGEVA^tm) under Part B, when administered in the physician clinic setting and the hospital outpatient and dialysis settings. Healthcare providers are reimbursed for these products under a “buy and bill” process where providers purchase the product in advance of treatment and then submit a reimbursement claim to Medicare following administration of the product. Medicare reimburses providers using a payment methodology based on a fixed percentage of each product’s average sales price (“ASP”). ASP is calculated by the manufacturer based on a statutorily defined formula and submitted to CMS. A product’s ASP is calculated and reported to CMS on a quarterly basis and therefore may change each quarter. The ASP in effect for a given quarter (the “Current Period”) is based upon certain historical sales and sales incentive data covering a statutorily defined period of time preceding the Current Period. CMS publishes the ASPs for products in advance of the quarter in which they go into effect so healthcare providers will know the applicable reimbursement rates. In the calculation of ASP, CMS currently allows manufacturers to make reasonable assumptions consistent with the general requirements and the intent of the Medicare statute and regulations and their customary business practices and in the future CMS may provide more specific guidance. Any changes to the ASP calculations directly affect the Medicare reimbursement for our products administered in the physician clinic setting, hospital outpatient setting and, to a lesser extent, the dialysis facility setting. (See EPOGEN^® and Dialysis Reimbursement.) Our ASP calculations are reviewed quarterly for completeness and based on such review, we have on occasion restated our reported ASPs to reflect calculation changes both prospectively and retroactively. (See Items 1A. Risk Factors — Our sales depend on coverage and reimbursement from third-party payers.)

 

Since 2005, in the physician office setting under Medicare Part B, Aranesp^®, Neulasta^® and NEUPOGEN^® have been reimbursed at 106% of their ASP (sometimes referred to as “ASP+6%”), and in 2011 will continue to be reimbursed at this rate pursuant to the 2011 Medicare Physician Fee Schedule Final Rule. In the hospital outpatient setting, from 2006 to 2010 Medicare reimbursement rates fell incrementally from ASP+6% to ASP+4%, but rose in 2011 to ASP+5% pursuant to the 2011 Hospital Outpatient Prospective Payment Final Rule. CMS has the regulatory authority to further adjust formulas in future years. The extent to which commercial payers adopt the use of ASP as a payment methodology is often based on the contractual relationship between the provider and the insurer.

 

Dialysis Reimbursement.  Currently, dialysis providers in the United States are reimbursed for EPOGEN^® primarily by Medicare through the ESRD Program, which is established by federal law and implemented by CMS. The ESRD Program reimburses Medicare providers for 80% of allowed dialysis costs; the remainder is paid by other sources, including patients, state Medicaid programs, private insurance, and to a lesser extent, state kidney patient programs. Until January 1, 2011, Medicare reimbursed for separately billable dialysis drugs (including EPOGEN^® and Aranesp^®) administered in both freestanding and hospital-based dialysis centers, at ASP+6%, using the same payment amount methodology used in the physician clinic setting under Part B. On January 1, 2011, CMS’s bundled payment system went into effect for dialysis facilities which provides a single payment for all dialysis services including drugs, supplies and non-routine laboratory tests that were previously reimbursed separately. Key provisions under the new system include:

 

Dialysis providers were given the choice of opting into the new bundled payment system 100% on January 1, 2011, or phasing in over a four-year period. Substantially, all dialysis providers in the United States have opted into the bundled payment system in its entirety.

 

To encourage dialysis facilities to continue to provide quality dialysis treatment under the new bundled payment system, on December 29, 2010, CMS issued the Final Rule to implement the ESRD Quality Improvement Program (“QIP”). Under the QIP, beginning in 2012, ESRD facilities will be subject to a payment penalty of up to 2% of amounts reimbursed for failure to meet or exceed CMS’ quality performance standards, including performance standards related to anemia management and dialysis adequacy. Under the QIP, the penalty will be based on a composite score of measures as follows:

 

 

Notwithstanding the implementation of the QIP in 2012, we expect the bundled payment system to decrease dose utilization of EPOGEN^® and that this decrease will have a material adverse impact on EPOGEN^® sales. Further, if CMS issues an NCD for the use of ESAs in patients who have kidney disease (see Other ESA Reimbursement Developments below), CMS could further adjust the bundled payment system and/or the QIP.

 

Other ESA Reimbursement Developments. Since April 1, 2006, Medicare reimbursement for ESAs administered to dialysis patients has been subject to a Erythropoietin Monitoring Policy (“EMP”), the Medicare payment review mechanism used by CMS to monitor EPOGEN^® and Aranesp^® utilization and appropriate hematocrit outcomes of dialysis patients. The EMP was revised, effective January 1, 2008, requiring a 50% reduction in Medicare reimbursement if a patient’s Hb is above 13 g/dL for three or more consecutive months. In addition, the revised EMP reduces the monthly dosing limits to 400,000 international units (“IUs”) of EPOGEN^®, from 500,000 IUs, and to 1,200 micrograms (“mcgs”) of Aranesp^®, from 1,500 mcgs.

 

On March 14, 2007, CMS announced a review of all Medicare policies related to the administration of ESAs in non-renal disease applications as part of an NCA, which is generally CMS’ first step toward developing an NCD. As a result of that review, CMS initiated an NCD for non-renal ESAs. After various CMS proposals and a public comment period, CMS issued a final NCD on July 30, 2007. The 2007 NCD determined that ESA treatment was not reasonable and necessary for certain clinical conditions and established Medicare coverage parameters for FDA-approved ESA use in oncology. We believe the restrictions in the 2007 NCD changed the way ESAs are used in clinical practice, for example, by decreasing the number of treated patients, the average ESA dose and the duration of ESA therapy. We believe this restriction on coverage of ESAs in the 2007 NCD has had a material adverse effect on the coverage, reimbursement and sales of Aranesp^®, and our business and results of operations. In addition, many private payers have implemented portions of the 2007 NCD and we believe many healthcare providers have reduced ESA utilization for all of their patients regardless of insurance coverage.

 

On March 24, 2010, CMS held a MEDCAC meeting to examine the currently available evidence on the use of ESAs to manage anemia in patients who have CKD. Although there was no clear outcome from the MEDCAC meeting, on June 16, 2010, CMS opened a new NCA to examine the use of ESAs to manage anemia in patients with CKD and dialysis-related anemia, which is generally CMS’ first step toward developing an NCD. CMS has stated that the NCA process for ESAs will conclude on or before June 16, 2011, but CMS could propose a new NCD at any time prior to that deadline. Additionally, on January 19, 2011, CMS held another MEDCAC meeting, this time to review the available evidence on the impact of ESA use on renal transplant graft survival.

 

ENBREL Reimbursement. The majority of prescription claims for ENBREL are paid through private insurance companies. Under Medicare, ENBREL is reimbursed through the Part D program, although less than 10% of all ENBREL U.S. prescriptions are reimbursed by Medicare.

Prolia^® Reimbursement

 

We estimate that the majority of potential U.S. Prolia^® patients are covered under Medicare and the remaining under commercial plans. Beginning in 2010, Prolia^® has been reimbursed under Medicare Part B through the buy and bill process. (See Reimbursement of Our Principal Products — Aranesp^®, Neulasta^® and NEUPOGEN^®.) The buy and bill reimbursement process for Prolia^® has required, and is expected to continue to require, time to become established, particularly among primary care physicians who may have limited experience using this reimbursement process. We expect that U.S. Medicare Part D plans will begin to cover Prolia^® in 2011 and that commercial coverage will continue to expand as more commercial plans make their decisions about Prolia^® coverage and reimbursement.

 

Medicaid Reimbursement

 

Since 1991, we have participated in the Medicaid drug rebate program established in Section 1927 of the Social Security Act by the Omnibus Budget Reconciliation Act of 1990 and subsequent amendments of that law. Under the Medicaid drug rebate program, we pay a rebate to the states for each unit of our product reimbursed by state Medicaid programs. As more fully described below, the new healthcare reform law enacted in the United States in March 2010 made certain changes in how those rebates are calculated and to whom they must be extended. (See U.S. Healthcare Reform.) The amount of the rebate for each of our products is currently set by law as a minimum of 23.1% of the Average Manufacturer Price (“AMP”) of that product, or if it is greater, the difference between AMP and the best price available from us to any non-government customer. The rebate amount is determined for each quarter based on our reports to CMS of the quarter’s AMP and best price for each of our products. The rebate amount also includes an inflation adjustment if AMP increases faster than inflation. As described below, the statutory definition of AMP changed in 2010 as a result of the new U.S. healthcare reform law, and we expect CMS to shortly issue a proposed rule further defining the new AMP definition. Until that rule is issued, we will be required to make reasonable assumptions when calculating AMP. Once CMS proposed rule is issued, and clarification is provided on the calculation of AMP, we will have to determine whether our reasonable assumptions need to be amended to comply with the regulation’s definition of AMP, and whether we need to restate our prior AMPs. The terms of our participation in the Medicaid drug rebate program impose an obligation to correct the prices reported in previous quarters, as may be necessary. Any such corrections could result in an overage or underage in our rebate liability for past quarters, depending on the direction of the correction. In addition to retroactive rebates, if we were found to have knowingly submitted false information to the government, in addition to other penalties available to the government, the statute provides for civil monetary penalties in the amount of $100,000 per item of false information.

 

Related to our participation in the Medicaid drug rebate program is a requirement that we extend comparable discounts under the Public Health Service (“PHS”) drug pricing program to a variety of community health clinics and other entities that receive health services grants from the PHS, as well as hospitals that serve a disproportionate share of Medicare and Medicaid beneficiaries. As more fully described below, the list of entities to which we are required to extend these discounts also expanded as a result of the new healthcare reform law.

 

We also make our products available to authorized users of the Federal Supply Schedule (“FSS”) of the General Services Administration. Since 1993, as a result of the Veterans Health Care Act of 1992 (the “VHC Act”), federal law has required that we offer deeply discounted FSS contract pricing for purchases by the Department of Veterans Affairs, the Department of Defense, the Coast Guard and the PHS (including the Indian Health Service) in order for federal funding to be available for reimbursement of our products under the Medicaid program or purchase of our products by those four federal agencies and certain federal grantees. FSS pricing to those four federal agencies must be equal to or less than the Federal Ceiling Price (“FCP”), which is 24% below the Non-Federal Average Manufacturer Price (“Non-FAMP”) for the prior fiscal year. The accuracy of our reported Non-FAMPs, FCPs and our FSS contract prices may be audited by the government under applicable federal procurement laws and the terms of our FSS contract. Among the remedies available to the government for inaccuracies in calculation of Non-FAMPs and FCPs is recoupment of any overcharges to the four specified Federal agencies based on those inaccuracies. Also, if we were found to have knowingly reported a false Non-FAMP, in addition to other penalties available to the government, the VHC Act provides for civil monetary penalties of $100,000 per item that is

incorrect. Finally, we are required to disclose in our FSS contract proposal all commercial pricing that is equal to or less than our proposed FSS pricing, and subsequent to award of an FSS contract, we are required to monitor certain commercial price reductions and extend commensurate price reductions to the government, under the terms of the FSS contract Price Reductions Clause. Among the remedies available to the government for any failure to properly disclose commercial pricing and/or to extend FSS contract price reductions is recoupment of any FSS overcharges that may result from such omissions.

 

U.S. Healthcare Reform. In March 2010, the Patient Protection and Affordable Care Act (the “PPACA”) and the companion Healthcare and Education Reconciliation Act, which made certain changes and adjustments to the PPACA, primarily with respect to the PPACA’s financial and budgetary impacts, were signed into law. We refer to those two laws collectively as the “new healthcare reform law.” The new healthcare reform law imposes additional costs on and reduces the revenue of companies in the biotechnology and pharmaceutical industries. The following paragraphs describe certain provisions of the new healthcare reform law that will affect the reimbursement of our products.

 

The new healthcare reform law increased the rebates we pay to the states for our products that are covered and reimbursed by state Medicaid programs. The healthcare reform law increased the minimum base Medicaid rebate rate payable on our products reimbursed by Medicaid from 15.1% to 23.1% of the AMP of the product, or if it is greater, the difference between the AMP and the best price available from us to any non-government customer. The change in the minimum rebate percentage was effective on January 1, 2010. The healthcare reform law also extended the Medicaid drug rebate program to patients in Medicaid managed care insurance plans for whom rebates were not previously required. The extension of rebates to patients in Medicaid managed care plans was effective on March 23, 2010.

 

As mentioned above, the new healthcare reform law also expanded the list of provider institutions to which we must extend discounts under the PHS 340B drug pricing program. The new healthcare reform law added certain cancer centers, children’s hospitals, critical access hospitals and rural referral centers to the list of entities to which these discounts must be extended. This change to the list of eligible entities was effective on January 1, 2010. The healthcare reform law also imposed a new fee on manufacturers and importers of “branded prescription drugs,” which includes drugs approved under section 505(b) of the Federal Food, Drug, and Cosmetic Act or biologicals licensed under section 351(a) of the Public Health Service Act. Beginning in 2011, the new healthcare reform law sets an aggregate annual fee, to be paid by these manufacturers and importers, totaling $28 billion over 10 years, of which $2.5 billion is payable in 2011. This annual fee will be apportioned among the participating companies, including us, based on each company’s sales of qualifying products to, and utilization by, certain U.S. government programs during the preceding calendar year. The additional fee became effective January 1, 2011, and is not deductible for U.S. federal income tax purposes. Manufacturers and importers of generic or biosimilar drugs are not subject to the fee. We estimate that we will be required to pay $150 million to $200 million as our portion of the 2011 fee.

 

Since the Medicare Part D drug benefit took effect in 2006, beneficiaries enrolled in Part D plans have been required to pay 100% of their prescription drug costs after their total drug spending exceeds an initial coverage limit until they qualify for catastrophic coverage. This coverage gap is sometimes referred to as the Part D “doughnut hole.” The new healthcare reform law reduces the “doughnut hole” by requiring manufacturers like us to provide a 50% discount to Medicare Part D patients whose prescription expenses exceed the Part D prescription drug coverage limit but have not yet reached the catastrophic coverage threshold. This provision became effective January 1, 2011.

 

The new healthcare reform law also expands the Medicaid eligibility to include those with incomes up to 133% of the federal poverty level (“FPL”), from 100% of the FPL. This provision becomes effective January 1, 2014.

 

We estimate that the total impact of U.S. healthcare reform in 2011 to us, including the industry fee described above, will be in the range of $400 million to $500 million.

Reimbursement Outside the United States

 

Generally, in Europe and other countries outside the United States, government-sponsored healthcare systems have traditionally been the primary payers of all healthcare costs, including payment for drugs and biologicals. Over the past several years, the reimbursement environment in Europe has become very challenging, with the advent of Health Technology Assessment (“HTA”) organizations (eg, NICE in the UK) that make recommendations and/or determinations of coverage and reimbursement based on both the clinical as well as the economic value of a product. Although the methods employed by different HTA agencies vary from country to country, the use of formal economic metrics has been increasing across Europe as well as in several emerging markets throughout the world. In addition to determining whether or not a new product will be reimbursed, these agencies are becoming increasingly involved in setting the maximum price at which the product will be reimbursed — the “value-based” price for a product.

 

With increased budgetary constraints, payers in many countries employ a variety of measures to exert downward price pressure. In some countries, international price referencing is the primary mechanism for price control whereby the ceiling price of a pharmaceutical or biological product is set based on the prices in particular benchmark countries. These price referencing rules are increasing in complexity as prices become more transparent and payers seek lower-price benchmarks against which to compare themselves. Additional cost-containment measures can include therapeutic reference pricing (eg, setting the reimbursement rate for a given class of agents at the lowest price within the class), generic substitution and government-mandated price cuts.

 

While mandatory price reductions have been a recurring aspect of business for the pharmaceutical and biotechnology industries in the EU, given the current worldwide economic conditions, some EU governmental agencies have increased the frequency and/or size of such mandatory price reductions to extract further cost savings. For example, in 2010, countries such as Greece announced price reductions and/or mandated rebates for certain pharmaceutical and biological products that substantially exceeded prior levels. Other countries may follow and/or take similar or more extensive actions to reduce expenditures on drugs and biologics, including implementing mandatory price reductions, establishing preferences for biosimilar products, or reducing the amount of reimbursement.

 

In many countries, the influence of regional and hospital payers also contributes to whether patients have access to certain products. For example, a product may be successfully listed on a national formulary, but may also be subject to further evaluations or competitive bidding by payers at a regional or hospital level. Finally, payers in some countries are beginning to experiment with alternative payment mechanisms (eg, payment caps) as a means to maintain access to innovative therapies.

 

Fraud and Abuse Regulations Related to Reimbursement

 

As participants in government reimbursement programs, we are subject to various U.S. federal and state laws, as well as foreign laws, pertaining to healthcare “fraud and abuse,” including anti-kickback laws and false claims laws. (See Government Regulation — Other.) Violations of fraud and abuse laws can result in stringent enforcement penalties up to and including complete exclusion from federal healthcare programs (including Medicare and Medicaid).

 

Manufacturing, Distribution and Raw Materials

 

Manufacturing

 

Biological products, which are produced in living systems, are inherently complex due to naturally-occurring molecular variations. Highly specialized knowledge and extensive process and product characterization are required to transform laboratory scale processes into reproducible commercial manufacturing processes. Our manufacturing operations consist of bulk manufacturing, formulation, fill and finish and distribution activities. Bulk manufacturing includes fermentation and cell culture, which are the processes by which our proteins are produced. The proteins are purified to a high quality and then formulated into a stable form. The fill process

dispenses the formulated bulk protein into vials or syringes. Finally, in the finish process, our products are packaged for distribution.

 

We operate commercial and/or clinical manufacturing facilities in the United States, Puerto Rico and the Netherlands. (See Item 2. Properties.) Manufacturing of Sensipar^®/Mimpara^®, our small molecule product, is currently performed by third-party contract manufacturers, although we are in the process of transferring certain finishing aspects to our facility in Puerto Rico. We also use and expect to continue to use third-party contract manufacturers to produce or assist in the production of certain of our large molecule marketed products, including ENBREL, Nplate^®, Prolia^® and XGEVA^tm as well as a number of our clinical product candidates. In addition to producing our own commercial quantities of Epoetin alfa, we also supply Epoetin alfa in the United States to J&J under a supply agreement. (See Business Relationships — Johnson & Johnson.)

 

The global supply of our principal products depends on actively managing the inventory produced at our facilities and by third-party contract manufacturers and the uninterrupted and efficient operation of our facilities and those of our third-party contract manufacturers. During the manufacturing scale-up process, and even after achieving sustainable commercial manufacturing, we may encounter difficulties or disruptions due to defects in raw materials or equipment, contamination or other factors that could impact product availability. (See Item 1A. Risk Factors — Manufacturing difficulties, disruptions or delays could limit supply of our products and limit our product sales and — We rely on third-party suppliers for certain of our raw materials, medical devices and components.)

 

We have obtained from various parties certain licenses we deem necessary or desirable for the manufacture of our products. The licenses generally require us to pay royalties to the licensors based on product sales.

 

Commercial Bulk Manufacturing

 

We operate commercial bulk manufacturing facilities in Puerto Rico and in several locations throughout the United States. (See Item 2. Properties.) We perform all of the commercial bulk manufacturing of all of our proteins except ENBREL, Prolia^® and XGEVA^tm, which we supplement with a third-party contract manufacturer.

 

Commercial Formulation, Fill and Finish Manufacturing

 

Our primary commercial formulation, fill and finish manufacturing facility is located in Puerto Rico. We perform the commercial formulation, fill and finish manufacturing for our proteins at that facility, except for Vectibix^® and Nplate^®. We operate a commercial formulation, fill and finish manufacturing facility in the United States for Vectibix^® and the formulation, fill and finish for Nplate^® is performed by a third-party contract manufacturer. In addition to the formulation, fill and finish of ENBREL performed by us in Puerto Rico, fill and finish of a certain portion of ENBREL is also performed by third-party contract manufacturers. We also conduct certain finish activities in the Netherlands. (See Item 2. Properties.)

 

Clinical Manufacturing

 

Clinical bulk, formulation, fill and finish manufacturing facilities are operated primarily in our Thousand Oaks, California location. (See Item 2. Properties.) Certain finishing activities for our clinical products are performed in the Netherlands. In addition, we also utilize third-party contract manufacturers for certain of our clinical products.

 

See Item 1A. Risk Factors — We perform a substantial amount of our commercial manufacturing activities at our Puerto Rico manufacturing facility and a substantial amount of our clinical manufacturing activities at our Thousand Oaks, California manufacturing facility; if significant natural disasters or production failures occur at the Puerto Rico facility, we may not be able to supply these products or, at the Thousand Oaks facility, we may not be able to continue our clinical trials.

 

Distribution

 

We operate distribution centers in the United States, principally in Kentucky and California, and in the Netherlands for worldwide distribution of the majority of our commercial and clinical products. In addition, we also

use third-party distributors to supplement distribution of our commercial and clinical products in certain areas of the world.

 

Other

 

In addition to the manufacturing and distribution activities noted above, our operations in the United States, Puerto Rico and the Netherlands perform key manufacturing support functions, including quality control, process development, procurement, distribution and production scheduling. Certain of those manufacturing and distribution activities are highly regulated by the FDA as well as other international regulatory agencies. (See Government Regulation — FDA Regulation of Manufacturing Standards.)

 

Manufacturing Initiatives

 

We have multiple ongoing initiatives that are designed to optimize our manufacturing network and mitigate risks while continuing to ensure adequate supply of our commercial products. For example, we are completing the construction and qualification of a new formulation and filling facility at our Puerto Rico site in order to mitigate the risk associated with the majority of our formulation and fill operations being performed in a single facility and we are qualifying the expansion of our existing bulk protein facilities at our Puerto Rico site in order to maintain supply and to satisfy anticipated future demand for denosumab. Upon completion, the facilities will require licensure by the various regulatory authorities.

 

We have also entered into an agreement with Boehringer Ingelheim (“BI”) for the divestiture of our manufacturing facility in Fremont, California to further optimize our manufacturing network.

 

In addition to these projects, we have initiatives designed to operate our facilities at appropriate production capacity over the next few years, further optimize manufacturing asset utilization, continue our use of third-party contract manufacturers and maintain a state of regulatory compliance. (See Item 1A. Risk Factors — Manufacturing difficulties, disruptions or delays could limit supply of our products and limit our product sales.)

 

Raw Materials and Medical Devices

 

Certain raw materials necessary for the commercial and clinical bulk manufacturing of our products are provided by unaffiliated third-party suppliers, certain of which may be our only source for such materials. Also, certain medical devices and components necessary for the formulation, fill and finish of our products are provided by unaffiliated third-party suppliers, certain of which may be the sole source. Certain of the raw materials, medical devices and components are the proprietary products of those unaffiliated third-party suppliers and are specifically cited in our drug application with regulatory agencies so that they must be obtained from the specific sole source or sources and could not be obtained from another supplier unless and until the regulatory agency approved such supplier. We currently attempt to manage the risk associated with such suppliers by inventory management, relationship management and evaluation of alternative sources when feasible. We also monitor the financial condition of certain suppliers, their ability to supply our needs and the market conditions for these items.

 

Certain of the raw materials required in the commercial and clinical manufacturing of our products are sourced from other countries and/or derived from biological sources, including mammalian tissues. In addition, one of our marketed products also uses bovine serum and human serum albumin (“HSA”). Some countries in which we market our products may restrict the use of certain biologically derived substances in the manufacture of drugs. We continue to investigate alternatives to certain biological sources and alternative manufacturing processes that do not require the use of certain biologically derived substances because such raw materials may be subject to contamination and/or recall. A material shortage, contamination, recall and/or restriction of the use of certain biologically derived substances or other raw materials, which may be sourced from other countries and that are used in the manufacture of our products could adversely impact or disrupt the commercial manufacturing of our products or could result in a mandated withdrawal of our products from the market. (See Item 1A. Risk Factors — We rely on third-party suppliers for certain of our raw materials, medical devices and components.)

We perform various procedures to assist in authenticating the source of raw materials, including intermediary materials used in the manufacture of our products, which include verification of the country of origin. These procedures are incorporated into the manufacturing processes we and our third-party contract manufacturers perform.

 

Business Relationships

 

From time to time, we enter into business relationships including, joint ventures and collaborative arrangements, for the R&D, manufacture and/or commercialization of products and product candidates. In addition, we also acquire product and R&D technology rights and establish R&D collaborations with third-parties to enhance our strategic position within our industry by strengthening and diversifying our R&D capabilities, product pipeline and marketed product base. These arrangements generally provide for non-refundable upfront license fees, R&D and commercial performance milestone payments, cost sharing, royalty payments and/or profit sharing. Our collaboration agreements are performed on a “best efforts” basis with no guarantee of either technological or commercial success and each is unique in nature.

 

Trade secret protection for our unpatented confidential and proprietary information is important to us. To protect our trade secrets, we generally require parties to business relationships to execute confidentiality agreements upon the commencement of the business relationship with us. However, others could either develop independently the same or similar information or obtain access to our information.

 

Kirin Holdings Company, Limited

 

We formed KA, a 50-50 joint venture with Kirin in 1984. KA develops and commercializes certain of our and Kirin’s product rights, which have been transferred to this joint venture. KA has given exclusive licenses to us to manufacture and market: (i) darbepoetin alfa in the United States, Europe, Canada, Australia, New Zealand, Mexico, all Central and South American countries and certain countries in Central Asia, Africa and the Middle East, (ii) pegfilgrastim and G-CSF in the United States, Europe, Canada, Australia and New Zealand, (iii) recombinant human erythropoietin in the United States and (iv) romiplostim in the United States, Europe, Canada, Australia, New Zealand, Mexico, all Central and South American countries and certain countries in Central Asia, Africa and the Middle East. We currently market darbepoetin alfa, pegfilgrastim, G-CSF, recombinant human erythropoietin and romiplostim under the brand names Aranesp^®, Neulasta^®, NEUPOGEN^®/GRANULOKINE^®, EPOGEN^® and Nplate^®, respectively.

 

KA has also given exclusive licenses to Kirin to manufacture and market: (i) darbepoetin alfa, pegfilgrastim, G-CSF and romiplostim in Japan, the People’s Republic of China (“China”), Taiwan, Korea and certain other countries in Asia, and (ii) recombinant human erythropoietin in Japan and China. Kirin markets darbepoetin alfa in Japan under the brand name NESP^®. Kirin markets G-CSF and recombinant human erythropoietin in China under separate agreements with KA. Kirin markets its G-CSF product in its respective territories under the trademark GRAN^®/Grasin^®/Filgrastim^®. Kirin markets its recombinant human erythropoietin product in Japan under the trademark ESPO^®. Kirin also markets G-CSF and recombinant human erythropoietin in China under a separate agreement with Amgen Greater China Ltd., a subsidiary of Amgen Inc.

 

KA has licensed to J&J rights to recombinant human erythropoietin in all geographic areas of the world outside the United States, China and Japan. (See Johnson & Johnson.) Under its agreement with KA, J&J pays a royalty to KA based on sales. KA has also licensed to Roche rights to pegfilgrastim and G-CSF in certain geographic areas of the world.

 

In connection with our various license agreements with KA, we pay KA royalties based on product sales. In addition, we also receive payment from KA for conducting certain R&D activities on its behalf. (See Note 7, Related party transactions to the Consolidated Financial Statements.)

Johnson & Johnson

 

We granted J&J a license to commercialize recombinant human erythropoietin as a human therapeutic in the United States in all indications other than dialysis and diagnostics. All recombinant human erythropoietin sold by J&J in the United States is manufactured by us and sold by J&J under the trademark PROCRIT^® (Epoetin alfa). PROCRIT^® brand Epoetin alfa is identical to EPOGEN^® brand Epoetin alfa, which is manufactured and sold by us in the U.S. market for the dialysis indication. Pursuant to the license agreement with J&J, we earn a 10% royalty on net sales of PROCRIT^® by J&J in the United States.

 

Outside the United States, with the exception of China and Japan, J&J was granted rights to manufacture and commercialize recombinant human erythropoietin as a human therapeutic for all uses under a licensing agreement with KA. With respect to its sales outside of the United States, J&J manufactures and commercializes its own brand of Epoetin alfa which is then sold by a subsidiary of J&J under various trademarks such as EPREX^® and ERYPO^®. We are not involved in the manufacture of Epoetin alfa sold by J&J outside of the United States.

 

Pfizer Inc.

 

Amgen and Pfizer are in a collaboration agreement to co-promote ENBREL in the United States and Canada. The rights to market ENBREL outside of the United States and Canada are reserved to Pfizer. Under the agreement, a management committee comprised of equal representation from Amgen and Pfizer is responsible for overseeing the marketing and sales of ENBREL, including strategic planning, the approval of an annual marketing plan, product pricing and the establishment of a brand team. The brand team, with equal representation from each party, prepares and implements the annual marketing plan, which requires a minimum level of financial and sales personnel commitment from each party, and is responsible for all sales activities. Further, pursuant to the collaboration agreement, Amgen and Pfizer share in the agreed-upon selling and marketing expenses approved by the joint management committee. We currently pay Pfizer a percentage of the annual gross profits on our ENBREL sales in the United States and Canada attributable to all approved indications for ENBREL on a scale that increases as gross profits increase; however, we maintain a majority share of ENBREL profits. After expiration of the collaboration agreement in the fourth quarter of 2013, we are required to pay Pfizer a percentage of net ENBREL sales in the United States and Canada for three years. The annual amount of such payments is anticipated to be significantly less than the current ENBREL profit share.

 

Glaxo Group Limited

 

In July 2009, we entered into a collaboration agreement with Glaxo for the commercialization of denosumab for osteoporosis indications in Europe, Australia, New Zealand and Mexico (the “Primary Territories”). We retained the rights to commercialize denosumab for all indications in the United States and Canada and for oncology indications in the Primary Territories. Under a related agreement, Glaxo will commercialize denosumab for all indications in countries, excluding Japan, where we do not currently have a commercial presence, including China, Brazil, India, Taiwan and South Korea (the “Expansion Territories”). In the Expansion Territories, Glaxo will be responsible for all development and commercialization costs and will purchase denosumab from us to meet demand. We have the option of expanding our role in the future in the commercialization of denosumab in the Primary Territories and certain of the Expansion Territories. In the Primary Territories, we share equally in the commercialization profits and losses related to the collaboration after accounting for expenses, including an amount payable to us in recognition of our discovery and development of denosumab. Glaxo will also be responsible for bearing a portion of the cost of certain specified development activities in the Primary Territories.

 

Takeda Pharmaceutical Company Limited

 

In February 2008, we entered into a collaboration agreement with Takeda, which provides Takeda the exclusive rights to develop and commercialize for the Japanese market up to 12 clinical stage molecules from our pipeline across a range of therapeutic areas, including oncology and inflammation. The products include Vectibix^® which received regulatory approval in Japan in 2010 for unresectable, advanced or recurrent colorectal cancer with wild-type KRAS, AMG 386, which is in a phase 3 trial in the United States for recurrent ovarian cancer, and

ganitumab (AMG 479) which is expected to enter into a phase 3 trial in the United States for first-line metastatic pancreatic cancer in 2011. We have the right to participate in the promotion of the products in Japan. In addition, we entered into a collaboration agreement with Takeda for the worldwide development and commercialization of our product candidate motesanib in the oncology area. Each party has the right to participate in the commercialization of motesanib in the other party’s territory.

 

Daiichi Sankyo Company, Limited

 

In July 2007, we entered into a collaboration and license agreement with Daiichi Sankyo, which provides Daiichi Sankyo the exclusive rights to develop and commercialize denosumab in Japan in postmenopausal osteoporosis (“PMO”), oncology and certain other indications. As part of the agreement, Amgen received exclusive worldwide rights to certain Daiichi Sankyo intellectual property to the extent applicable to denosumab.

 

Fresenius Medical Care North America

 

In October 2006, we entered into a five-year sole sourcing and supply agreement with an affiliate of Fresenius Medical Care North America (“Fresenius North America”) (a wholly owned subsidiary of Fresenius Medical Care), on its behalf and on behalf of certain of its affiliates, whereby Fresenius North America agreed to purchase, and we have agreed to supply, all of Fresenius North America’s commercial requirements for ESAs for use in managing the anemia of its hemodialysis patients in the United States and Puerto Rico, based on forecasts provided by Fresenius and subject to the terms and conditions of the agreement.

 

Government Regulation

 

Regulation by government authorities in the United States and other countries is a significant factor in the production and marketing of our products and our ongoing R&D activities.

 

In order to clinically test, manufacture and market products for therapeutic use, we must satisfy mandatory procedures and safety and effectiveness standards established by various regulatory bodies. In the United States, the Public Health Service Act, the Federal Food, Drug and Cosmetic Act (“FDCA”) and the regulations promulgated thereunder, as well as other federal and state statutes and regulations govern, among other things, the raw materials and components used in the production, research, development, testing, manufacture, quality control, labeling, storage, record keeping, approval, advertising and promotion, and distribution of our products. Failure to comply with the applicable regulatory requirements may subject us to a variety of administrative and/or judicially imposed sanctions. The sanctions could include the FDA’s refusal to approve pending applications, withdrawals of approvals, delay or suspension of clinical trials, warning letters, product recalls, product seizures, total or partial suspension of our operations, injunctions, fines, civil penalties and/or criminal prosecution.

 

Clinical Development. We must conduct extensive clinical trials designed to establish the safety and efficacy of product candidates in order to file for regulatory approval to market a product. Product development and approval within that regulatory framework takes a number of years and involves our expenditure of substantial resources, and any approval we obtain remains costly for us to maintain. After laboratory analysis and preclinical testing in animals, we file an investigational new drug application (“IND”) with the FDA to begin human testing. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA raises concerns or questions. In such a case, we and the FDA must resolve any outstanding concerns before the clinical trial can begin.

 

Typically, we undertake a three-phase human clinical testing program. In phase 1, we conduct small clinical trials to investigate the safety and proper dose ranges of our product candidates in a small number of human subjects. In phase 2, we conduct clinical trials to investigate side effect profiles and the efficacy of our product candidates in a larger number of patients who have the disease or condition under study. In phase 3, we conduct clinical trials to investigate the safety and efficacy of our product candidates in a large number of patients who have the disease or condition under study. The time and expense required for us to perform this clinical testing is substantial and may vary by product. For example, the clinical trials for the BLA for Prolia^®/XGEVA^tm were large and required substantial time and resources to recruit patients and significant expense to execute. Historically, our products have required smaller, shorter trials. Foreign studies performed under an IND must meet the same

requirements that apply to U.S. studies. The FDA will accept a foreign clinical study not conducted under an IND only if the study is well-designed, well-conducted, performed by qualified investigators, and conforms to good clinical practice. Phase 1, 2 and 3 testing may not be completed successfully within any specified time period, if at all. (See Item 1A. Risk Factors — We may not be able to develop commercial products.) The FDA monitors the progress of each trial conducted under an IND and may, at its discretion, re-evaluate, alter, suspend, or terminate the testing based on the data accumulated to that point and the FDA’s risk/benefit assessment with regard to the patients enrolled in the trial. (See Item 1A. Risk Factors — We must conduct clinical trials in humans before we can commercialize and sell any of our product candidates or existing products for new indications.)

 

Applications. The results of preclinical and clinical trials are submitted to the FDA in the form of a BLA for biologic products subject to the Public Health Service Act or a new drug application (“NDA”) for drugs subject to the approval provisions of the FDCA. The submission of the application is no guarantee that the FDA will find it complete and accept it for filing. If an application is accepted for filing, following the FDA’s review, the FDA may grant marketing approval, request additional information, or deny the application if it determines that the application does not provide an adequate basis for approval. We cannot take any action to market any new drug or biologic product in the United States until our appropriate marketing application has been approved by the FDA.

 

Post-approval Phase. After we have obtained approval to market our products, we monitor adverse events from the use of our products and report such events to regulatory agencies, along with information from post marketing surveillance or studies. We may utilize other research approaches to learn or confirm information about our marketed products, including observational studies and patient registries, and may engage in risk management activities such as physician education initiatives and patient advocacy group initiatives. We may also conduct, or be required by regulatory agencies to conduct, further clinical trials to provide additional information on our marketed products’ safety and efficacy. Those additional trials may include studying different doses or schedules of administration that were used in previous studies, use in other patient populations or other stages of the disease or use over a longer period of time. Additional trials of this nature are sometimes required by regulatory agencies as a condition of their approval to market our products and they might also request or require that we conduct specific studies, including observational epidemiological studies, in order to identify or assess possible safety risks of our marketed products that are observed or suggested by available scientific data and such trials are sometimes referred to as PMCs or PMRs. In the United States, under the Food and Drug Administration Amendments Act of 2007 (the “FDAAA”), if the FDA becomes aware of new safety information after approval of a product, it may require us to conduct further clinical trials to assess a known or potential serious risk. If we are required to conduct such a post-approval study, periodic status reports must be submitted to the FDA. Failure to conduct such post-approval studies in a timely manner may result in substantial civil or criminal penalties. Data resulting from these clinical trials may result in expansions or restrictions to the labeled indications for which our products have already been approved and to the reimbursement provided by government and commercial payers for our products.

 

The FDAAA also gave the FDA authority to require companies to implement a REMS for a product to ensure that the benefits of the drugs outweigh the risks. While risk management activities and programs are not new, with FDAAA the FDA gained new authority to implement specific risk management requirements and new enforcement power to ensure that the goals of the REMS are being met. The FDA began to implement REMS in 2008. The FDA may require the submission of a REMS before a product is approved or after approval based on new safety information, including new analyses of existing safety information. In determining whether a product will require a REMS before the product is approved, the FDA may consider a number of factors including:

 

All REMS are required to have a timetable for assessment and may have one or more of the following:

 

 

 

 

Each REMS is unique and varies depending on the specific factors required. While the elements of REMS may vary, all REMS require the sponsor to submit periodic assessment reports to the FDA to demonstrate that the goals of the REMS are being met. Failure to comply with a REMS, including submission of a required assessment or any modification to a REMS, may result in substantial civil or criminal penalties and can result in additional limitations being placed on a product’s use and, potentially, withdrawal of the product from the market. We currently have approved REMS for our ESAs, ENBREL, Prolia^® and Nplate^®. Because REMS are relatively new, the FDA and sponsor companies continue to learn how best to implement, operate and monitor the effectiveness of REMS, and the requirements of our REMS and those of other companies may change over time.

 

Adverse events that are reported after marketing approval also can result in additional limitations being placed on a product’s use and, potentially, withdrawal of the product from the market. The FDA has authority to mandate labeling changes to products at any point in a product’s lifecycle based on new safety information or as part of an evolving label change to a particular class of products. Also under the FDA’s PLR implemented in 2006, we are required to make changes to the existing format of U.S. product package inserts for human prescription drug and biological products with the intent of making product information more easily accessible. The PLR requires revised standards of content and format of labeling and provides timelines for when new and previously approved products must comply with the new regulations. During the PLR conversion process from an old format to the new PLR format, the FDA has the authority to evaluate the package insert information to ensure that it accurately reflects current knowledge and the FDA may revise, add or remove information in the old format that could substantively impact the content of the product package insert for the new format. Failure to implement FDA-mandated changes may result in civil or criminal penalties. (See Item 1A. Risk Factors — Our ESA products continue to be under review and receive scrutiny by regulatory authorities and — Our current products and products in development cannot be sold if we do not maintain or gain regulatory approval.) The package inserts for our ENBREL and Neulasta^® products have already been converted to the new PLR format and we are currently working with the FDA on converting the package inserts for Aranesp^®, EPOGEN^® and Sensipar^®. Our Vectibix^®, Nplate^®, Prolia^® and XGEVA^tm products were approved in the PLR format.

 

The FDA also uses various advisory committees of external experts to assist in its mission to protect and promote the public health, to obtain independent expert advice on scientific, technical and policy matters. The committees are generally advisory only and FDA officials are not bound to or limited by their recommendations. We have participated in meetings of the ODAC, the CRDAC and the Advisory Committee for Reproductive Health Drugs, among others, to address certain issues related to our products, including Aranesp^®, EPOGEN^® and Prolia^®.

 

FDA Approval of Biosimilar Products. The new healthcare reform law authorizes the FDA to approve biosimilar products under a separate, abbreviated pathway. The new law establishes a period of 12 years of data exclusivity for reference products in order to preserve incentives for future innovation and outlines statutory criteria for science-based biosimilar approval standards that take into account patient safety considerations. Under this framework, data exclusivity protects the data in the innovator’s regulatory application by prohibiting others, for a period of 12 years, from gaining FDA approval based in part on reliance or reference to the innovator’s data in their application to the FDA. The new law does not change the duration of patents granted on biologic products. While the FDA now has the authority to approve biosimilar products, the FDA has not announced whether it will first

publish guidance or rules for biosimilar applicants before approving biosimilar products. The FDA held a public meeting in November 2010 to seek stakeholder input on the subject and accepted written comments through 2010.

 

FDA Regulation of Product Marketing and Promotion. The FDA closely reviews and regulates the marketing and promotion of products. We are required to obtain FDA approval before marketing or promoting a product as a treatment for a particular indication. Our product promotion for approved product indications must comply with the statutory standards of the FDCA, and the FDA’s implementing regulations and standards. The FDA’s review of marketing and promotional activities encompasses, but is not limited to, direct-to-consumer advertising, healthcare provider-directed advertising and promotion, sales representative communications to healthcare professionals, promotional programming and promotional activities involving the Internet. The FDA may also review industry-sponsored scientific and educational activities. The FDA may take enforcement action against a company for promoting unapproved uses of a product (“off-label promotion”) or for other violations of its advertising and labeling laws and regulations. Enforcement action may include product seizures, injunctions, civil or criminal penalties or regulatory letters, which may require corrective advertising or other corrective communications to healthcare professionals. Failure to comply with the FDA’s regulations also can result in adverse publicity or increased scrutiny of company activities by the U.S. Congress or other legislators.

 

FDA Regulation of Manufacturing Standards. The FDA regulates and inspects equipment, facilities, laboratories and processes used in the manufacturing and testing of products prior to providing approval to market a product. If after receiving approval from the FDA, we make a material change in manufacturing equipment, location or process, additional regulatory review may be required. We also must adhere to current Good Manufacturing Practice (“GMP”) regulations and product-specific regulations enforced by the FDA through its facilities inspection program. The FDA also conducts regular, periodic visits to re-inspect our equipment, facilities, laboratories and processes following an initial approval. If, as a result of those inspections, the FDA determines that our equipment, facilities, laboratories or processes do not comply with applicable FDA regulations and conditions of product approval, the FDA may seek civil, criminal or administrative sanctions and/or remedies against us, including suspension of our manufacturing operations. Such issues may also delay the approval of new products undergoing FDA review.

 

Approval and Post-Approval Regulation Outside the United States. In the EU countries, Switzerland, Canada and Australia, regulatory requirements and approval processes are similar in principle to those in the United States. Additionally, depending on the type of drug for which approval is sought, there are currently two potential tracks for marketing approval in the EU, including a centralized procedure. In the centralized procedure, which is required of all products derived from biotechnology, a company submits a single marketing authorization application to the EMA who conducts a thorough evaluation, drawing from its scientific resources across Europe. If the drug product is proven to fulfill the requirements for quality, safety and efficacy, the CHMP adopts a positive opinion, which is transmitted to the EC for final approval of the marketing authorization. While the EC generally follows the CHMP’s opinion, it is not bound to do so. In the EU, biosimilar products have been approved under a sub-pathway of the centralized procedure since 2006. The pathway allows sponsors of a biosimilar product to seek and obtain regulatory approval based in part on the clinical trial data of an originator product to which the biosimilar product has been demonstrated to be “similar.” In many cases, this allows biosimilar products to be brought to market without conducting the full suite of clinical trials typically required of innovators. After evaluation and marketing authorization, various parties, including the national competent authorities, the EMA, the EC and the marketing authorization holders share responsibilities for the detection, assessment and prevention of adverse effects and other medicine-related problems in a process known as pharmacovigilance. Healthcare professionals and patients are also encouraged to report adverse effects and other medicine-related problems. This process includes the collection of adverse drug reaction reports as part of the follow-up on any side effects of a product, and upon assessment, the authorities can decide to demand that product labels be updated with safety data or warnings, that safety data or warnings be provided to healthcare professionals, or recommend the temporary suspension or complete withdrawal of a product from the market.

 

Other. We are also subject to various federal and state laws, as well as foreign laws, pertaining to healthcare “fraud and abuse,” including anti-kickback laws and false claims laws. Anti-kickback laws make it illegal to solicit, offer, receive or pay any remuneration in exchange for, or to induce, the referral of business, including the purchase or prescription of a particular drug that is reimbursed by a state or federal program. The federal government and the states have published regulations that identify “safe harbors” or exemptions for certain arrangements that do not

violate the anti-kickback statute. We seek to comply with the safe harbors wherever possible. Due to the breadth of the statutory provisions and the absence of guidance in the form of regulations or court decisions addressing some of our practices, it is possible that our practices might be challenged under anti-kickback or similar laws. False claims laws prohibit knowingly and willingly presenting, or causing to be presented for payment to third-party payers (including Medicare and Medicaid), claims for reimbursed drugs or services that are false or fraudulent, claims for items or services not provided as claimed or claims for medically unnecessary items or services. Our activities related to the sale and marketing of our products may be subject to scrutiny under these laws. Violations of fraud and abuse laws may be punishable by criminal and/or civil sanctions, including fines and civil monetary penalties, as well as the possibility of exclusion from federal healthcare programs (including Medicare and Medicaid). If the government were to allege against or convict us of violating those laws or if we entered into a settlement with the government, there could be a material adverse effect on our business, including our stock price. Our activities could be subject to challenge for the reasons discussed above and due to the broad scope of those laws and the increasing attention being given to them by law enforcement authorities.

 

We are also subject to regulation under the Occupational Safety and Health Act, the Toxic Substances Control Act, the Resource Conservation and Recovery Act and other current and potential future federal, state or local laws, rules and/or regulations. Our R&D activities involve the controlled use of hazardous materials, chemicals, biological materials and various radioactive compounds. We believe our procedures comply with the standards prescribed by federal, state or local laws, rules and/or regulations; however, the risk of injury or accidental contamination cannot be completely eliminated. While we are not required to do so, we strive to conduct our research and manufacturing activities in a manner that meets the intents and purposes of the National Institutes of Health Guidelines for Recombinant DNA Research.

 

Additionally, the U.S. Foreign Corrupt Practices Act (“FCPA”) prohibits U.S. corporations and their representatives from offering, promising, authorizing or making payments to any foreign government official, government staff member, political party or political candidate in an attempt to obtain or retain business abroad. The scope of the FCPA includes interactions with certain healthcare professionals in many countries.

 

Our present and future business has been and will continue to be subject to various other U.S. and foreign laws, rules and/or regulations.

 

Research and Development and Selected Product Candidates

 

Our vision is to deliver therapeutics that can make a meaningful difference in patients’ lives. Therefore, we focus our R&D on novel human therapeutics for the treatment of grievous illness in the areas of oncology, hematology, inflammation, bone, nephrology, cardiovascular and general medicine, which includes neurology. We take a modality-independent approach to R&D — that is, we identify targets, and then choose the modality best suited to address a specific target. As such, our discovery research programs may yield targets that lead to the development of human therapeutics delivered as large molecules (such as proteins, antibodies and peptibodies) or small molecules.

 

We have major R&D centers in several locations throughout the United States and in the United Kingdom, as well as smaller research centers in Canada and Germany, and smaller development facilities throughout Europe and in Canada, Australia, Mexico, Hong Kong and India. (See Item 2. Properties.)

 

To execute our clinical trial programs, we need to maintain an effective development organization and associated R&D support organizations. We conduct clinical trial activities with both our internal staff and third-party contract clinical trial service providers. In order to increase the number of patients available for enrollment for our clinical trials, we have and will continue to open clinical sites and enroll patients in a number of geographic locations. (See Item 1A. Risk Factors — We must conduct clinical trials in humans before we can commercialize and sell any of our product candidates or existing products for new indications.)

 

Some of our competitors are actively engaged in R&D in areas where we have products or where we are developing product candidates or new indications for existing products. For example, we compete with other clinical trials for eligible patients, which may limit the number of available patients who meet the criteria for certain

clinical trials. The competitive marketplace for our product candidates is significantly dependent upon the timing of entry into the market. Early entry may have important advantages in gaining product acceptance, contributing to the product’s eventual success and profitability. Accordingly, we expect that in some cases, the relative speed with which we can develop products, complete clinical testing, receive regulatory approval and supply commercial quantities of the product to the market is expected to be important to our competitive position.

 

In addition to product candidates and marketed products generated from our internal R&D efforts, we acquire companies, acquire and license certain product and R&D technology rights and establish R&D collaborations with third parties to enhance our strategic position within our industry by strengthening and diversifying our R&D capabilities, product pipeline and marketed product base. These licenses and collaboration agreements generally provide for non-refundable upfront license fees, R&D and commercial performance milestone payments, cost sharing, royalty payments and/or profit sharing.

 

Various public and privately owned companies, research organizations, academic institutions and governmental agencies conduct a significant amount of R&D in the biotechnology industry. We face competition in pursuing collaborative arrangements and licensing or acquisition activities from other pharmaceutical and biotechnology companies that also seek to license or acquire technologies, product candidates or marketed products from these entities. Accordingly, we may have difficulty entering into collaborative arrangements and licensing or acquiring technologies, product candidates and marketed products on acceptable terms.

 

See Government Regulation — Clinical Development for a discussion of the government regulation over clinical development.

The following table is a selection of certain of our product candidates by phase of development in our therapeutic areas of focus as of February 9, 2011, unless otherwise indicated. Each target indication for product candidates in phase 3 is listed separately. Additional product candidate (pipeline) information can be found on our website at http://www.amgen.com. (This website address is not intended to function as a hyperlink, and the information contained on our website is not intended to be a part of this filing.)

 

 

The following text provides additional information about selected product candidates that have advanced into human clinical trials.

 

AMG 386

 

AMG 386 is a peptibody that inhibits the interaction between the endothelial cell-selective Tie2 receptor and its ligands Ang1 and Ang2. It is being investigated as a cancer treatment.

 

In 2007 and 2008, we initiated five randomized phase 2 studies of AMG 386 for the treatment of renal cell carcinoma (“RCC”), metastatic breast cancer, ovarian cancer, gastric cancer and colorectal cancer, and numerous other supportive studies. In June 2010 at a medical meeting, we presented the results from the phase 2 recurrent ovarian cancer trial. Based on study results, we initiated a phase 3 study in recurrent ovarian cancer in 2010. We also initiated a phase 1b study in first-line ovarian cancer in 2010. We are initiating other phase 2 studies in 2011.

 

Ganitumab (AMG 479)

 

Ganitumab (AMG 479) is a fully human monoclonal antibody antagonist of IGF-1 receptor. It is being investigated as a cancer treatment.

 

In 2007, we initiated a phase 2 study of ganitumab (AMG 479) as a potential cancer therapeutic in Ewing’s sarcoma. We also initiated, in 2008, phase 2 studies for the treatment of advanced breast, pancreatic, colorectal and small cell lung cancers. We reported the results from the phase 2 Ewing’s sarcoma and pancreatic cancer studies at a medical meeting in June 2010 and results from the breast cancer study at a meeting in December 2010. Results from a study in mCRC in combination with Vectibix^® were reported at a meeting in January 2011. We are initiating a phase 3 study in first-line metastatic pancreatic cancer in 2011.

 

Aranesp^® (darbepoetin alfa)

 

Aranesp^® is a recombinant human protein agonist of the erythropoietin receptor.

 

The Reduction of Events with Darbepoetin alfa in Heart Failure (“RED-HF^®”) Trial phase 3 study, initiated in 2006, is a large (2,600 subjects planned), global, randomized, double-blind, placebo-controlled study to evaluate the effect of treatment of anemia with darbepoetin alfa on morbidity and mortality in patients with symptomatic left ventricular heart failure. The RED-HF^® Trial continues to enroll subjects and we anticipate completion of the study in 2012.

 

Motesanib

 

Motesanib is an orally-administered small molecule antagonist of vascular endothelial growth factor receptors 1, 2 and 3, platelet-derived growth factor receptors and stem cell factor receptor. It is being investigated as a cancer treatment. We are developing this product in collaboration with Takeda/Millennium Pharmaceuticals.

 

Enrollment in the phase 3 first-line NSCLC study (MONET1) evaluating motesanib in combination with paclitaxel and carboplatin for the first-line treatment of advanced NSCLC is complete. Based on current event rates, we anticipate completion of the study in the first half of 2011.

 

At a medical meeting in June 2010, we shared the results of biomarkers as predictors of response to treatment with motesanib or bevacizumab in combination with carboplatin/paclitaxel in patients with NSCLC or in combination with paclitaxel in patients with locally recurrent or metastatic breast cancer.

 

Denosumab

 

Denosumab is a fully human monoclonal antibody that specifically targets a ligand known as RANKL (that binds to a receptor known as RANK) which is a key mediator of osteoclast formation, function, and survival. Denosumab is being studied across a range of conditions including osteoporosis, treatment-induced bone loss, RA and numerous tumor types across the spectrum of cancer-related bone diseases.

 

Prolia^® (denosumab)

 

The phase 3 study evaluating Prolia^® patients with male osteoporosis is ongoing.

XGEVA^tm (denosumab)

 

In February 2010, we announced that a pivotal, phase 3, head-to-head study evaluating XGEVA^tm versus Zometa^® (zoledronic acid) in the treatment of bone metastases in 1,901 men with advanced prostate cancer met its primary and secondary endpoints. XGEVA^tm demonstrated superiority over Zometa^® for both delaying the time to the first on-study SRE (fracture, radiation to bone, surgery to bone or spinal cord compression) (hazard ratio (“HR”) 0.82, 95% confidence interval (“CI”): 0.71, 0.95), and reducing the rate of multiple SREs (HR 0.82, 95% CI: 0.71, 0.94). Both results were statistically significant.

 

In December 2010, we announced top-line results from a phase 3 trial evaluating XGEVA^tm versus placebo in 1,432 men with non-metastatic castrate-resistant prostate cancer. The trial, known as the ’147 study, demonstrated that XGEVA^tm significantly improved median bone metastasis-free survival by 4.2 months (HR=0.85, 95% CI 0.73-0.98, p=0.03) compared to placebo (primary endpoint), and significantly improved time to first occurrence of bone metastases (secondary endpoint). Overall survival was similar between the XGEVA^tm and placebo groups (secondary endpoint). Overall rates of adverse events and serious adverse events were generally similar between XGEVA^tm and placebo, with hypocalcemia and osteonecrosis of the jaw (“ONJ”) observed at increased frequencies in the XGEVA^tm arm. The yearly rate of ONJ in the XGEVA^tm-treated group was similar to what has been observed in prior XGEVA^tm trials. This study will form the basis of planned marketing applications, which we expect to submit to regulatory authorities beginning in the first half of 2011, for a new indication for the prevention of bone metastases in prostate cancer.

 

Also, we are currently conducting a study for the prevention of bone metastases in patients with breast cancer and are planning an additional SRE study in patients with multiple myeloma.

 

Sensipar^®/Mimpara^® (cinacalcet)

 

Sensipar^®/Mimpara^® is an orally-administered small molecule that lowers PTH levels in blood by signaling through the calcium-sensing receptor in parathyroid tissue to inhibit PTH secretion. It also lowers blood calcium and phosphorous levels.

 

The phase 3 EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (“E.V.O.L.V.E^tm”) trial, initiated in 2006, is a large (3,800 patient), multi-center, international, randomized, double-blind study to assess the effects of Sensipar^®/Mimpara^® in mortality and cardiovascular morbidity in patients with CKD undergoing maintenance dialysis. The E.V.O.L.V.E^tm study completed enrollment in January 2008. Based on current event rates, we anticipate completion of the study in dialysis patients in 2012.

 

Sensipar^®/Mimpara^® is also being evaluated in post renal transplant patients.

 

Vectibix^® (panitumumab)

 

Vectibix^® is a monoclonal antibody antagonist of the EGFr pathway. It is being investigated as a cancer treatment.

 

On April 16, 2010, our application for marketing authorization for the use of Vectibix^® in first- and second-line treatment of mCRC in patients whose tumors contain wild-type KRAS genes was submitted to the EMA. In the United States, we filed supplemental BLA submissions for first- and second-line mCRC with the FDA on October 29, and November 4, 2010.

 

In August 2010, we announced top-line results from a randomized phase 3 trial evaluating Vectibix^® as a first-line treatment in patients with recurrent and/or metastatic squamous cell head and neck cancer. The data showed the addition of Vectibix^® to platinum-based chemotherapy did not result in a statistically significant improvement in overall survival, the primary endpoint, compared to chemotherapy alone [median 11.1 months versus 9.0 months, HR 0.87 (95% CI: 0.73, 1.05)]. Secondary endpoints of progression-free survival [median 5.8 months versus 4.6 months, HR 0.78 (95% CI: 0.66, 0.92)] and objective response rate (36% versus 25%) were numerically improved but were not tested for statistical significance.

 

Additionally, we have two ongoing phase 2 trials in locally advanced head and neck cancer.

AMG 785

 

AMG 785 is a humanized monoclonal antibody that targets sclerostin, a protein secreted by bone cells that inhibits bone formation. AMG 785 (also known as CDP7851) is being developed in collaboration with UCB for bone-related conditions, including PMO and fracture healing.

 

In 2009, we initiated phase 2 studies of AMG 785 for the treatment of PMO and fracture healing (tibial diaphyseal).

 

In 2010, we initiated a phase 2 study of AMG 785 for the treatment of fracture healing (hip).

 

AMG 827

 

AMG 827 is a fully human monoclonal antibody that binds to and blocks signaling via the interleukin-17 receptor. It is being investigated as a treatment for a variety of inflammatory disorders.

 

In 2009, we initiated phase 2 studies of AMG 827 as a potential treatment for psoriasis and RA. In 2010, we initiated phase 2 studies of AMG 827 as a potential treatment for Crohn’s disease and asthma. We received the results from the phase 2 study in psoriasis in 2010 and plan to share these data at an upcoming medical meeting.

 

AMG 853

 

AMG 853 is an orally-administered small molecule antagonist of the CRTH2 and D-prostanoid receptors of prostaglandin D2. It is being investigated as a treatment for asthma.

 

Phase 1 single- and multiple-ascending dose studies have been completed. A global, randomized, double-blind, placebo controlled, multiple dose phase 2 study in subjects with inadequately controlled asthma was initiated in December 2009 and is ongoing.

 

Conatumumab

 

Conatumumab is a fully human monoclonal antibody agonist that targets death receptor 5 and induces apoptosis in sensitive tumor cells. It is being investigated as a cancer treatment.

 

We have an ongoing phase 2 study in mCRC.

 

Nplate^® (romiplostim)

 

Nplate^® is a peptibody agonist of the TPO receptor.

 

In December 2010, we announced results at a medical meeting from studies evaluating Nplate^® in adult and pediatric patients with chronic immune (idiopathic) thrombocytopenic purpura.

 

Results from completed phase 2 studies in myelodysplastic syndromes (“MDS”) were presented in 2010. In late February 2011, an independent Data Monitoring Committee (“DMC”) recommended that we modify the study conduct in another ongoing phase 2 study exploring the use of Nplate^® in MDS, expressing concern that the demonstrated benefits seen in treated patients might not outweigh the potential risks of accelerated disease progression to AML. The DMC was also concerned that transient blast cell increases in the Nplate^® arm put patients at risk for diagnosis of, and treatment for, AML, irrespective of whether or not the disease had actually developed. We accepted the recommendation of the DMC and notified investigators that subjects in this study should discontinue Nplate^® treatment and enter into the observational long-term follow-up phase of the study.

 

Nplate^® is also being evaluated in chemotherapy-induced thrombocytopenia.

 

Omecamtiv mecarbil (AMG 423)

 

Omecamtiv mecarbil is a small molecule activator of cardiac myosin. Omecamtiv mecarbil is being investigated to improve cardiac contractility in subjects with heart failure. We are developing this product in collaboration with Cytokinetics, Inc. (“Cytokinetics”).

Rilotumumab (AMG 102)

 

Rilotumumab (AMG 102) is a fully human monoclonal antibody that blocks the action of hepatocyte growth factor/scatter factor. It is being investigated as a cancer treatment.

 

Results from a study in mCRC in combination with Vectibix^® were reported at a meeting in January 2011. Phase 2 combination studies with rilotumumab (AMG 102) in the gastric, prostate, mCRC and small cell lung cancer settings continue.

 

Human Resources

 

As of December 31, 2010, Amgen had approximately 17,400 staff members, which includes approximately 300 part-time staff members. There can be no assurance that we will be able to continue attracting and retaining qualified personnel in sufficient numbers to meet our needs. None of our staff members are covered by a collective bargaining agreement, and we have experienced no work stoppages. We consider our staff relations to be good.

 

Trade secret protection for our unpatented confidential and proprietary information is important to us. To protect our trade secrets, we generally require our staff members, material consultants and scientific advisors to execute confidentiality agreements upon commencement of employment or a consulting relationship with us. However, others could either develop independently the same or similar information or obtain access to our information.

 

Executive Officers of the Registrant

 

The executive officers of the Company as of February 11, 2011 are as follows:

 

Mr. Kevin W. Sharer, age 62, has served as a director of the Company since November 1992. Mr. Sharer has been the Company’s Chief Executive Officer since May 2000 and has also been Chairman of the Board of Directors since January 2001. From May 2000 to May 2010, Mr. Sharer also served as the Company’s President. From October 1992 to May 2000, Mr. Sharer served as President and Chief Operating Officer of the Company. From April 1989 to October 1992, Mr. Sharer was President of the Business Markets Division of MCI Communications Corporation. From February 1984 to March 1989, Mr. Sharer held numerous executive capacities at General Electric Company (“GE”). Mr. Sharer is a director of Chevron Corporation and Northrop Grumman Corporation. He is Chairman of the Board of the Los Angeles County Museum of Natural History.

 

Mr. David W. Beier, age 62, became Senior Vice President, Global Government and Corporate Affairs in March 2008. He joined the Company in 2003 as Senior Vice President, Global Government Affairs. Previously, Mr. Beier was a partner with the law firm of Hogan and Hartson in Washington, D.C. From 1998 to early 2001, Mr. Beier served as Chief Domestic Policy Advisor to the Vice President of the United States. He also held positions as Vice President of Government Affairs and Public Policy for Genentech and staff counsel in the U.S. House of Representatives. Mr. Beier is a director of ARYx Therapeutics, Inc.

 

Dr. Fabrizio Bonanni, age 64, became Executive Vice President, Operations in August 2007. He has served as Senior Vice President, Manufacturing of the Company since 2004. Dr. Bonanni joined the Company in 1999 as Senior Vice President, Quality and Compliance, and in June 2001 he also became the Corporate Compliance Officer. Previously, Dr. Bonanni held various management positions at Baxter International, Inc. from 1974 to 1999, including positions as Corporate Vice President, Regulatory and Clinical Affairs and Corporate Vice President, Quality System.

 

Mr. Robert A. Bradway, age 48, became President and Chief Operating Officer of Amgen in May 2010. Mr. Bradway joined the Company in 2006 as Vice President, Operations Strategy and served as Executive Vice President and Chief Financial Officer from April 2007 to May 2010. Prior to joining the Company, he was a Managing Director at Morgan Stanley in London where he had responsibility for the firm’s banking department and corporate finance activities in Europe. Mr. Bradway joined Morgan Stanley in New York as a health care industry investment banker in 1985 and moved to London in 1990 where he served as head of the firm’s international health care investment banking activities until assuming broader corporate finance management responsibilities.

Mr. Brian McNamee, age 54, became Senior Vice President, Human Resources in June 2001. From November 1999 to June 2001, Mr. McNamee served as Vice President of Human Resources at Dell Computer Corp. From 1998 to 1999, Mr. McNamee served as Senior Vice President, Human Resources for the National Broadcasting Corporation, a division of GE. From July 1988 to November 1999, Mr. McNamee held human resource positions at GE.

 

Mr. Jonathan M. Peacock, age 52, became Executive Vice President and Chief Financial Officer in September 2010. Prior to joining Amgen, Mr. Peacock served as Chief Financial and Administration Officer of Novartis Pharmaceuticals AG beginning in 2005. From 1998 to 2005, Mr. Peacock was a partner at McKinsey and Co., where he co-led the European Corporate Finance Practice. Mr. Peacock was also a partner at Price Waterhouse in London and New York from 1993 to 1998.

 

Dr. Roger M. Perlmutter, age 58, became Executive Vice President, Research and Development in January 2001. From July 1999 to December 2000, Dr. Perlmutter was Executive Vice President, Worldwide Basic Research and Preclinical Development of Merck Research Laboratories. From February 1999 to July 1999, Dr. Perlmutter served as Executive Vice President of Merck Research Laboratories, and from February 1997 to January 1999, as Senior Vice President of Merck Research Laboratories. From May 1989 to January 1997, Dr. Perlmutter was also Chairman of the Department of Immunology, University of Washington, and from January 1991 to January 1997, Professor in the Departments of Immunology, Biochemistry and Medicine, University of Washington. From July 1984 to January 1997, Dr. Perlmutter served as Investigator at the Howard Hughes Medical Institute at the University of Washington. Dr. Perlmutter currently serves on the Board of Directors of StemCells, Inc.

 

Ms. Anna S. Richo, age 50, became Senior Vice President and Chief Compliance Officer in June 2008. From December 2003 to June 2008, Ms. Richo served as Vice President, Law. Prior to Amgen, she spent 12 years at Baxter Healthcare Corporation in roles of increasing responsibility in law, including Vice President, Law, for Baxter’s BioScience Division. Also, for more than five years, Ms. Richo served on the Board of Directors of Cytyc Corporation and was a member of the Audit and Finance Committees.

 

Mr. David J. Scott, age 58, became Senior Vice President, General Counsel and Secretary in March 2004. From May 1999 to February 2004, Mr. Scott served as Senior Vice President and General Counsel of Medtronic, Inc. and also as Secretary from January 2000. From December 1997 to April 1999, Mr. Scott served as General Counsel of London-based United Distillers & Vintners. Mr. Scott also served in executive roles at Grand Metropolitan plc and RJR Nabisco, Inc., and was an attorney in private practice.

 

Geographic Area Financial Information

 

For financial information concerning the geographic areas in which we operate, see Note 20, Segment information — Geographic information to the Consolidated Financial Statements.

 

Investor Information

 

Financial and other information about us is available on our website (http://www.amgen.com) (This website address is not intended to function as a hyperlink, and the information contained in our website is not intended to be a part of this filing). We make available on our website, free of charge, copies of our annual report on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act as soon as reasonably practicable after filing or submitting such material electronically or otherwise furnishing it to the SEC. In addition, we have previously filed registration statements and other documents with the SEC. Any document we file may be inspected, without charge, at the SEC’s public reference room at 100 F Street NE, Washington, D.C. 20549 or at the SEC’s internet address at http://www.sec.gov (This website address is not intended to function as a hyperlink, and the information contained in the SEC’s website is not intended to be a part of this filing). Information related to the operation of the SEC’s public reference room may be obtained by calling the SEC at 1-800-SEC-0330.

 

This report and other documents we file with the SEC contain forward looking statements that are based on current expectations, estimates, forecasts and projections about us, our future performance, our business or others on our behalf, our beliefs and our management’s assumptions. These statements are not guarantees of future performance and involve certain risks, uncertainties and assumptions that are difficult to predict. You should carefully consider the risks and uncertainties facing our business. The risks described below are not the only ones facing us. Our business is also subject to the risks that affect many other companies, such as employment relations, general economic conditions, geopolitical events and international operations. Further, additional risks not currently known to us or that we currently believe are immaterial also may impair our business, operations, liquidity and stock price materially and adversely.

 

Our sales depend on coverage and reimbursement from third-party payers.

 

Sales of all of our principal products are dependent on the availability and extent of coverage and reimbursement from third-party payers, including government healthcare programs and private insurance plans. Governments and private payers may regulate prices, reimbursement levels and/or access to our products to control costs or to affect levels of use of our products. We rely in large part on the reimbursement of our principal products through government programs such as Medicare and Medicaid in the United States and similar programs in foreign countries and a reduction in the coverage and/or reimbursement for our products could have a material adverse effect on our product sales and results of operations.

 

The government-sponsored healthcare systems in Europe and many other foreign countries are the primary payers for healthcare expenditures, including payment for drugs and biologics, in those regions. While mandatory price reductions have been a recurring aspect of business for the pharmaceutical and biotechnology industries in Europe, given the current worldwide economic conditions, certain European country governments have increased the frequency and size of such mandatory price reductions to extract further cost savings. For example, in 2010 countries such as Greece announced price reductions and/or mandated rebates for certain pharmaceutical and biological products that substantially exceeded prior levels. We expect that other countries may follow and/or take similar or more extensive actions to reduce expenditure on drugs and biologics, including mandatory price reductions, preference for biosimilar products or reduction in the amount of reimbursement. While we cannot fully predict the extent of further price reductions by countries in Europe or the impact such price reductions will have on our business, such reductions in price and/or the coverage and reimbursement for our products in European countries could have a material adverse effect on our product sales and results of operations.

 

In March 2010 the United States adopted significant healthcare reform through the enactment of the PPACA and the Heathcare and Education Reconciliation Act. (See Reimbursement — U.S. Healthcare Reform.) A major goal of the new healthcare reform law is to provide greater access to healthcare coverage for more Americans. Accordingly, the new healthcare reform law requires individual U.S. citizens and legal residents to maintain qualifying health coverage, imposes certain requirements on employers with respect to offering health coverage to employees, amends insurance regulations regarding when coverage can be provided and denied to individuals, and expands existing government healthcare coverage programs to more individuals in more situations, with most of these changes going into effect in January 2014. We do not expect a significant increase in sales of our products as a result of the 2014 expansions in healthcare coverage. The new healthcare reform law does have several components, with varied implementation dates that began in 2010, that have and are expected to continue to adversely impact our business. While we cannot fully predict the ultimate impact the new healthcare reform law will have on us, we expect that the new law will continue to have a material adverse effect on our business and results of operations.

 

Public and private insurers have pursued, and continue to pursue, aggressive cost containment initiatives, including increased focus on comparing the effectiveness, benefits and costs of similar treatments, which could result in lower reimbursement rates for our products. A substantial portion of our U.S. business relies on reimbursement under Medicare Part B coverage. Any deterioration in the timeliness or certainty of payment from CMS to physicians, including as a result of changes in policy or regulations, or as a result of operational difficulties, could negatively impact the willingness of physicians to prescribe our products for patients relying on

Medicare for their medical coverage. Most of our products furnished to Medicare beneficiaries in both a physician office setting and hospital outpatient setting are reimbursed under the ASP payment methodology. ASP-based reimbursements of products under Medicare may be below or could fall below the cost that some medical providers pay for such products, which would adversely affect sales of our products. We also face certain risks relating to the calculation of ASP. ASP is calculated by the manufacturer based on a statutorily defined formula and submitted to CMS. However, the statute, regulations and CMS guidance do not define specific methodologies for all aspects of the calculation of ASP. For example, in the Medicare Physician Fee Schedule Final Rule for 2011, CMS did not address a proposed methodology for treatment of bundled price concessions. Consequently, the current CMS guidance is that manufacturers may make “reasonable assumptions” in their calculation of ASP consistent with the general requirements and the intent of the Medicare statute, federal regulations and their customary business practices. As a result, we are required to apply our judgment in certain aspects of calculating ASP which are disclosed to CMS and also are subject to further CMS review. If our calculation of ASP is incorrect, we could be subject to substantial fines and penalties which could have a material adverse impact on our results of operations. Additionally, we are required to pay rebates to the federal government on products reimbursed by Medicaid at a rate of 23.1% of the average manufacturers price (“AMP”) of a product, or if it is greater, the difference between the AMP and the best price available to any non-government customer. The definition of AMP recently changed and we expect CMS to shortly issue a proposed rule further defining the new AMP definition. Until that rule is issued, we will be required to apply our judgment in certain aspects of the AMP calculation. Once the CMS rule is issued, we will have to determine whether our interpretation of AMP follows the rule or would need to be restated and this could have a material adverse impact on our business and results of operations.

 

Other initiatives reviewing the coverage or reimbursement of our products could result in less extensive coverage or lower reimbursement rates. For example, in July 2007, CMS issued an NCD where it determined that ESA treatment was not reasonable and necessary for certain clinical conditions and established Medicare coverage parameters for FDA-approved ESA use in oncology. Generally, an NCD is a national policy statement granting, limiting or excluding Medicare coverage or reimbursement for a specific medical item or service. We believe the restrictions in the 2007 NCD changed the way ESAs are used in clinical practice, for example, by decreasing the number of treated patients, the average ESA dose and the duration of ESA therapy in the oncology setting. As a result, we believe these restrictions have had a material adverse effect on the use, reimbursement and sales of Aranesp^®, which has had a significant impact to our business.

 

The reimbursement of ESAs in the nephrology setting is also receiving attention. On March 24, 2010, CMS held a MEDCAC meeting to examine the currently available evidence on the use of ESAs to manage anemia in patients who have CKD and on June 16, 2010, CMS opened an NCA to examine the use of ESAs to manage anemia in patients with CKD and dialysis-related anemia. This NCA initiates the process of reviewing and evaluating potential changes in Medicare coverage policies for the use of ESAs in those patients and may result in the issuance of a new NCD by CMS. The 30-day public comment period on the NCA ended on July 17, 2010 and CMS has stated that the NCA process for ESAs will conclude on or before June 16, 2011, but CMS could propose a new NCD at any time prior to that deadline. Additionally, on January 19, 2011, CMS held another MEDCAC meeting, this time to review the available evidence on the impact of ESA use on renal transplant graft survival. This development continues CMS’s process of reviewing and evaluating potential changes in Medicare coverage policies for the use of ESAs in patients with CKD. We cannot predict if and when a new NCD will be issued or the details of any potentially changed coverage decisions for the use of ESAs in patients with CKD, including whether or how a new NCD could change CMS’s bundled payment system and/or the ESRD QIP. However, similar to the impact of the 2007 NCD on the use of ESAs in oncology, a new NCD around the use of ESAs to manage anemia in patients with CKD and dialysis-related anemia may negatively affect use, coverage and reimbursement, and/or product sales of our ESA products in the nephrology setting, which could have a material adverse effect on our business and results of operations.

 

Further, the list of potential future NCDs issued by CMS in late 2008 included the category of thrombopoiesis stimulating agents (platelet growth factors), the category of drugs that includes Nplate^®, and a discussion on bisphosphonates used to treat osteoporosis. CMS has not announced whether it will proceed with an NCA related to

thrombopoiesis stimulating agents and, while Prolia^® is not a bisphosphonate, there is the possibility that CMS might evaluate other agents, including RANK Ligand inhibitors such as Prolia^® and XGEVA^tm.

 

In the dialysis setting, the reimbursement rates for our products are also subject to downward pressure. In the United States, dialysis providers are reimbursed for EPOGEN^® primarily by the federal government through the ESRD Program of Medicare. The ESRD Program reimburses approved dialysis providers for 80% of allowed dialysis costs while the remainder is paid by other sources, including patients, state Medicaid programs, private insurance and, to a lesser extent, state kidney patient programs. The ESRD Program reimbursement methodology is established by federal law and is implemented by CMS. Until January 1, 2011, Medicare reimbursed for separately billable dialysis drugs (including EPOGEN^® and Aranesp^®) administered in both freestanding and hospital-based dialysis centers at ASP+6%, using the same payment amount methodology used in the physician clinic setting under Part B. On January 1, 2011, CMS’s bundled payment system went into effect for dialysis facilities which provides a single payment for all dialysis services including drugs, supplies, and non-routine laboratory tests that were previously reimbursed separately. (See Reimbursement — Reimbursement of Our Principal Products — Dialysis Reimbursement.) Dialysis providers were given the choice of opting into the new bundled payment system in its entirety on January 1, 2011, or phasing in ratably over a four-year period beginning in 2011. Substantially all dialysis providers in the United States have opted into the bundled payment system in its entirety beginning in 2011. We expect that the implementation of the bundled payment system by ESRD facilities will have a material adverse impact on the reimbursement, use and sales of EPOGEN^® beginning in 2011, and Sensipar^® beginning in 2014.

 

Additional initiatives addressing the coverage or reimbursement of our products could result in less extensive coverage or lower reimbursement, which could negatively affect sales of our products. For example, since April 2006, the Medicare reimbursement for ESAs administered to dialysis patients has also been subject to an EMP, the Medicare payment review mechanism used by CMS to monitor EPOGEN^® and Aranesp^® utilization and hematocrit outcomes of dialysis patients. CMS revised the EMP, effective January 2008, further limiting reimbursement for EPOGEN^® and Aranesp^® in certain cases. Further reduction in reimbursement in the dialysis setting could have a material adverse effect on sales of EPOGEN^® and Aranesp^®, and our business.

 

If, for any of these or other reasons, reimbursement rates are reduced, or if healthcare providers anticipate reimbursement being reduced, providers may narrow the circumstances in which they prescribe or administer our products, which could reduce the use and/or sales of our products. A reduction in the use and sales of our products could have a material adverse effect on our business and our results of operations.

 

Our current products and products in development cannot be sold if we do not maintain or gain regulatory approval.

 

Our business is subject to extensive regulation by numerous state and federal governmental authorities in the United States, including the FDA, and by foreign regulatory authorities, including the EMA. We are required in the United States and in foreign countries to obtain approval from regulatory authorities before we can manufacture, market and sell our products. Once approved, the FDA and other U.S. and foreign regulatory agencies have substantial authority to require additional testing, change product labeling or mandate withdrawals of our products. Also, legislative bodies or regulatory agencies could enact new laws or regulations or change existing laws or regulations at any time, which could affect our ability to obtain or maintain approval of our products. For example, the 2007 creation of the FDAAA significantly added to the FDA’s authority, allowing the FDA to (i) require sponsors of marketed products to conduct post-approval clinical studies; (ii) mandate labeling changes to products and (iii) require sponsors to implement a REMS for a product. Failure to comply with FDAAA requirements could result in significant civil monetary penalties, reputational harm and increased product liability risk. Current policy discussions underway in the United States include debates about the implementation of the new, abbreviated pathway for biosimilars established under the new healthcare reform law; renegotiation of the Prescription Drug User Fee Act, which governs the user fees pharmaceutical and biological companies pay to the FDA that provide a substantial portion of the FDA’s operating budget, in anticipation of re-authorization before September 30, 2012; and reforms to the regulations that govern diagnostics and medical devices which are sometimes used in conjunction with our products. We are unable to predict when and whether any changes to laws or regulatory policies affecting our business could occur, and such changes could have a material adverse impact on our business.

Obtaining and maintaining regulatory approval has been and will continue to be increasingly difficult, time-consuming and costly. For example, in October 2009 we received Complete Response Letters from the FDA for the BLA for Prolia^® in the treatment and prevention of PMO and in the treatment and prevention of bone loss due to hormone ablation therapy (“HALT”) in breast and prostate cancer patients. The Complete Response Letter related to the PMO indication requested several items, including further information on the design and background adverse event rates to inform the methodology of our previously submitted post-marketing surveillance program. The FDA also requested a new clinical program to support the approval of Prolia^® for the prevention of PMO, updated safety data and stated that a REMS is necessary for Prolia^®. The Complete Response Letter related to the HALT indication requested additional information regarding the safety of Prolia^® in patients with breast cancer receiving aromatase inhibitor therapy and patients with prostate cancer receiving Androgen Deprivation Therapy. The FDA specifically requested results from additional adequate and well-controlled clinical trials demonstrating that Prolia^® has no detrimental effects on either time to disease progression or overall survival.

 

In addition, there may be situations in which demonstrating the efficacy and safety of a product candidate may not be sufficient to gain regulatory approval unless superiority to comparative products can be shown. Further some of our products are approved by U.S. and foreign regulatory authorities on a conditional basis with full approval conditioned upon fulfilling requirements of regulators. Vectibix^®, for example, received conditional approval in the United States and EU, with full approval conditioned on conducting additional clinical trials of the use of Vectibix^® as a therapy in treating mCRC. (See Marketed Products and Selected Product Candidates — Vectibix^® (panitumumab).) If we are unable to fulfill the requirements of regulators that were conditions of our products’ accelerated or conditional approval, we may not receive full approval for these products and may be required to change the products’ labeled indications or even withdraw the products from the market. Further, some of our products or product candidates may be used with a companion diagnostic product, such as a test kit, or companion device, such as an injector or other delivery system. These product candidates or expanded indications of our products may not be approved if the companion diagnostic product or companion device does not gain or maintain regulatory approval. These companion diagnostics and devices may be provided by single-source unaffiliated third-party companies. We are dependent on the sustained cooperation and effort of those third-party companies in conducting the studies required for such approval by the applicable regulatory agencies. Delays in the studies or failure of the third-party company to obtain regulatory approval of the companion diagnostic or device could negatively impact the approval of our product candidate or the expanded indication of our product and we may incur increased development costs, delays in regulatory approval and/or associated delays in a product candidate reaching the market or the expansion of existing product labels for new indications.

 

The occurrence of a number of high profile safety events has caused an increased public and governmental concern about potential safety issues relating to pharmaceutical and biological products and certain of our products and product candidates. (See Our ESA products continue to be under review and receive scrutiny by regulatory authorities.) As a result of this increased concern in recent years, the U.S. regulatory environment has evolved and safety signals and safety concerns resulting from clinical trials (including sub-analyses and meta-analyses), market use or other sources are receiving greater scrutiny. Actual or perceived safety problems could lead to revised or restrictive labeling of our approved products or a class of products, potentially including limitations on the use of approved products in certain patients because of:

 

 

 

For example, in December 2009, based on the TREAT results, we updated the boxed warning in the labeling information for ESAs, to reflect an increased risk of stroke when ESAs are administered to CRF patients to target Hb levels of 13 g/dL and above. In October 2010, we submitted additional proposed labeling changes regarding the use of ESAs in CRF patients not on dialysis that would limit treatment to patients who are most likely to benefit, specifically those with significant anemia (<10 g/dL), and who are at high risk for transfusion and for whom transfusion avoidance is considered clinically important, including those in whom it is important to preserve kidney transplant eligibility. We are working with the FDA to determine the appropriate use of ESAs in CKD patients and to determine any future ESA labeling changes required in connection with TREAT or the CRDAC meeting. (See Our ESA products continue to be under review and receive scrutiny by regulatory authorities.)

 

In addition to revised labeling for our products, discovery of new safety information or previously unknown safety concerns and/or safety signals with our products or similar products could also lead to:

 

 

Product safety concerns could cause regulatory agencies to impose risk management activities upon us (including a REMS), which may require substantial costs and resources to negotiate, develop, implement and administer. The results of these risk management activities could:

 

 

We currently have approved REMS for our ESAs, ENBREL, Prolia^® and Nplate^®, and we use third-party service providers to assist in the administration of our REMS that include elements to assure safe use. For example, our Nplate^® and ESA REMS each require applicable healthcare providers and institutions to enroll in the program, receive education about the product and the REMS and document and report certain information to us over time. We are responsible for tracking and documenting certain elements of healthcare provider and institution compliance with the Nplate^® and ESA REMS and providing the FDA with periodic assessment reports to demonstrate that the goals of the REMS are being met. If we or third-party service providers acting on our behalf fail to effectively implement and/or administer the REMS for our products, we may be required to modify such REMS, and we may be subject to FDA enforcement actions or to civil penalties.

 

Further, if new medical data or product quality issues suggest an unacceptable safety risk or previously unidentified side-effects, we may withdraw some or all affected product — either voluntarily or by regulatory

mandate — in certain therapeutic areas, or completely recall a product presentation from the market for some period or permanently. For example, in September 2009, we initiated a voluntary recall of a limited number of ENBREL SureClick^® lots due to a defect in the glass syringe barrel which resulted in a small number of broken syringes following assembly of the autoinjector device. In October 2010, we initiated a voluntary recall of certain lots of ENBREL due to identification of cracks in a small number of the glass syringes which may have resulted in product leakage and syringe breakage. Further, beginning in September 2010, we initiated a voluntary recall of certain lots of EPOGEN^® and J&J voluntarily recalled certain lots of PROCRIT^®, manufactured by us, because a small number of vials in each lot were found to contain glass lamellae (extremely thin, barely visible glass flakes) which we believed was a result of the interaction of the formulation with glass vials during the shelf life of the product. The recalls were executed in close collaboration with the FDA. We may experience the same or other problems in the future, resulting in broader product recalls, adverse event trends, delayed shipments, supply constraints, contract disputes and/or stock-outs of our products, which may adversely affect the sales of our products. Additionally, if other parties (including our independent clinical trial investigators or our licensees, such as J&J, Pfizer, Glaxo, Takeda and Daiichi Sankyo) report or fail to effectively report to regulatory agencies side effects or other safety concerns that occur from their use of our products in clinical trials or studies or from marketed use, resulting regulatory action could adversely affect the sales of our products and our business and results of operations.

 

If regulatory authorities determine that we have not complied with regulations in the R&D of a product candidate, a new indication for an existing product or information to support a current indication, they may not approve the product candidate or new indication or maintain approval of the current indication in its current form or at all, and we would not be able to market and sell it. If we were unable to market and sell our products or product candidates, our business and results of operations would be materially and adversely affected. Further, safety signals, trends, adverse events or results from clinical trials or studies performed by us or by others (including our licensees or independent investigators) from the marketed use of our drugs or similar products that result in revised safety-related labeling or restrictions on the use of our approved products could negatively impact healthcare provider prescribing behavior, use and sales of our products, regulatory or private health organization medical guidelines and reimbursement for our products all of which could have a material adverse effect on our business and results of operations.

 

Our ESA products continue to be under review and receive scrutiny by regulatory authorities.

 

Beginning in 2006, adverse safety results involving ESA products were observed and since that time our ESAs have been the subject of ongoing review and scrutiny by regulatory authorities and reimbursement agencies. In the United States, the FDA continues to review the benefit-risk profile of ESAs, which have resulted and could result in future changes to ESA labeling and usage. For example, we revised the labeling for our ESAs in August 2008, as the FDA directed. In addition, in July 2007 CMS issued an NCD for non-renal ESAs that determined that ESA treatment was not reasonable and necessary for certain clinical conditions, and established Medicare coverage parameters for FDA-approved ESA use in oncology. Since these labeling and reimbursement changes, we experienced a substantial reduction in our ESA sales, in particular Aranesp^® sales in the U.S. supportive cancer care setting. In October 2009, the results from TREAT, a phase 3 pivotal study of patients with CKD not on dialysis were published in the New England Journal of Medicine. The study failed to meet its primary objectives of demonstrating a reduction in all-cause mortality, cardiovascular morbidity, including heart failure, heart attack, stroke or hospitalization for myocardial ischemia, or time to ESRD. On December 16, 2009, based on the TREAT results, we updated the boxed warning in the labeling information for ESAs, to reflect an increased risk of stroke when ESAs are administered to CRF patients to target Hb levels of 13 g/dL and above. CMS held a MEDCAC meeting on March 24, 2010 to examine the currently available evidence on the use of ESAs to manage anemia in patients who have CKD, which considered the results from the TREAT study, and on June 16, 2010, CMS opened a new NCA to examine the use of ESAs to manage anemia in patients with CKD and dialysis-related anemia. On October 18, 2010 the FDA’s CRDAC discussed the results from the TREAT study conducted in patients not on dialysis, and how those results informed the appropriate use of ESAs in patients with CKD. Prior to the CRDAC meeting, we submitted proposed labeling changes regarding the use of ESAs in CRF patients not on dialysis that would limit treatment to patients who are most likely to benefit, specifically those with significant anemia (<10 g/dL), and who are at high risk for transfusion and for whom transfusion avoidance is

considered clinically important, including those in whom it is important to preserve kidney transplant eligibility. A variety of opinions regarding the appropriate use of ESAs in patients with CKD were offered at the CRDAC meeting by the various meeting participants. On January 19, 2011, CMS held another MEDCAC meeting, this time to review the available evidence on the impact of ESA use on renal transplant graft survival. (See Our sales depend on coverage and reimbursement from third-party payers.) We are working with the FDA to determine the appropriate use of ESAs in CKD patients and we continue to cooperate with CMS in determining appropriate reimbursement for our ESAs. Although we cannot predict what impact all of these activities (including the revised ESA labeling; any future ESA labeling changes required in connection with TREAT or the CRDAC meeting or from our ongoing discussions with the FDA regarding the conversion of the format of our ESA U.S. labels in accordance with the Physician’s Labeling Rule; the outcome from the NCA or MEDCAC meetings, including an NCD; and the impact of the approved REMS for ESAs) could have on our business, these activities could, individually or together, have a material adverse impact on the coverage, reimbursement, use and/or sales of our ESAs, which would have a material adverse effect on our business and results of operations. (See Our current products and products in development cannot be sold if we do not maintain or gain regulatory approval.)

 

We also have ongoing PMCs for our ESAs that must be conducted to maintain regulatory approval and marketing authorization. We have agreed with the FDA to a robust pharmacovigilance program to continue to study the safety surrounding the use of ESAs in the oncology setting and we initiated Study’782 as part of our Aranesp^® pharmacovigilance program, a phase 3 non-inferiority study evaluating overall survival when comparing NSCLC patients on Aranesp^® to patients receiving placebo. We continue to identify clinical sites for Study’782 and to enroll patients in the study. In addition, J&JPRD’s EPO-ANE-3010 study, which evaluates the use of Epoetin alfa in patients with breast cancer, is ongoing and is designated as an FDA PMC. Further, in 2008 the FDA and the EMA reviewed interim results from the Preoperative Epirubicin Paclitaxel Aranesp^® (“PREPARE”) study in neo-adjuvant breast cancer, a PMC study, which were ultimately incorporated into the ESA labeling in both the United States and the EU. We received the final results from the PREPARE study in 2009, which were substantially consistent with the interim results, and provided that data to the FDA and EMA. Although we cannot predict the results or the outcomes of ongoing clinical trials, or the extent to which regulatory authorities may require additional labeling changes as a result of these or other trials, we cannot exclude the possibility that adverse results from clinical trials, including PMCs, could have a material adverse impact on the reimbursement, use and sales of our ESAs, which would have a material adverse effect on our business and results of operations.

 

Regulatory authorities outside the United States have also reviewed and scrutinized the use of our ESA products. In June 2008, the EMA recommended updating the product information for ESAs with a new warning for their use in cancer patients, which was approved by the EC in October 2008. The product information for all ESAs was updated to advise that, in some clinical situations, blood transfusions should be the preferred treatment for the management of anemia in patients with cancer and that the decision to administer ESAs should be based on a benefit-risk assessment with the participation of the individual patient. Since the October 2008 revision, we have experienced a reduction of Aranesp^® sales in the supportive cancer care setting in the EU and, although we cannot predict what further impact the revised EU ESA product information could have on our business, the coverage, reimbursement, use and sales of Aranesp^® in Europe could further be materially adversely affected, which would have a material adverse effect on our business and results of operations.

 

Moreover, we continue to receive results from meta-analyses or previously initiated clinical trials using ESAs, including PMCs, and adverse results could negatively impact the use and sales of our ESAs. For example, in September 2008, we announced that we had received a summary of preliminary results from the Cochrane Collaboration’s independent meta-analysis of patient-level data from previously conducted, randomized, controlled, clinical studies evaluating ESAs in cancer patients which we submitted to the FDA and the EMA. This Cochrane meta-analysis of patient-level data from previous studies corroborates prior analyses indicating that the use of ESAs may increase the risk of death in cancer patients. The studies in the analysis all predate the current label, which advises using the least amount of ESA necessary to avoid transfusion but they do not exclude the potential for adverse outcomes when ESAs are prescribed according to the current label.

We must conduct clinical trials in humans before we can commercialize and sell any of our product candidates or existing products for new indications.

 

Before we can sell any products, we must conduct clinical trials to demonstrate that our product candidates are safe and effective for use in humans. The results of those clinical trials are used as the basis to obtain approval from regulatory authorities such as the FDA and EMA. (See Our current products and products in development cannot be sold if we do not maintain or gain regulatory approval.) We are required to conduct clinical trials using an appropriate number of trial sites and patients to support the product label claims. The length of time, number of trial sites and patients required for clinical trials vary substantially and therefore, we may spend several years and incur substantial expense in completing certain clinical trials. Delays in planned clinical trials can result in increased development costs, delays in regulatory approvals, associated delays in product candidates reaching the market and revisions to existing product labels. For example, in 2006 we delayed the start of our phase 3 trial in first-line NSCLC due to an increased frequency of cholecystitis (inflammation of the gall bladder) in patients treated with our late-stage product candidate motesanib. Following initiation of the trial in November 2008, enrollment in this phase 3 trial was temporarily suspended following a planned safety data review of 600 patients by the study’s independent DMC. In February 2009, the DMC recommended the trial resume enrollment of patients with non-squamous NSCLC only, and in June 2009, we reinitiated enrollment in this patient population following an FDA-approved revision to the study protocol.

 

In addition, in order to increase the number of patients available for enrollment for our clinical trials, we have and will continue to open clinical sites and enroll patients in a number of new geographic locations where our experience conducting clinical trials is more limited, including Russia, India, East Asia and some Central and South American countries either through utilization of third-party contract clinical trial providers entirely or in combination with local staff. Conducting clinical trials in locations where we have limited experience requires substantial time and resources to identify and understand the unique regulatory environments of individual countries. Further, we must ensure the timely production, distribution and delivery of the clinical supply of our product candidates to the numerous and varied clinical trial sites. If we fail to adequately manage the design, execution and regulatory aspects of our large, complex and regulatorily diverse clinical trials or manage the production or distribution of our clinical supply, corresponding regulatory approvals may be delayed or we may fail to gain approval for our product candidates or could lose our ability to market existing products in certain therapeutic areas or altogether. If we are unable to market and sell our product candidates or are unable to obtain approvals in the timeframe needed to execute our product strategies, our business and results of operations would be materially adversely affected. Additional information on our clinical trials can be found on our website at www.amgen.com. (This website address is not intended to function as a hyperlink, and the information contained on our website is not intended to be a part of this filing.)

 

Further, we rely on unaffiliated third-party vendors to perform certain aspects of our clinical trial operations. In the event that any of these vendors has unforeseen issues that negatively impact the quality of its work, our ability to evaluate clinical results may also be negatively impacted. As a result, this could adversely affect our ability to file for, gain or maintain regulatory approvals worldwide on a timely basis.

 

Patients may also suffer adverse medical events or side effects in the course of our, our licensees, partners or independent investigator’s clinical trials which could:

 

 

Clinical trials must be designed based on the current standard of medical care. However in certain diseases, such as cancer, the standard of care is evolving rapidly. In these diseases, the duration of time needed to complete certain clinical trials may result in the design of such clinical trials being based on an out of date standard of medical

care, limiting the utility and application of such trials. We may not obtain favorable clinical trial results and may not be able to obtain regulatory approval for new product candidates, new indications for existing products or maintenance of our current labels on this basis. Further, clinical trials conducted by others, including our licensees, partners or independent investigators, may result in unfavorable clinical trials results that may call into question the safety of our products in off-label or on label uses that may result in label restrictions and/or additional trials.

 

Even after a product is on the market, safety concerns may require additional or more extensive clinical trials as part of a pharmacovigilance program of our product or for approval of a new indication. For example, we have initiated Study’782 as part of our Aranesp^® pharmacovigilance program. (See Our ESA products continue to be under review and receive scrutiny by regulatory authorities.) Additional clinical trials we initiate, including those required by the FDA, could result in substantial additional expense and the outcomes could result in additional label restrictions or the loss of regulatory approval for an approved indication, each of which may have a material adverse effect on our business and results of operations. Additionally, any negative results from such trials could materially affect the extent of approvals, the use, reimbursement and sales of our products.

 

We expect to face increasing competition from biosimilar products which could impact our profitability.

 

We currently face competition in Europe from biosimilar products, and we expect to face increasing competition from biosimilars in the future. Lawmakers in the United States have recently enacted healthcare reform legislation which included an abbreviated regulatory pathway for the approval of biosimilars. The EU has already created such a regulatory pathway. To the extent that governments adopt more permissive approval frameworks and competitors are able to obtain broader marketing approval for biosimilars, our products will become subject to increased competition. Expiration or successful challenge of applicable patent rights could trigger such competition, and we could face more litigation regarding the validity and/or scope of our patents.

 

In the EU, the EC has granted marketing authorizations for several biosimilars pursuant to a set of general and product class-specific guidelines for biosimilar approvals issued over the past few years. In 2006, the EMA developed and issued final regulatory guidelines related to the development and approval of biosimilar products. The final guidelines included clinical trial guidance for certain biosimilar products, including erythropoietins and G-CSFs, recommending that applicants seeking approval of such biosimilar products conduct pharmacodynamic, toxicological and clinical safety studies as well as a pharmacovigilance program. Some companies have received and other companies are seeking approval to market erythropoietin and G-CSF biosimilars in the EU, presenting additional competition for our products. (See Our marketed products face substantial competition.) For example, following the expiration of the principal European patent relating to recombinant G-CSF in August 2006, the EC issued marketing authorizations for the first G-CSF biosimilar products and the products were launched in certain EU countries in 2008 and 2009. There are now several G-CSF biosimilars available in the EU marketed by different companies and these G-CSF biosimilar products compete with NEUPOGEN^® and Neulasta^®. Further, as in an effort to reduce costs, countries in the EU may in the future permit the automatic substitution by pharmacists of biosimilars for the corresponding innovator products. We cannot predict to what extent the entry of biosimilar products or other competing products will impact future sales of our products in the EU. Our inability to compete effectively could reduce sales, which could have a material adverse effect on our results of operations.

 

On March 23, 2010, President Obama signed into law the PPACA which authorized the FDA to approve biosimilar products under a new abbreviated pathway. The new law established a period of 12 years of data exclusivity for reference products in order to preserve incentives for future innovation and outlined statutory criteria for science-based biosimilar approval standards that take into account patient safety considerations. Under this framework, data exclusivity protects the data in the innovator’s regulatory application by prohibiting, for a period of 12 years, others from gaining FDA approval based in part on reliance or reference to the innovator’s data in their application to the FDA. The new law does not change the duration of patents granted on biologic products. As part of the implementation process, the FDA published several questions in the Federal Register for public comment. The FDA held a public meeting in November 2010 to seek stakeholder input on the subject and accepted written comments through 2010. The agency has the authority to approve biosimilar products but has not announced whether it will first publish guidance or rules for biosimilar applicants before approving biosimilar products. With the likely introduction of biosimilars in the United States, we expect in the future to face greater competition from

biosimilar products and downward pressure on our product prices, sales and revenues, subject to our ability to enforce our patents. Further, biosimilar manufacturers with approved products in Europe may seek to quickly obtain U.S. approval now that the regulatory pathway for biosimilars has been enacted. In addition, critics of the 12-year exclusivity period in the biosimilar pathway law will likely seek to shorten the data exclusivity period. President Obama’s proposed 2012 budget includes a proposal to lower the data exclusivity period to seven years, but this would require new legislation be passed by the Congress. Critics may also encourage the FDA to interpret narrowly the law’s provisions regarding which new products receive data exclusivity.

 

We may not be able to develop commercial products.

 

Successful product development in the biotechnology industry is highly uncertain, and very few R&D projects produce a commercial product. We intend to continue to make significant R&D investments. Product candidates or new indications for existing products (collectively, “product candidates”) that appear promising in the early phases of development may fail to reach the market for a number of reasons, such as:

 

 

For example, after discussions with the FDA we have decided not to file for approval of motesanib in refractory thyroid cancer until there is more clarity on what would constitute an appropriate regulatory filing package for that indication. Further, several of our product candidates have failed or been discontinued at various stages in the product development process. For example, in June 2004, we announced that the phase 2 study of Glial Cell Lined-Derived Neurotrophic Factor (“GDNF”) for the treatment of advanced Parkinson’s disease did not meet the primary study endpoint upon completion of nine months of the double-blind treatment phase of the study. The conclusion was reached even though a small phase 1 pilot investigator-initiated open-label study over a three-year period appeared to result in improvements for advanced Parkinson’s disease patients. Subsequently, we discontinued clinical development of GDNF in patients with advanced Parkinson’s disease.

 

Our marketed products face substantial competition.

 

We operate in a highly competitive environment. Our products compete with other products or treatments for diseases for which our products may be indicated. Our competitors market products or are actively engaged in R&D in areas where we have products, where we are developing product candidates or new indications for existing products. In the future, we expect that our products will compete with new drugs currently in development, drugs currently approved for other indications that may later be approved for the same indications as those of our products and drugs approved for other indications that are used off-label. Large pharmaceutical companies and generic manufacturers of pharmaceutical products are expanding into the biotechnology field with increasing frequency. These companies may have greater resources than we do. In addition, some of our competitors may have technical

or competitive advantages over us for the development of technologies and processes. These resources may make it difficult for us to compete with them to successfully discover, develop and market new products and for our current products to compete with new products or new product indications that these competitors may bring to market. As a result, our products may compete against products that have lower prices, equivalent or superior performance, better safety profile, are easier to administer or that are otherwise competitive with our products.

 

Concentration of sales at certain of our wholesaler distributors and consolidation of free-standing dialysis clinic businesses may negatively impact our bargaining power and profit margins.

 

The substantial majority of our U.S. product sales are made to three pharmaceutical product wholesaler distributors, AmerisourceBergen Corporation, Cardinal Health, Inc. and McKesson Corporation. These distributors, in turn, sell our products to their customers, which include physicians or their clinics, dialysis centers, hospitals and pharmacies. In addition, one of our products, EPOGEN^®, is sold primarily to free-standing dialysis clinics, which have experienced significant consolidation. Two organizations, DaVita Inc. and Fresenius North America own or manage a large number of the outpatient dialysis facilities located in the United States and account for a substantial majority of all EPOGEN^® sales in the free-standing dialysis clinic setting. Due to this concentration, these entities have substantial purchasing leverage, which may put pressure on our pricing by their potential ability to extract price discounts on our products or fees for other services, correspondingly negatively impacting our bargaining position and profit margins. In October 2006, we entered into a five-year sole sourcing and supply agreement with an affiliate of Fresenius North America, on its behalf and on behalf of certain of its affiliates, whereby they have agreed to purchase, and we have agreed to supply, all of Fresenius North America’s commercial requirements for ESAs for use in managing the anemia of its hemodialysis patients in the United States and Puerto Rico, based on forecasts provided by Fresenius North America and subject to the terms and conditions of the agreement.

 

We rely on third-party suppliers for certain of our raw materials, medical devices and components.

 

We rely on unaffiliated third-party suppliers for certain raw materials, medical devices and components necessary for the manufacturing of our commercial and clinical products. Certain of those raw materials, medical devices and components are the proprietary products of those unaffiliated third-party suppliers and are specifically cited in our drug application with regulatory agencies so that they must be obtained from that specific sole source or sources and could not be obtained from another supplier unless and until the regulatory agency approved such supplier.

 

Among the reasons we may be unable to obtain these raw materials, medical devices and components include:

 

 

These events could adversely affect our ability to satisfy demand for our products, which could adversely affect our product use, sales and operating results materially. For example, we have experienced shortages in certain components necessary for the formulation, fill and finish of certain of our products in our Puerto Rico facility without impact on our ability to supply these products. Further, quality issues which result in unexpected additional demand for certain components may lead to shortages of required raw materials or components (such as we have experienced with EPOGEN^® glass vials). We may experience or continue to experience these or other shortages in the future resulting in delayed shipments, supply constraints, contract disputes and/or stock-outs of our products.

Also, certain of the raw materials required in the commercial and clinical manufacturing of our products are sourced from other countries and/or derived from biological sources, including mammalian tissues. In addition, one of our marketed products also uses bovine serum and human serum albumin. Some countries in which we market our products may restrict the use of certain biologically derived substances in the manufacture of drugs. We continue to investigate alternatives to certain biological sources and alternative manufacturing processes that do not require the use of certain biologically derived substances because such raw materials may be subject to contamination and/or recall.

 

A material shortage, contamination, recall and/or restriction of the use of certain biologically derived substances or other raw materials, which may be sourced from other countries and that are used in the manufacture of our products could adversely impact or disrupt the commercial manufacturing of our products or could result in a mandated withdrawal of our products from the market. This could adversely affect our ability to satisfy demand for our products, which could adversely affect our product sales and operating results materially. Further, any disruptions or delays by us or by third-party suppliers or partners in converting to alternatives to certain biologically derived substances and alternative manufacturing processes or our ability to gain regulatory approval for the alternative materials and manufacturing processes could increase our associated costs or result in the recognition of an impairment in the carrying value of certain related assets, which could have a material and adverse affect on our results of operations.

 

Manufacturing difficulties, disruptions or delays could limit supply of our products and limit our product sales.

 

Manufacturing biologic human therapeutic products is difficult, complex and highly regulated. We currently manufacture all of our principal products and plan to manufacture many of our product candidates. In addition, we currently use third-party contract manufacturers to produce or assist in the production of ENBREL, Prolia^®, Sensipar^®/Mimpara^®, Nplate^® and XGEVA^tm and plan to use contract manufacturers to produce or assist in the production of a number of our late-stage product candidates. Our ability to adequately and timely manufacture and supply our products is dependent on the uninterrupted and efficient operation of our facilities and those of our third-party contract manufacturers, which may be impacted by:

 

 

If the efficient manufacture and supply of our products is interrupted, we may experience delayed shipments, supply constraints, stock-outs and/or recalls of our products. For example, over the past several years we have initiated a number of voluntary recalls of certain lots of our products. (See Our current products and products in development cannot be sold if we do not maintain or gain regulatory approval.) If we are at any time unable to provide an uninterrupted supply of our products to patients, we may lose patients and physicians may elect to prescribe competing therapeutics instead of our products, which could materially and adversely affect our product sales and results of operations.

Our manufacturing processes and those of our third-party contract manufacturers must undergo a potentially lengthy FDA or other regulatory approval process and are subject to continued review by the FDA and other regulatory authorities. It can take longer than five years to build, validate and license a new manufacturing plant and it can take longer than three years to qualify and license a new contract manufacturer. For example, in order to maintain supply and to satisfy anticipated future demand for denosumab, we are qualifying the expansion of our existing bulk protein facilities at our Puerto Rico site. In addition, we are completing the construction and qualification of a new formulation and filling facility at our Puerto Rico site in order mitigate the risk associated with the majority of our formulation and fill operations being performed in a single facility. Upon completion, these facilities will require licensure by the various regulatory authorities.

 

If regulatory authorities determine that we or our third-party contract manufacturers or certain of our third-party service providers have violated regulations or if they restrict, suspend or revoke our prior approvals, they could prohibit us from manufacturing our products or conducting clinical trials or selling our marketed products until we or the affected third-party contract manufacturers or third-party service providers comply, or indefinitely. Because our third-party contract manufacturers and certain of our third-party service providers are subject to the FDA and foreign regulatory authorities, alternative qualified third-party contract manufacturers and third-party service providers may not be available on a timely basis or at all. If we or our third-party contract manufacturers or third-party service providers cease or interrupt production or if our third-party contract manufacturers and third-party service providers fail to supply materials, products or services to us, we may experience delayed shipments, supply constraints, stock-outs and/or recalls of our products. Additionally, we distribute a substantial volume of our commercial products through a single distribution center in Louisville, Kentucky for the United States and another in Breda, the Netherlands for Europe and much of the rest of the world. We also conduct all the labeling and packaging of our products distributed in Europe and much of the rest of the world in Breda, the Netherlands. Our ability to timely supply products is dependent on the uninterrupted and efficient operations of our distribution and logistics centers, our third-party logistics providers and our labeling and packaging facility in Breda. Further, we rely on commercial transportation for the distribution of our products to our customers which may be negatively impacted by natural disasters, such as earthquakes or volcanic eruptions, or security threats.

 

We perform a substantial amount of our commercial manufacturing activities at our Puerto Rico manufacturing facility and a substantial amount of our clinical manufacturing activities at our Thousand Oaks, California manufacturing facility; if significant natural disasters or production failures occur at the Puerto Rico facility, we may not be able to supply these products or, at the Thousand Oaks facility, we may not be able to continue our clinical trials.

 

We currently perform all of the formulation, fill and finish for EPOGEN^®, Aranesp^®, Neulasta^®, NEUPOGEN^®, Prolia^® and XGEVA^tm and substantially all of the formulation, fill and finish operations for ENBREL, and all of the bulk manufacturing for Aranesp^®, Neulasta^®, and NEUPOGEN^® at our manufacturing facility in Juncos, Puerto Rico. In addition, we expect/plan to perform substantially all of the bulk manufacturing for Prolia^® and XGEVA^tm at the Puerto Rico facility once the facility has been approved by the FDA for that purpose. We also perform substantially all of the bulk manufacturing and formulation, fill and finish, and packaging for product candidates to be used in clinical trials at our manufacturing facility in Thousand Oaks, California. The global supply of our products and product candidates is significantly dependent on the uninterrupted and efficient operation of these facilities. A number of factors could adversely affect our operations, including:

 

 

 

In the past, the Puerto Rico facility has experienced manufacturing component shortages and there was evidence of adverse trends in the microbial bioburden of the production environment that reduced the production output. The same or other problems may result in our being unable to supply these products, which could adversely affect our product sales and operating results materially. Although we have obtained limited insurance to protect against certain business interruption losses, there can be no assurance that such coverage will be adequate or that such coverage will continue to remain available on acceptable terms, if at all. The extent of the coverage of our insurance could limit our ability to mitigate for lost sales and such losses could materially adversely affect our product sales and operating results. Our Puerto Rico facility is also subject to the same difficulties, disruptions or delays in manufacturing experienced in our other manufacturing facilities. For example, the limited number of lots of ENBREL and EPOGEN^® voluntarily recalled in 2009 and 2010 were manufactured at our Puerto Rico facility. In future inspections, our failure to adequately address the FDA’s expectations could lead to further inspections of the facility or regulatory actions. (See Manufacturing difficulties, disruptions or delays could limit supply of our products and limit our product sales.)

 

If our intellectual property positions are challenged, invalidated, circumvented or expire, or if we fail to prevail in present and future intellectual property litigation, our business could be adversely affected.

 

Our success depends in part on our ability to obtain and defend patent rights and other intellectual property rights that are important to the commercialization of our products and product candidates. The patent positions of pharmaceutical and biotechnology companies can be highly uncertain and often involve complex legal, scientific and factual questions. Third parties may challenge, invalidate or circumvent our patents and patent applications relating to our products, product candidates and technologies. In addition, our patent positions might not protect us against competitors with similar products or technologies because competing products or technologies may not infringe our patents. For certain of our product candidates, there are third parties who have patents or pending patent applications that they may claim necessitate payment of a royalty or prevent us from commercializing these product candidates in certain territories. Patent disputes are frequent, costly and can preclude, delay or increase the cost of commercialization of products. We are currently, and in the future may be, involved in patent litigation. (See Note 19, Contingencies and commitments in the notes to our consolidated financial statements in our annual report.) A patent dispute or litigation may not discourage a potential violator from bringing the product that is alleged to infringe to market prior to a final resolution of the dispute or litigation. For example, despite the ongoing litigation, Teva has stated that it intends to sell its filgrastim product, upon approval from the FDA, in the United States without a license from us and prior to the expiration of our G-CSF patents. The period of time from inception until resolution of a patent dispute or litigation is subject to the availability and schedule of the court, agency or tribunal before which the dispute or litigation is pending. We may be subject to competition during this period and may not be able to fully recover for the losses, damages, and harms we incur from infringement by the competitor product even if we prevail. Moreover, if we lose or settle current or future litigations at certain stages or entirely, we could be subject to competition and/or significant liabilities, be required to enter into third-party licenses for the infringed product or technology or be required to cease using the technology or product in dispute. In addition, we cannot guarantee that such licenses will be available on terms acceptable to us, or at all.

 

Further, under the Hatch-Waxman Act, products approved by the FDA under a NDA may be the subject of patent litigation with generic competitors before the five year period of data exclusivity provided for under the Hatch-Waxman Act has expired and prior to the expiration of the patents listed for the product.

 

Over the next several years, the existing patents on our principal products will begin to expire. (See Item 1. Business — Marketed Products.) As our patents expire, competitors may be able to legally produce and market similar products or technologies, including biosimilars, which may result in a reduction in the use and sales of our products. While we have, and we continue to seek, additional patent protection on certain of our products, including for specific processes for making our products, formulations and particular uses of our products, competitors may be able to design around or otherwise circumvent any such additional patents and sell competing products. Although we continue to develop and obtain patent protection for new product candidates, we may not be able to replace the revenue lost upon the expiration of the patents on our current products.

In recent years, policymakers have proposed reforming U.S. patent laws and regulations. For example, patent reform legislation was introduced in both the House and the Senate during the 111th Congress in 2009 but was not adopted into law. Legislation was again introduced in the Senate and passed the Senate Judiciary Committee on February 3, 2011. In general, the proposed legislation attempts to address issues surrounding the increase in patent litigation by, among other things, establishing new procedures for challenging patents. While we cannot predict what form any new patent reform laws or regulations may ultimately take, final legislation could introduce new substantive rules and procedures for challenging patents, and certain reforms that make it easier for competitors to challenge our patents could have a material adverse effect on our business.

 

Our business may be affected by litigation and government investigations.

 

We and certain of our subsidiaries are involved in legal proceedings. (See Note 19, Contingencies and commitments in the notes to our consolidated financial statements in our annual report.) Civil and criminal litigation is inherently unpredictable, and the outcome can result in excessive verdicts, fines, penalties, exclusion from the federal healthcare programs and/or injunctive relief that affect how we operate our business. Defense of litigation claims can be expensive, time-consuming and distracting and it is possible that we could incur judgments or enter into settlements of claims for monetary damages or change the way we operate our business, which could have a material adverse effect on our results of operations, financial position or cash flows. In addition, product liability is a major risk in testing and marketing biotechnology and pharmaceutical products. We may face substantial product liability exposure in human clinical trials and for products that we sell after regulatory approval. Product liability claims, regardless of their merits, could be costly and divert management’s attention, and adversely affect our reputation and the demand for our products. Amgen and Immunex have previously been named as defendants in product liability actions for certain of our products.

 

We are also involved in government investigations that arise in the ordinary course of our business. We have received subpoenas from a number of government entities, including the U.S. Attorney’s Offices for the Eastern District of New York and the Western District of Washington, as well as the Attorneys General of New York and New Jersey. The federal subpoenas have been issued pursuant to the Health Insurance Portability and Accountability Act of 1996 (18 U.S.C. 3486), and by a federal grand jury, while the Attorneys General subpoenas have been issued pursuant to state specific statutes relating to consumer fraud laws and state false claims acts. The government is allowed to use materials produced in response to a section 3486 administrative subpoena in both criminal and civil investigations. In general, the subpoenas request documents relating to the sales and marketing of our products, and our collection and dissemination of information reflecting clinical research as to the safety and efficacy of our ESAs. Based on representations in a U.S. government filing, that became public in May 2009 relating to the Massachusetts Qui Tam Action, we now believe the subpoenas we received from the U.S. Attorney’s Offices for the Eastern District of New York and the Western District of Washington also relate to nine additional Qui Tam Actions which are purportedly pending against Amgen, including eight pending in the U.S. District Court for the Eastern District of New York and one pending in the U.S. District Court for the Western District of Washington. The U.S. government filing further alleges that a large number of states are involved in the Qui Tam investigations, led by the State of New York. These investigations are represented to be joint criminal and civil investigations.

 

Throughout these investigations, and in litigation, the government entities are asserting that we violated various state and federal laws. These investigations are very burdensome, expensive and time-consuming for us to explain and defend to these entities. Although we cannot predict whether additional proceedings may be initiated against us, or predict when these matters may be resolved, it is not unusual for investigations such as these to continue for a considerable period of time and to require management’s attention and significant legal expense. A determination that we are in violation of the various federal and state laws that govern the sales and marketing of our products could result in federal criminal liability and/or federal or state civil or administrative liability, and thus could result in substantial financial damages or criminal penalties and possible exclusion from future participation in the Medicare and Medicaid programs. In addition, we may see new governmental investigations of or actions against us citing novel theories of recovery. Any of these results could have a material adverse effect on our results of operations, financial position or cash flows in the period in which such liabilities are incurred.

Our stock price is volatile.

 

Our stock price, like that of our peers in the biotechnology industry, is volatile. Our revenues and operating results may fluctuate from period to period for a number of reasons. Events such as a delay in product development or even a relatively small revenue shortfall may cause financial results for a period to be below our expectations or projections. As a result, our revenues and operating results and, in turn, our stock price may be subject to significant fluctuations.

 

The capital and credit markets may experience extreme volatility and disruption which may lead to uncertainty and liquidity issues for both borrowers and investors. Historically, we have occasionally and opportunistically accessed the capital markets to support certain business activities including acquisitions, in-licensing activities, share repurchases and to refinance existing debt. In the event of adverse capital and credit market conditions, we may not be able to obtain capital market financing on similar favorable terms, or at all, which could have a material adverse effect on our business and results of operations. Changes in credit ratings issued by nationally recognized credit rating agencies could adversely affect our cost of financing and have an adverse effect on the market price of our securities.

 

Current economic conditions may magnify certain risks that affect our business.

 

Our operations and performance have been, and may continue to be, affected by economic conditions. Sales of our principal products are dependent, in part, on the availability and extent of reimbursement from third-party payers, including government programs such as Medicare and Medicaid and private payer healthcare and insurance programs. (See Our sales depend on coverage and reimbursement from third-party payers.) In the United States, there is an increased focus from the federal government and others on analyzing the impact of various regulatory programs on the federal deficit, which could result in increased pressure on federal programs to reduce costs. Financial pressures may cause government or other third-party payers to more aggressively seek cost containment through mandatory discounts on our products, policies requiring the automatic substitution of biosimilar or generic products or other similar measures. (See We expect to face increasing competition from biosimilar products which could impact our profitability.) Additionally, as a result of the current global economic downturn, our third-party payers may delay or be unable to satisfy their reimbursement obligations. A reduction in the availability or extent of reimbursement from government and/or private payer healthcare programs or increased competition from lower cost biosimilar products could have a material adverse affect on the sales of our products, our business and results of operations.

 

We are exposed to sovereign risk in some European countries where we sell directly to public healthcare systems. Economic and fiscal conditions in these countries could affect the amount and timing of the collection of our receivables. For example, the government of Greece has issued one-, two- and three-year zero-coupon bonds to various pharmaceutical vendors in lieu of payment of past due receivables dating from 2007 to 2009.

 

In addition, as a result of the economic downturn, some employers may seek to reduce costs by reducing or eliminating employer group healthcare plans or transferring a greater portion of healthcare costs to their employees. Job losses or other economic hardships may also result in reduced levels of coverage for some individuals, potentially resulting in lower levels of healthcare coverage for themselves or their families. These economic conditions may affect patients’ ability to afford healthcare as a result of increased co-pay or deductible obligations, greater cost sensitivity to existing co-pay or deductible obligations, lost healthcare insurance coverage or for other reasons. We believe such conditions have led and could continue to lead to changes in patient behavior and spending patterns that negatively affect usage of certain of our products, including delaying treatment, rationing prescription medications, leaving prescriptions unfilled, reducing the frequency of visits to healthcare facilities, utilizing alternative therapies and/or foregoing healthcare insurance coverage. In addition to its effects on consumers, the economic downturn may have also increased cost sensitivities among medical providers in the United States, such as oncology clinics, particularly in circumstances where providers may experience challenges in the collection of patient co-pays or be forced to absorb treatment costs as a result of coverage decisions or reimbursement terms. Collectively, we believe these changes have resulted and may continue to result in reduced demand for our products, which could continue to adversely affect our business and results of operations. Any resulting decrease in demand

for our products could also cause us to experience excess inventory write-offs and/or excess capacity or impairment charges at certain of our manufacturing facilities.

 

Additionally, we rely upon third-parties for certain parts of our business, including licensees and partners, wholesale distributors of our products, contract clinical trial providers, contract manufacturers and single third-party suppliers. Because of the recent volatility in the financial markets, there may be a disruption or delay in the performance or satisfaction of commitments to us by these third-parties which could have a material adverse affect on our business and results of operations. Current economic conditions may adversely affect the ability of our distributors, customers and suppliers to obtain liquidity required to buy inventory or raw materials and to perform their obligations under agreements with us, which could disrupt our operations. Further, economic conditions appear to have affected, and may continue to affect, the business practices of our wholesale distributors in a manner that has and may continue to contribute to lower sales of our products. For example, in the first quarter of 2009, certain of our wholesale distributors lowered their levels of inventory on hand, which we believe was done to reduce their carrying costs and improve their results of operations. Although we monitor our distributors’, customers’ and suppliers’ financial condition and their liquidity in order to mitigate our business risks, some of our distributors, customers and suppliers may become insolvent, which could negatively impact our business and results of operations.

 

We maintain a significant portfolio of investments disclosed as cash equivalents and marketable securities on our Consolidated Balance Sheet. The value of our investments may be adversely affected by interest rate fluctuations, downgrades in credit ratings, illiquidity in the capital markets and other factors that may result in other than temporary declines in the value of our investments. Any of those events could cause us to record impairment charges with respect to our investment portfolio or to realize losses on the sale of investments.

 

Guidelines and recommendations published by various organizations can reduce the use of our products.

 

Government agencies promulgate regulations and guidelines directly applicable to us and to our products. However, professional societies, health technology assessment organizations, practice management groups, insurance carriers, physicians, private health/science foundations and organizations involved in various diseases from time to time may also publish guidelines or recommendations to healthcare providers, administrators and payers, and patient communities. Recommendations by government agencies or those other groups/organizations may relate to such matters as usage, dosage, route of administration and use of related therapies as well as reimbursement of our products by government and private payers. Recommendations or guidelines that are followed by patients, healthcare providers and payers could result in decreased use and/or dosage of our products. Some examples of agency and organizational guidelines include:

 

 

In addition, Health Technology Assessment organizations, such as NICE in the United Kingdom and the Canadian Agency for Drugs and Technologies in Health, make reimbursement recommendations to payers in their jurisdictions based on the clinical effectiveness, cost-effectiveness and service impact of new, emerging and existing medicines and treatments.

 

Any recommendations or guidelines that result in decreased use, dosage or reimbursement of our products could adversely affect our product sales and operating results materially. In addition, the perception by the investment community or stockholders that such recommendations or guidelines will result in decreased use and dosage of our products could adversely affect the market price for our common stock.

 

The commercialization of certain of our product candidates and the marketing of certain of our products is dependent in part on our partners.

 

We have entered into agreements with third parties to assist in the commercialization of certain of our product candidates and the marketing of certain of our products in specified geographic areas. (See Business Relationships.) Many of these agreements involve the sharing of certain decisions and a division of responsibilities, costs and benefits. If our partners fail to effectively deliver on their marketing and commercialization commitments to us or if we and our partners fail to coordinate our efforts effectively, sales of our products may be materially adversely affected.

 

Our corporate compliance and risk mitigation programs cannot guarantee that we are in compliance with all potentially applicable U.S. federal and state regulations and all potentially applicable foreign regulations and/or that we effectively manage all operational risks.

 

The development, manufacturing, distribution, pricing, sales, marketing and reimbursement of our products, together with our general operations, are subject to extensive federal and state regulation in the United States and to extensive regulation in foreign countries. (See Our current products and products in development cannot be sold if we do not maintain or gain regulatory approval and Manufacturing difficulties, disruptions or delays could limit supply of our products and limit our product sales.) While we have developed and instituted a corporate compliance program, we cannot guarantee that we, our employees, our consultants or our contractors are or will be in compliance with all potentially applicable U.S. federal and state regulations and/or laws or all potentially applicable foreign regulations and/or laws. If we or our agents fail to comply with any of those regulations and/or laws, a range of actions could result, including, but not limited to, the termination of clinical trials, the failure to approve a product candidate, restrictions on our products or manufacturing processes, withdrawal of our products from the market, significant fines, exclusion from government healthcare programs or other sanctions or litigation. Additionally, while we have implemented numerous risk mitigation measures, we cannot guarantee that we will be able to effectively mitigate all operational risks. If we fail to effectively mitigate all operational risks, our product supply may be materially adversely affected, which could have a material adverse effect on our product sales and results of operations.

 

Continual process improvement efforts may result in the carrying value of certain existing manufacturing facilities or other assets becoming impaired or other related charges being incurred

 

Our business continues to face many challenges. In response to these challenges, we have worked and continue to work to improve cost efficiencies and to reduce discretionary expenditures. As part of those efforts, we undertake continuous process improvement activities to evaluate our processes and procedures in order to identify opportunities for achieving greater efficiencies in how we conduct our business. In particular, we evaluate our manufacturing operations to identify opportunities to increase production yields and/or success rates as well as capacity utilization. Depending on the timing and outcomes of these process improvement initiatives, the carrying value of certain manufacturing or other assets may not be fully recoverable and could result in the recognition of impairment and/or other related charges. The recognition of such charges, if any, could have a material adverse affect on our results of operations.

The adoption of new tax legislation or exposure to additional tax liabilities could affect our profitability.

 

We are subject to income and other taxes in the United States and other jurisdictions in which we do business. Our provision for income taxes and results of operations in the future could be adversely affected by changes to our operating structure, changes in the mix of earnings in countries with differing statutory tax rates, changes in the valuation of deferred tax assets and liabilities, and changes in applicable tax laws. In addition, President Obama’s administration has announced proposals for U.S. tax legislation that, if adopted, could adversely affect our provision for income taxes. There are also other tax proposals that have been introduced, that are being considered, or that have been enacted by the U.S. Congress or the legislative bodies in foreign jurisdictions that could materially adversely affect our provision for income taxes, tax liabilities or our results of operations. For example, the Commonwealth of Puerto Rico recently enacted tax legislation effective on January 1, 2011 that, in certain circumstances, imposes a temporary excise tax for companies that purchase products from related Puerto Rico manufacturers.

 

Item 1B.  UNRESOLVED STAFF COMMENTS

 

None.

 

The following table summarizes our significant properties and their primary functions as of December 31, 2010. For additional information regarding manufacturing initiatives, see Item 1. Business — Manufacturing, Distribution and Raw Materials.

 

Our corporate headquarters are located in Thousand Oaks, California. In addition to the properties listed above, we have undeveloped land at certain U.S. locations, principally in Thousand Oaks, California; Longmont, Colorado; Louisville, Kentucky; Allentown, Pennsylvania; West Greenwich, Rhode Island; Seattle and Bothell, Washington; and in Juncos, Puerto Rico, to accommodate future expansion, as required. Excluded from the table above are leased properties that have been abandoned and certain buildings that we still own but are no longer used in our business. There are no material encumbrances on our properties.

 

We believe our facilities are suitable for their intended use and, in conjunction with our third-party contracting manufacturing agreements, provide adequate capacity. We also believe that our existing facilities, third-party contract manufacturing agreements and our anticipated additions are sufficient to meet our expected needs. (See Item 1A. Risk Factors — We perform a substantial amount of our commercial manufacturing activities at our Puerto Rico manufacturing facility and a substantial amount of our clinical manufacturing activities at our Thousand Oaks, California manufacturing facility; if significant natural disasters or production failures occur at the Puerto Rico facility, we may not be able to supply these products or, at the Thousand Oaks facility, we may not be able to continue our clinical trials, — We rely on third-party suppliers for certain of our raw materials, medical devices and components and — Manufacturing difficulties, disruptions or delays could limit supply of our products and limit our product sales.)

 

 

Certain of the legal proceedings in which we are involved are discussed in Note 19, Contingencies and commitments to our Consolidated Financial Statements in our 2010 Form 10-K and are hereby incorporated by reference.

 

PART II

 

 

Common stock

 

Our common stock trades on The NASDAQ Global Select Market under the symbol AMGN. As of February 11, 2011, there were approximately 10,156 holders of record of our common stock. No cash dividends have been paid on the common stock to date.

 

The following table sets forth, for the periods indicated, the range of high and low quarterly closing sales prices of the common stock as quoted on The NASDAQ Global Select Market:

 

Performance graph

 

The following graph shows the value of an investment of $100 on December 31, 2005 in each of Amgen common stock, the Amex Biotech Index, the Amex Pharmaceutical Index and Standard & Poor’s 500 Index (“S&P 500”). All values assume reinvestment of the pretax value of dividends paid by companies included in these indices and are calculated as of December 31 of each year. The historical stock price performance of the Company’s common stock shown in the performance graph is not necessarily indicative of future stock price performance.

 

Amgen vs. Amex Biotech, Amex Pharmaceutical and S&P 500 Indices
Comparison of Five-Year Cumulative Total Return
Value of Investment of $100 on December 31, 2005

 

 

 

The material in this performance graph is not soliciting material, is not deemed filed with the SEC, and is not incorporated by reference in any filing of the Company under the Securities Act or the Exchange Act, whether made on, before or after the date of this filing and irrespective of any general incorporation language in such filing.

Stock repurchase program

 

Repurchases under our stock repurchase program reflect, in part, our confidence in the long-term value of our common stock. Additionally, we believe it is an effective way of returning cash to our stockholders. The manner of purchases, the amount we spend and the number of shares repurchased will vary based on a number of factors including stock price, blackout periods in which we are restricted from repurchasing shares, and the impact of repurchases on our credit rating and may include private block purchases as well as market transactions.

 

During the three months ended December 31, 2010, we had one outstanding stock repurchase program. A summary of our repurchase activity for the three months ended December 31, 2010 is as follows:

 

 

 

 

In addition to the following notes, see Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations and the consolidated financial statements and accompanying notes and previously filed Form 10-K’s for further information regarding our consolidated results of operations and financial position for periods reported therein and for known factors that will impact comparability of future results.

 

 

Forward looking statements

 

This report and other documents we file with the SEC contain forward looking statements that are based on current expectations, estimates, forecasts and projections about us, our future performance, our business or others on our behalf, our beliefs and our management’s assumptions. In addition, we, or others on our behalf, may make forward looking statements in press releases or written statements, or in our communications and discussions with investors and analysts in the normal course of business through meetings, webcasts, phone calls and conference calls. Such words as “expect,” “anticipate,” “outlook,” “could,” “target,” “project,” “intend,” “plan,” “believe,” “seek,” “estimate,” “should,” “may,” “assume” and “continue,” as well as variations of such words and similar expressions are intended to identify such forward looking statements. These statements are not guarantees of future performance and involve certain risks, uncertainties and assumptions that are difficult to predict. We describe our respective risks, uncertainties and assumptions that could affect the outcome or results of operations in Item 1A. Risk Factors. We have based our forward looking statements on our management’s beliefs and assumptions based on information available to our management at the time the statements are made. We caution you that actual outcomes and results may differ materially from what is expressed, implied or forecast by our forward looking statements. Reference is made in particular to forward looking statements regarding product sales, regulatory activities, clinical trial results, reimbursement, expenses, earnings per share (“EPS”), liquidity and capital resources and trends. Except as required under the federal securities laws and the rules and regulations of the SEC, we do not have any intention or obligation to update publicly any forward looking statements after the distribution of this report, whether as a result of new information, future events, changes in assumptions or otherwise.

 

Overview

 

The following management’s discussion and analysis (“MD&A”) is intended to assist the reader in understanding Amgen’s business. MD&A is provided as a supplement to, and should be read in conjunction with, our consolidated financial statements and accompanying notes. Our results of operations discussed in MD&A are presented in conformity with accounting principles generally accepted in the United States (“GAAP”).

 

We are the largest independent biotechnology medicines company. We discover, develop, manufacture and market medicines for grievous illnesses. We concentrate on innovative novel medicines based on advances in cellular and molecular biology. Our mission is to serve patients. We operate in one business segment — human therapeutics. Therefore, our results of operations are discussed on a consolidated basis.

 

We earn revenues and income and generate cash primarily from sales of human therapeutic products in the areas of supportive cancer care, nephrology and inflammation. Our principal products include Aranesp^®, EPOGEN^®, Neulasta^®, NEUPOGEN^® and ENBREL, all of which are sold in the United States. ENBREL is marketed under a collaboration agreement with Pfizer in the United States and Canada. Our international product sales consist principally of European sales of Aranesp^®, Neulasta^® and NEUPOGEN^®. For additional information about our products, their approved indications and where they are marketed, see Item 1. Business — Marketed Products.

 

Throughout 2010 and early 2011, various developments occurred regarding our business, including regulatory and reimbursement developments associated with certain of our marketed products and product candidates. Most notably, the FDA approved Prolia^® and XGEVA^tm, and the EC granted marketing authorization for Prolia^® for certain indications. In addition, healthcare reform legislation was enacted in the United States. As a result of these and other developments, we have various opportunities to grow our business but will also continue to face various challenges. The following summarizes certain key opportunities and challenges.

 

We have various opportunities to grow our business. In the near term, we believe the currently approved indications for Prolia^® and XGEVA^tm represent significant commercial opportunities. In addition, receipt of regulatory approvals in new geographic territories or for additional indications for these products may also provide further significant opportunities. For example, the results of our recently announced phase 3 trial evaluating

XGEVA^tm versus placebo in men with castrate-resistant prostate cancer met its primary endpoint. This study will form the basis of planned marketing applications, which we expect to submit to regulatory authorities beginning in the first half of 2011, for the prevention of bone metastases in prostate cancer. Longer-term growth may also be achieved by the successful development of our late-stage pipeline and strategic business development opportunities, such as our recently announced agreement to acquire BioVex. In addition, longer-term growth may also be achieved by expansion into emerging markets and Japan.

 

Looking forward, we believe our products will continue to face various regulatory, reimbursement and competitive challenges. Our ESA products, in particular, have several near-term challenges that could result in further reductions in sales. For example, EPOGEN^® sales will be impacted by the Final Rule on Bundling in Dialysis that became effective in 2011. Further, the NCA opened by CMS in June 2010 and the results of the MEDCAC meetings held in March 2010 and January 2011 could lead to an NCD for the use of ESAs in patients with kidney disease, which could impact the use of or reimbursement for ESAs to manage anemia in patients with CKD and/or dialysis-related anemia. In addition, the FDA-approved REMS for ESAs may continue to impact Aranesp^® sales in the supportive cancer care setting. Future product label changes (including those we proposed prior to the 2010 CRDAC meeting, any others required in connection with TREAT or the CRDAC meeting and any from the PLR conversion process), may also impact the use of ESAs in CKD. Since we rely in large part on the reimbursement of our products through government programs such as Medicare and Medicaid, the recently enacted healthcare reform law has had and will continue to have a material adverse impact on sales of our products in the United States and on our results of operations. The provisions of the new legislation impacted our U.S. product sales by approximately $200 million in 2010, and we anticipate that our U.S. product sales in 2011 will be impacted by $250 million to $300 million. Furthermore, we estimate that our results of operations for 2011 will be impacted by an additional $150 million to $200 million related to a new fee on manufacturers and importers of “branded prescription drugs” established by that legislation, which is not deductible for U.S. federal income tax purposes. Certain of our products will also continue to face increasing competitive pressure, in particular ENBREL in the United States, as well as Aranesp^®, Neulasta^® and NEUPOGEN^® in Europe as a result of biosimilars. In addition, over the next several years, the existing patents on our principal products will begin to expire, and we expect to face increasing competition thereafter. (See Item 1. Business — Marketed Products.)

 

Certain of these developments are expected to have a material adverse impact on our sales and results of operations. However, these effects may be mitigated by certain of the opportunities we have to grow our business, discussed above, by other strategic initiatives or by increased efforts to manage our expenses.

 

Selected Financial Data

 

The following table presents selected financial data for the years ended December 31, 2010 and 2009 (amounts in millions, except percentages and per share data):

 

 

The following discusses certain key changes in our results of operations for the year ended December 31, 2010 as well as our financial condition as of December 31, 2010.

The increase in our U.S. product sales for 2010 reflects overall growth for all of our marketed products, except for our ESA products, which declined 5%. The growth in sales of our non-ESA products reflects increases primarily in average net sales prices and, to a lesser extent, favorable changes in wholesaler inventories. U.S. product sales in 2010 were unfavorably impacted by $198 million as a result of the recently enacted U.S. healthcare reform law.

 

The increase in our international product sales for 2010 reflects overall growth for all of our marketed products, except for Aranesp^®, which declined 1%.

 

The increase in other revenues for 2010 was due primarily to milestone payments earned from Glaxo in connection with certain commercial milestones for Prolia^® in the EU and from Takeda in connection with certain regulatory milestones for Vectibix^® in Japan.

 

The increase in operating expenses for 2010 was due principally to higher cost of sales, due primarily to higher bulk manufacturing costs, as well as higher selling, general and administrative (“SG&A”) expenses, due primarily to increased promotional costs for Prolia^® and our other marketed products.

 

Net income was relatively unchanged in 2010 as the increases in operating income, discussed above, and interest and other income were offset substantially by an increase in our provision for income taxes. The increase in interest and other income was due primarily to higher net realized gains on sales of investments and higher interest income. The increase in our provision for income taxes was due principally to reduced benefits resulting from settlements with tax authorities in 2010.

 

The increase in diluted EPS for 2010 principally reflects a reduction in our weighted-average shares used to compute diluted EPS resulting from our stock repurchase program, including approximately 67 million shares repurchased in 2010 at a total cost of $3.8 billion.

 

Although changes in foreign currency rates result in increases or decreases in our reported international product sales, the benefit or detriment that such movements have on our international product sales is offset partially by corresponding increases or decreases in our international operating expenses and our related foreign currency hedging activities. Our hedging activities seek to offset the impact, both positive and negative, that foreign currency exchange rate changes may have on our net income by hedging our net foreign currency exposure, primarily with respect to product sales denominated in the Euro.

 

As of December 31, 2010, our cash, cash equivalents and marketable securities totaled $17.4 billion, and total debt outstanding was $13.4 billion, including $2.5 billion which was repaid in February 2011. Of our total cash, cash equivalents and marketable securities balance as of December 31, 2010, approximately $15.1 billion was generated from operations in foreign tax jurisdictions and is intended to be invested indefinitely outside of the United States. Under current tax laws, if those funds were repatriated for use in our U.S. operations, we would be required to pay additional U.S. federal and state income taxes at the applicable marginal tax rates.

Results of Operations

 

Product sales

 

For the years ended December 31, 2010, 2009 and 2008, worldwide product sales and total product sales by geographic region were as follows (dollar amounts in millions):

 

 

Product sales are influenced by a number of factors, some of which may impact the sales of certain of our existing products more significantly than others, including, but not necessarily limited to:

 

 

 

 

 

Our U.S. product sales are also subject to certain other influences throughout the year, including wholesaler and end-user buying patterns (eg, holiday-driven wholesaler and end-user stocking, contract-driven buying and patients purchasing products later in the year after satisfying their annual insurance deductibles). Such factors can result in higher demand for our products and/or higher wholesaler inventory levels and, therefore, higher product sales for a given three-month period, generally followed by a reduction in demand and/or a drawdown in wholesaler inventories and a corresponding decline in product sales in the subsequent three-month period. For example, sales of our products in the United States for the three months ended March 31 have been slightly lower relative to the immediately preceding three-month period, which we believe to be due, in part, to certain of these factors. While this can result in variability in quarterly product sales on a sequential basis, these effects have generally not been significant when comparing product sales in the three months ended March 31 with product sales in the corresponding period of the prior year.

 

In addition, general economic conditions may affect, or in some cases amplify, certain of these factors with a corresponding impact on our product sales. (See Item 1. Business — Marketed Products for a discussion of our principal products and their approved indications.)

 

Aranesp^®

 

For the years ended December 31, 2010, 2009 and 2008, total Aranesp^® sales by geographic region were as follows (dollar amounts in millions):