Amgen 2012 Annual Report Download - page 45

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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. In 2012, new pharmacovigilance legislation became effective in the EU that enhanced the authority of European
regulatory authorities to require companies to conduct additional post-approval clinical efficacy and safety studies and increased
the burden on sponsor companies in terms of adverse event management and reporting and safety data analyses. As with FDAAA,
failure to comply with the new EU pharmacovigilance legislation could result in significant monetary penalties as well as
reputational and other harms. We are unable to predict when and whether any further changes to laws or regulatory policies
affecting our business could occur, such as efforts to reform medical device regulation or the pedigree requirements for medical
products or implement new requirements for combination products, and whether such changes could have a material adverse effect
on our business and results of operations.
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 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. Following the
submission of further information, including clinical trial data from a number of trials evaluating denosumab in various oncology
indications, in September 2011 the FDA approved Prolia® as a treatment to increase bone mass in women at high risk for fracture
receiving adjuvant aromatase inhibitor therapy for breast cancer and as a treatment to increase bone mass in men at high risk for
fracture receiving androgen deprivation therapy for non-metastatic prostate cancer. 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.
In addition to our innovative products, we are working to develop and commercialize biosimilar versions of six products
currently manufactured, marketed and sold by other pharmaceutical companies. (See Item 1. Research and Development and
Selected Product Candidates — Amgen Development of Biosimilars.) In many markets there is not yet a legislative or regulatory
pathway for the approval of biosimilars. In the United States, the U.S. healthcare reform law provided for such a pathway; while
the FDA is working to establish regulations to implement it, significant questions remain as to how products will be approved
under the pathway. (See We expect to face increasing competition from biosimilars.) Delays or uncertainties in the development
of such pathways could result in delays or difficulties in getting our products approved by regulatory authorities, subject us to
unanticipated development costs or otherwise reduce the value of the investments we have made in the biosimilars area.
Some of our products are approved by U.S. and foreign regulatory authorities on a conditional basis with full approval
conditioned upon fulfilling the requirements of regulators. Regulatory authorities are placing greater focus on monitoring products
originally approved on an accelerated or conditional basis and on whether the sponsors of such products have met the conditions
of the accelerated or conditional approvals. Vectibix®, for example, received accelerated approval in the United States and
conditional approval in the EU, with full approval conditioned on conducting additional clinical trials of the use of Vectibix® as
a therapy in treating mCRC. (See Item 1. Business — Marketed Products — Other Marketed Products — Vectibix® (panitumumab).)
If we are unable to fulfill the requirements of regulators that were conditions of our products' accelerated or conditional approval
and/or if regulators re-evaluate the data or risk-benefit profile of our product in connection with a renewal assessment, our
conditional approval may not be renewed or we may not receive full approval for these products or may be required to change the
products' labeled indications or even withdraw the products from the market.
Following recent FDA and FDA advisory committee discussions and actions with respect to other therapeutic oncology
products previously granted accelerated approval by the FDA, questions remain about regulatory authorities' views regarding the
adequacy for approval of therapeutic oncology products that have demonstrated a statistically significant improvement in
progression-free survival but have not shown a statistically significant improvement in overall survival. A number of our products
and product candidates have used endpoints other than overall survival, such as progression-free survival and bone-metastasis-
free survival (BMFS), in clinical trials. The use of endpoints such as progression-free survival or BMFS, in the absence of other
measures of clinical benefit, may not be sufficient for approval even when such results are statistically significant. For example,
our pivotal phase 3 Study '147 evaluated XGEVA® for its ability to improve BMFS in men with castration-resistant prostate cancer
that has not yet spread to bone. The '147 trial demonstrated that XGEVA® significantly improved median bone metastasis-free
survival by 4.2 months compared to placebo and significantly prolonged median time to first bone metastases. However, overall