Amgen 2012 Annual Report Download - page 46

39
survival (a secondary endpoint) was similar between the XGEVA® and placebo arms. On February 8, 2012, the FDA convened
the ODAC to discuss our sBLA filing for XGEVA® to delay bone metastases in prostate cancer. During its presentation to the
ODAC, the FDA questioned the magnitude of the improvement in BMFS demonstrated in Study '147, and indicated that a further
clinical trial might help address some of the remaining unresolved questions regarding the clinical significance of the benefit
achieved by XGEVA® in this setting. The ODAC panel concluded that the magnitude of benefit demonstrated with early treatment
with XGEVA® to delay bone metastases was not sufficient to conclude a positive risk-benefit ratio for XGEVA® in the absence
of additional measures impacting quality of life or other disease outcomes. On April 26, 2012, the FDA issued a Complete Response
Letter to us citing the same conclusion.
In addition to the clinical trials that we choose to or are required to conduct, other organizations may also conduct clinical
trials that use our products. Such clinical trials may evaluate our products in areas in which we do not have and are not seeking
an approved indication. However, negative results or safety signals arising in other organizations' clinical trials may nonetheless
prompt regulatory agencies to take regulatory actions that affect our approved indications, including requiring the addition of
relevant safety data to the approved labeling or even withdrawing approval for our products.
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 ESAs 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 preclinical data,
clinical trials (including sub-analyses and meta-analyses), market use or other sources are receiving greater scrutiny. For example,
a number of regulatory agencies around the world, including the FDA and the EMA, have initiated programs to directly monitor
for safety issues rather than wait for patients, providers or manufacturers to report safety problems with products or medical
devices. And at least one private, for-profit company has begun aggregating and analyzing FDA adverse event data on its website
using its own independent methodology, which could highlight new perceived risks of our products and product candidates. We
are required to communicate to regulatory agencies adverse events reported to us by patients taking our products. Regulatory
agencies may periodically perform inspections of our pharmacovigilance processes, including our adverse event reporting. If
regulatory agencies determine that we have not complied with the applicable reporting or other pharmacovigilance requirements,
we may become subject to additional inspections, warning letters or other enforcement actions, including monetary fines and other
penalties. Actual or perceived safety problems or signals 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:
• the identification of actual or theoretical safety or efficacy concerns with respect to any of our products by regulatory
agencies;
• an increased rate or number of previously-identified safety-related events;
• the discovery of significant problems or safety signals or trends with a similar product that implicates an entire class of
products;
• subsequent concerns about the sufficiency of the data or studies underlying the label or changes to the underlying safety/
efficacy analysis related to results from clinical trials, including sub-analyses, or meta-analysis (a meta-analysis is the
review of studies using various statistical methods to combine results from previous separate but related studies) of
clinical trials or clinical data performed by us or others; and
• new legislation or rules by regulatory agencies.
For example, in December 2009, based on the Trial to Reduce Cardiovascular Events with Aranesp® Therapy (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. In
June 2011, we announced that the FDA had approved further changes to the labels for the use of ESAs, including Aranesp® and
EPOGEN®, in patients with CKD. (With the June 2011 label changes, the FDA changed the term CRF to CKD in the ESA labels.
We use CRF when referring to labels prior to June 2011 for historical accuracy.) See Our ESAs continue to be under review and
receive scrutiny by regulatory authorities.