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U.S. Department of Health and Human Services

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Questions and Answers for Erythropoiesis-stimulating Agents (ESAs) Labeling Changes

TODAY’S ACTION

1. What action are you taking today? How does today’s action differ from the labeling changes announced in March? 

Today, FDA approved revised Boxed Warnings and other safety-related product labeling changes for erythropoiesis-stimulating agents (ESAs). There were also changes in the Indications and Usage section of the labeling to address quality of life claims and in the Dosage and Administration and Clinical Experience sections. The major changes are in four sections of labeling, including:

A.  BOXED WARNING

FDA revised the March 2007 boxed warning to address issues regarding ESA use by both patients with cancer and patients with chronic kidney failure.

For patients with cancer, the Boxed Warning now includes:

  • A list of cancers for which ESA dosing to try to achieve a hemoglobin of 12 g/dL or greater has resulted in more rapid cancer progression or shortened overall survival. These cancers are advanced breast, head and neck, lymphoid and non-small cell lung malignancies.
  • A statement that the risks of shortened survival and cancer progression have not been excluded in patients with cancer who are receiving chemotherapy when ESAs are dosed to try to achieve hemoglobin levels of less than 12 g/dL.
  • A warning that ESAs should only be used to treat anemia that occurs in patients with cancer while they are undergoing chemotherapy.  There are other potential underlying causes of anemia that can occur in patients with cancer, but ESAs are not intended to treat those.
  • Advice to stop using ESAs when chemotherapy treatment ends.

For patients with chronic kidney failure the Boxed Warning now includes:

  • A statement that there is a greater risk of death and serious cardiovascular events including heart attack, stroke and heart failure when ESAs are administered to attempt to achieve higher versus lower hemoglobin levels. One clinical trial compared 13.5 g/dL versus 11.3 g/dL, another compared 14 g/dL and 10 g/dL.
  • Advice that dosing should be individualized to achieve and maintain hemoglobin levels within the range of 10 g/dL to 12 g/dL.

B.  INDICATIONS SECTION

A statement was added to Indications stating that ESAs have not been shown in controlled trials (the type of studies that meet FDA’s standards for approval) to improve symptoms of anemia, quality of life, fatigue or patient well-being for patients with cancer or HIV undergoing AZT therapy.

A statement was added to the Indications that ESAs should not be used in patients with cancer unless they are receiving myelosuppressive chemotherapy (chemotherapy that causes very low blood counts).

C. CLINICAL EXPERIENCE SECTION

The Clinical Experience section of the labeling that describes studies of the use of Epogen and Procrit for the treatment of the anemia due to chronic kidney failure has been updated to clearly state its effects on improving exercise tolerance and functional ability. Other portions of this section pertaining to clinical outcomes such as happiness and well-being have been deleted
           

D. DOSAGE AND ADMINISTRATION SECTION

The label now includes specific instructions for doctors on dose adjustments and hemoglobin monitoring for patients with chronic kidney failure who do not respond to ESA treatment with an adequate increase in their hemoglobin levels.

 

2.  ESA labels were revised in March 2007.  Why is FDA revising the label again?

In March 2007, FDA approved revised ESA product labeling,  That revised labeling was intended to be an interim change pending recommendations from two FDA advisory committees.

The safety and efficacy of ESAs in patients with cancer were discussed at a May 2007 meeting of the Oncologic Drugs Advisory Committee.  The safety and efficacy of ESAs in patients with chronic kidney failure were discussed at a September 2007 joint meeting of the Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee.  Both committees recommended additional revisions to the ESA product labels.  Today’s changes incorporate the recommendations and discussions from the May and September advisory committee meetings.

 

3. Why is FDA acting now?

FDA has closely monitored emerging safety information since ESAs first came onto the market in the late 1980s, and especially since 1996.  Based on monitoring of the medical literature and public input from an Oncologic Drugs Advisory Committee in 2004, we requested post-marketing studies to address actual and potential safety concerns.  These included requests for post-marketing studies to assess risks of blood clots and effects on cancer. Many of those studies have only recently been completed and the data only recently available for FDA review.  Before the labeling changes announced today, the ESA product labeling underwent substantial revisions in 1997, 2004, 2005 and, March of 2007.

 

4.   The dosing recommendations are different for patients with cancer than they are for patients with chronic kidney failure. Why is this?

ESA therapy differs among patients depending upon the cause of the anemia, the duration of ESA use, and other considerations.  The anemia of chronic kidney failure is generally a life-long anemia that may require many blood transfusions while the anemia due to cancer chemotherapy may end once the chemotherapy is stopped.  As a result, ESAs are generally administered to patients with chronic kidney failure for many years while ESAs, if used to treat the anemia due to cancer chemotherapy, may be administered for only several weeks. 

 

PATIENTS WITH CANCER

5.  Given the concerns about the risks of more rapid tumor progression or shortened survival, why is FDA not removing all cancer indications from labeling?

ESA products do have an important supportive role in the treatment of patients with cancer who are undergoing chemotherapy.  There is no doubt that use of ESAs in that setting reduces the need for a blood transfusion.

The current labeling provides flexibility for patients and physicians to decide whether the use of an ESA is appropriate in each individual case. These considerations may include the type and anticipated duration of chemotherapy and its known effect on red blood cell production. Patients should discuss with their physicians the new information provided today before beginning or continuing ESA treatment.

 

6.  What studies have shown the risk of cancer progression and how do they compare to studies that have not shown this?

Six randomized, controlled studies, ranging in size from 70 to 989 patients, are cited in the new ESA labeling.  These studies are important because they are among the most rigorously designed studies to collect information regarding the safety of these products. Three of these six studies were originally designed to examine whether ESA use would improve tumor control or survival; the majority of these studies were restricted to a single cancer type, such as metastatic breast cancer.  Unfortunately, the studies showed that ESA use resulted in shorter survival or faster tumor growth.

There have been other attempts to assess the risk of tumor progression with ESAs.  For example, two groups, the Cochrane Collaborative and the Agency for Healthcare Research and Quality recently published meta-analyses (results from multiple studies combined into a single result) of ESA-treatment studies. The meta-analyses combined data from studies of many different cancers and included studies with inadequate follow-up for tumor growth or survival.  While meta-analyses are important contributions to scientific knowledge about drug risks in some settings, this analytic method can obscure safety signals, especially when meta-analyses combine data from different patient populations, cancer types and chemotherapy regimens.

There are other individual studies in the medical literature that have not shown an increased risk of cancer growth or decreased survival.  However, this does not mean that the risk did not exist in those studies.  In many cases, the studies were not conducted in a way that allows meaningful conclusions about the risk.

 

7. Was the risk of cancer growth with ESAs a concern at the time of their original approval?

When these drugs were approved, studies in the test tube (in vitro) and in animals did not suggest that ESAs cause faster tumor growth. However, because of the theoretical risk of tumor growth, at FDA’s request, Amgen conducted a post-marketing study to assess this risk in patients with small cell lung cancer. That study did not suggest there was a risk of tumor progression associated with ESAs, but the study was stopped early because of slow enrollment.  Subsequent studies in other cancers, however, began to identify the risk. These studies were conducted by a variety of investigators in Europe and more recently in the United States.

 

8.   Without any clinical information, why does the labeling mention possible risks of ESA dosing to achieve hemoglobin levels of less than 12 g/dL in the new boxed warning?

Studies have not been completed which characterize whether these risks are the same or lower than in studies with more aggressive ESA dosing.  Physicians should be aware that although studies showing increased risk of tumor growth and survival sought to dose patients with the goal of achieving higher hemoglobin levels above 12 g/dL, those levels were not necessarily reached for most of the patients.  This fact, plus the lack of a plausible reason why a higher hemoglobin level in and of itself might be associated with tumor growth, make it ill-advised to assume there is no risk when ESAs are administered to achieve hemoglobin levels below any specific mark.

 

MEDICARE COVERAGE

9. How does the new labeling differ from the Center for Medicare and Medicaid Services’s coverage policy for ESAs?

CMS coverage policy and product labeling have different purposes.  The product label provides the basis for information about how to use a product, independent of coverage decisions.  Nonetheless, the approved labeling for ESAs is generally consistent with Medicare’s current coverage policy.

 

QUALITY OF LIFE

10.  What were the specific "quality of life" claims in the ESA labels before?

ESA labeling has never included information or claims about quality of life with regard to patients with cancer.  Epogen and Procrit labeling contained quality of life claims related to chronic kidney failure, which was based on the original clinical trial in which patients reported improvement on measures including energy and activity level, functional ability, sleep and eating behavior, health status, satisfaction with health, sex life, well-being, psychological effect, life satisfaction and happiness. These claims were based on clinical data from studies conducted approximately 20 years ago, a time when the science related to assessments of quality of life was substantially less advanced than it is today.  This is the reason that these claims have been removed from labeling for Epogen and Procrit.

There were no quality of life claims for Aranesp in professional labeling, although the prior patient labeling described the symptoms of anemia, such as feeling tired or lacking energy. This description may have implied that the drug would improve these symptoms, which has not been shown.  The March 2007 label revisions eliminated these statements.  The changes in the newly revised labeling clarify this further by specifically stating that no quality of life benefit has been shown for ESAs being used as supportive care in patients with cancer undergoing chemotherapy or for patients with HIV.

 

11.  Isn't it reasonable to infer improved quality of life claims for the use of ESAs in cancer, since the company has shown Epogen/Procrit improves exercise tolerance and functional ability in patients with anemia due to chronic kidney failure?

The causes, consequences and manifestations of anemia are different for patients with chronic renal failure and patients with anemia due to cancer chemotherapy.  Clinical studies conducted among patients with anemia due to cancer chemotherapy have not tested whether these patients have improved in exercise tolerance or functional ability. Some studies have sought to determine whether these patients experience improved outcomes related to “quality of life,” but none have reliably demonstrated such improvement.

 

PATIENTS WITH CHRONIC KIDNEY DISEASE

12.  The new label states that the dose of ESAs used in the treatment of anemic patients with chronic kidney failure should be based upon maintaining a hemoglobin level within the range of 10 g/dL to 12 g/dL.  The previous label stated that prescribers should use the lowest ESA dose necessary to avoid a blood transfusion.  Why did the recommendations change?

The recommendation for use of ESAs to maintain hemoglobin levels within the range of 10 g/dL  to 12 g/dL is more precise and is based upon Advisory Committee discussions and studies that demonstrated clinical benefit associated with maintaining these levels -- such as avoidance of blood transfusion and improved exercise tolerance and physical functioning -- and the risks associated with maintaining higher hemoglobin levels. 

 

13. Why does the label state that patients are at higher risk for death and serious cardiovascular events such as heart attack, stroke and heart failure if they receive ESA doses that maintain hemoglobin levels higher than the recommended range of 10 g/dL to 12 g/dL range?

Patients experienced greater risks for death and serious cardiovascular events when administered ESAs in an attempt to achieve higher versus lower hemoglobin levels (13.5 g/dL vs 11.3 g/dL; 14 g/dL vs 10 g/dL) in two clinical studies.  Both studies showed increased risks for serious cardiovascular reactions (including death) among patients who were assigned to achieve higher hemoglobin levels.

 

14. Does the recommendation to maintain hemoglobin levels within the range of 10 g/dL to 12 g/dL only apply to anemic patients with chronic kidney failure or to other patients, such as patients with cancer who are anemic?

The recommendation to maintain a hemoglobin within the range of 10 g/dL to 12 g/dL only applies to patients with anemia due to chronic kidney failure, who typically require ongoing treatment over years with ESAs.  Well conducted clinical studies clearly show that these patients benefit from hemoglobin levels in this range.

For patients with anemia due to cancer chemotherapy, which is expected to last only a short period of time during and shortly after chemotherapy, we continue to recommend using the lowest ESA dose needed to avoid blood transfusion and not to exceed an upper safety limit of 12 g/dL. 

 

15. Why does the new label warn that anemic patients with chronic kidney failure who "have an insufficient hemoglobin response to ESA therapy" may have an "even greater risk for cardiovascular events and mortality than other patients"?

This statement mainly pertains to the results from two studies, one referred to as the “Normal Hematocrit” study and the other referred to as the “CHOIR” study. Both studies showed increased risks for serious cardiovascular reactions among patients who were assigned to achieve higher hemoglobin levels.  Both studies also showed even greater risks for patients who were assigned to achieve the higher hemoglobin levels and yet did not actually achieve these levels.  These patients, sometimes referred to as being "hypo-responsive" or poor responders to ESAs, appeared to have forms of anemia that were relatively resistant to ESA therapy, perhaps due to more severe underlying illness. 

These patients who appeared "hypo-responsive" also generally received higher ESA doses in order to try to achieve the desired hemoglobin level.   It is not known whether the higher ESA doses, underlying illness or other factors were responsible for the apparently greater risk for serious cardiovascular reactions observed among patients who are ESA "hypo-responsive.”

 

16.  Does the new label contain any information about how to identify and manage patients who receive ESAs and are "hypo-responsive"?

The new label contains three sections that apply to the use of ESAs among patients who are "hypo-responsive" to ESAs.

The Warnings section of the label notes that patients with chronic kidney failure and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular events and mortality than other patients.

The Precautions section of the label (in the "Lack or Loss of Response" portion) describes the procedures for identifying and evaluating patients whose hemoglobin level does not increase in response to ESA therapy or whose increased hemoglobin level is not maintained during ESA therapy.

The Dosage and Administration section of the label describes how ESA dosing should be individualized to maintain hemoglobin levels within the range of 10 g/dL to 12 g/dL.  This section also contains information to help identify patients with an inadequate hemoglobin response ("hypo-responsive") to ESA therapy and also includes specific directions for either adjusting or discontinuing the ESA dose. 

 

17.  The "Clinical Experience" section of the labeling, when describing studies of ESAs in chronic kidney disease, for epoetin alfa (Epogen and Procrit) appears to have been changed.  Why was this done?

The new label has been updated to provide clearer and more meaningful information about the clinical benefit of ESAs.  For example, the prior label described multiple outcomes (such as improved sleep and eating behavior, happiness, sex life, etc.) reported from patients who received Epogen and Procrit in a clinical study that was not designed sufficiently to evaluate these reports.  These unverifiable outcomes have been removed from the new label.

The new label describes a well designed clinical study that demonstrated improved exercise tolerance and physical functioning for anemic patients who received Epogen or Procrit. In this randomized, double-blinded clinical study, 118 anemic dialysis patients with an average hemoglobin level of approximately 7 g/dL were randomized to either Epogen or Procrit or placebo.  By the end of the 26 week study, the average hemoglobin had increased to approximately 11 g/dL in the group receiving Epogen or Procrit and the group had also experienced improved exercise tolerance and physical functioning. 

 

NEXT STEPS

18.  What happens next?

FDA is currently reviewing Medication Guides for ESAs.  These guides will replace   the current patient labeling to improve communication to patients on safe and effective use of ESAs. 

Additionally, clinical studies are planned or on-going to more thoroughly examine the safety of ESAs among patients with cancer and patients with chronic renal failure.

 

19. What are some of the on-going or planned studies for patients with anemia due to cancer chemotherapy?

 As discussed at the May 2007 ODAC meeting, there is an ongoing trial in women with advanced breast cancer.  The planned sample size is 1000 patients randomized to receive either an ESA to target a hemoglobin of 12 g/dL or to receive transfusion support.   In addition, several other trials of ESAs in specific tumor types are ongoing. The company and FDA have discussed other trials to evaluate the safety and efficacy when ESAs are used to achieve hemoglobin values < 12 g/dL.

 

20. What are some of the on-going or planned studies for patients with anemia due to chronic kidney failure?

Amgen is currently conducting an important clinical study (referred to as the TREAT study) that compares the use of an ESA to a placebo in patients who are not yet on dialysis.  This study is designed to provide important information regarding the safe use of ESAs, especially with respect to the hemoglobin goals of ESA therapy.

 

GENERAL INFORMATION

21.  What are ESAs and what are they used to treat?

Erythropoiesis stimulating agents (ESAs) are used to treat anemia. They are a bioengineered version of a natural protein that is made in the kidney. This protein stimulates the bone marrow to produce more red-blood cells. ESAs are currently approved for use in patients with chronic kidney disease, for certain cancer patients taking chemotherapy, for patients with HIV taking AZT therapy, and for anemic patients prior to elective surgery.

 

22. What products are covered by this labeling change?

The products include darbepoetin alfa and epoetin alfa. Darbepoetin alfa was originally approved on September 17, 2001 and is licensed and marketed by Amgen, Inc as Aranesp.  Epoetin alfa was originally approved on June 1, 1989 and is also licensed by Amgen, Inc.  It is marketed by Johnson and Johnson Pharmaceutical Research & Development LLC as Procrit and marketed by Amgen, Inc as Epogen.

The labeling changes apply to all ESAs because all of these products work by the same mechanism (increasing red blood cell production by stimulating the bone marrow cells that produce red blood cells).