DEPARTMENT OF HEALTH & HUMAN SERVICES 	 Office of Inspector General 
Washington, D.C.  20201 
NOV  5 2009 

TO: 	 Charlene Frizzera 
Acting Administrator 
Centers for Medicare & Medicaid Services 
Margaret A. Hamburg, M.D. 

Commissioner 

Food and Drug Administration 

FROM:  Stuart Wright 
Deputy Inspector General 
for Evaluation and Inspections 
SUBJECT: 	 Memorandum Report:  "Renal Dialysis Facilities' Dosage Protocols for 
Administering Erythropoiesis-Stimulating Agents," 0 EI -03 -09-000 10 
This memorandum report presents the results of our review to (1) determine the extent to which 
Medicare-certified dialysis facilities have protocols for administering erythropoiesis-stimulating 
agents (ESAs), (2) determine the extent to which facilities' protocols are consistent with the 
boxed warning and selected guidelines on ESAs' labels, and (3) determine the extent to which 
facilities' protocols conform with Medicare's benefit policy for ESAs and payment monitoring 
policy for ESA claims. 
While they are not required to do so, dialysis facilities may develop their own protocols for 
administering ESAs to patients with chronic kidney failure.  The protocols may define target 
hemoglobin levels and dosage instructions for administering ESAs.  When physicians approve 
the protocols for specific patients, the patients' target hemoglobin levels and ESA dosages are 
based on the protocols. 
According to the boxed warning on ESAs' labels, maintaining higher rather than lower 
hemoglobin levels in a patient with chronic kidney failure can adversely affect the patient's 
health and increase the risk of death.  Specifically, the boxed warning states that providers 
should administer ESAs "to achieve and maintain hemoglobin levels within the range of 
10 to 12 grams per deciliter (g/dL)."  The Medicare benefit policy for ESAs reflects the target 
hemoglobin range specified in the boxed warning.  A separate Medicare policy for monitoring 
ESA payments states that the Centers for Medicare & Medicaid Services (CMS) will reduce 
reported dosages upon which ESA claims are paid when patients' hemoglobin levels exceed 
13g/dL. 
OEI-03-09-00010  Renal Dialysis Facilities' Dosage Protocols for Administering ESAs  Page 2  Charlene Frizzera and Margaret A. Hamburg, M.D. 
 
We conducted this review in response to a request from Chairman Fortney Pete Stark of the 
Subcommittee on Health, Committee on Ways and Means, U.S. House of Representatives.  
Some members of Congress have raised concerns that dialysis facilities protocols for 
administering ESAs may not be consistent with the current boxed warning for these drugs. 
  
We found that most Medicare-certified dialysis facilities had protocols in place for administering 
ESAs, but only 56 percent of facilities protocols explicitly state a target hemoglobin range.  We 
could not determine whether the remaining 44 percent of protocols were consistent with the 
boxed warning and Medicares benefit policy because they do not specify a target hemoglobin 
range.  Of the protocols that state a target hemoglobin range, 94 percent are consistent with the 
boxed warning and the Medicare benefit policy for ESAs because the upper limit of the stated 
target range is equal to or less than 12 g/dL. 
 
In addition, our review of protocols to determine whether they are consistent with selected 
guidelines on ESAs labels revealed that some protocols contain information that differs from 
labeling guidelines regarding starting doses, dose adjustments, and withholding ESA doses.  
Finally, all of the protocols that include a target hemoglobin range or level at which to increase 
ESA doses conform with CMSs monitoring policy for ESA claims. 
 
BACKGROUND 
 
End Stage Renal Disease 
Chronic kidney failure is the gradual loss of kidney function.  When chronic kidney failure 
progresses, it may eventually lead to end stage renal disease (ESRD).  ESRD is a permanent 
kidney impairment that requires either a regular course of dialysis or a kidney transplant.  
Generally, patients with ESRD are entitled to Medicare benefits regardless of their age.1  CMS 
covers an estimated 400,000 beneficiaries with ESRD and spends about $8.1 billion annually for 
ESRD services, including dialysis and related supplies, equipment, and drugs.2 
 
According to the National Kidney Foundation, dialysis is a treatment for ESRD patients that 
functions in place of healthy kidneys.  Dialysis removes waste, salt, and extra water from the 
body; keeps a safe level of certain chemicals in the blood; and helps to control blood pressure.3  
Dialysis facilities provide outpatient dialysis to ESRD patients.  Dialysis facilities must be 
certified in order to receive Medicare reimbursement.4  A dialysis facility may be a freestanding 
unit or be located in a hospital.5  As of October 2008, there were 5,113 Medicare-certified 
                                                 
1 Section 226A of the Social Security Act; 42 CFR  406.13. 
2 Payment, Safety, and Quality Issues in Treatment of Patients With End-Stage Renal Disease:  Hearing Before 
U.S. House Committee on Ways and Means Subcommittee on Health, 109th Congress, 2007.  Statement of Leslie 
Norwalk, Acting Administrator, CMS. 
3 National Kidney Foundation, Dialysis.  Available online at http://www.kidney.org/atoz/atozItem.cfm?id=39.  
Accessed on May 11, 2009.  
4 42 CFR  405.2102 and 488.60. 
5 42 CFR  405.2102; CMS, Medicare Benefit Policy Manual, Pub. No. 100-02, ch. 11,  10.B. 
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dialysis facilities in the United States.  Eighty-one percent of these facilities (4,120) were        
for-profit entities, while 19 percent (993) were nonprofit entities. 
 
Anemia 
Nearly all patients with ESRD have anemia, which may begin to develop in the early stages of 
chronic kidney failure.  Healthy kidneys produce a hormone that stimulates bone marrow to 
produce the proper number of red blood cells.  Diseased kidneys often do not produce sufficient 
amounts of this hormone, which results in fewer red blood cells and the development of anemia.  
Tests that measure patients hemoglobin (a protein made by red blood cells) and hematocrit (the 
proportion of red blood cells in whole blood) can be used to monitor anemia. 
 
Erythropoeisis-Stimulating Agents  
ESAs are prescription drugs that increase the number of red blood cells in patients suffering from 
anemia.  For ESRD patients, ESAs are typically administered during dialysis treatments by 
intravenous or subcutaneous injection.  After an ESA dose is administered or a dose adjustment 
is made, it may take several weeks for a patients hemoglobin level to change significantly.  
Epoetin alfa (marketed under the names Epogen and Procrit) and darbepoetin alfa (marketed 
under the name Aranesp) are the two ESAs approved by FDA for the treatment of anemia 
associated with chronic kidney failure. 
 
ESAs are covered under the Medicare Part B benefit for ESRD patients.6  CMS currently pays 
dialysis facilities a composite rate for most dialysis services, including labor costs, related 
supplies, and certain drugs.7  However, the composite rate does not include ESAs and other 
specific drugs.  Dialysis facilities bill separately for these drugs.8 9  Payments for ESAs account 
for over 60 percent of separately billable drugs, and over 25 percent of total Medicare spending 
on ESRD services annually.10 
 
Protocols for Administering ESAs 
While not required, dialysis facilities may develop their own protocols for administering ESAs to 
ESRD patients.  The protocols may define target hemoglobin levels and dosage instructions for 
ESAs.  For dialysis facilities with protocols in place for administering ESAs, physicians may 
approve the protocols as patients standing orders. 
 
When physicians approve the protocols for specific patients, the patients target hemoglobin 
levels and ESA dosages are based on the protocols.  Anemia managers, frequently nurses 
                                                 
6 CMS, Medicare Benefit Policy Manual,  90. 
7 CMS, Medicare Benefit Policy Manual,  30. 
8 CMS, Medicare Claims Processing Manual, Pub. No. 100-04, ch. 8,  60.4 (epoetin alfa) and  60.7 (darbepoetin 
alfa). 
9 Pursuant to section 153(b) of the Medicare Improvements for Patients and Providers Act of 2008                      
(P.L. No. 110-275), CMS is required to implement a fully bundled payment system for ESRD services by January 1, 
2011.  The new bundled payment will include reimbursement for both ESAs and services currently included in the 
composite rate.   
10 Norwalk, loc. cit. 
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employed by dialysis facilities, oversee patients anemia management.  These practitioners may 
make dosage changes based on the protocols without new orders from physicians. 
 
For facilities with protocols, physicians may still choose not to approve the protocols and instead 
may write individual ESA orders for their patients.  For dialysis facilities that do not have 
protocols for administering ESAs, physicians must write individual orders for ESAs. 
 
FDAs Requirements for Labeling of ESAs 
FDA determines whether new drugs are safe, effective, and should be approved for marketing in 
the United States.  Once a drug is approved, FDA conducts postmarket surveillance and risk 
assessment to identify adverse reactions and safety risks that did not appear during clinical trials 
before drug approval. 
 
Clinical trials conducted after ESAs were approved have provided new safety information on the 
use of these drugs to treat anemia in patients with chronic kidney failure.  Results of studies 
conducted in 1996 and 2006 showed that patients with chronic kidney failure were at increased 
risk for serious cardiovascular complications when ESAs were administered to target higher, 
rather than lower, hemoglobin levels.  These complications included stroke, heart attack, heart 
failure, and death. 
 
FDAs Cardiovascular and Renal Drugs Advisory Committee and Drug Safety and Risk 
Management Advisory Committee met in September 2007 to discuss the risks and benefits of 
ESAs when used to treat anemia due to chronic kidney failure.11  Although the committees did 
not reach consensus in recommending a specific target hemoglobin level, many members at the 
meeting recommended a target range of 10 to 12 g/dL or a specific target within that range. 
 
Boxed Warning.  Based on the results of clinical trials and input from the FDA advisory 
committees, FDA required the manufacturer of ESAs to revise the labeling for ESAs and add a 
boxed warning.  The warning information is placed prominently at the top of the labeling and is 
enclosed in a box.  A boxed warning is the strongest warning for an FDA-approved product.  It is 
used to highlight warning information that is especially important to the prescriber, including an 
adverse reaction so serious in proportion to the potential benefit from the drug (e.g., a fatal,    
life-threatening, or permanently disabling adverse reaction) that it is essential that it be 
considered in assessing the risks and benefits of using a drug.  It is also used to highlight a 
serious adverse reaction that can be prevented or reduced in frequency or severity by appropriate 
use of the drug. 
 
The current boxed warning on ESA labels for patients with chronic kidney failure states: 
 
Patients experienced greater risks for death and serious cardiovascular events when 
administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower 
                                                 
11 FDA establishes advisory committees to obtain independent, expert advice on products regulated by FDA, 
including drugs.   
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hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies.  
Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 
12 g/dL.12 
 
The ESAs labels contain other information, including guidelines for selecting the starting dose 
and adjusting subsequent dosages for patients with chronic kidney failure. 
 
Medicare Policies for ESAs 
According to Chapter 11 of the Medicare Benefit Policy Manual, ESAs are covered under Part B 
for ESRD patients suffering from anemia.  The benefit policy states that ESRD patients who 
have been receiving [ESA] therapy should have a hematocrit between 30 and 36.  This 
hematocrit range is equivalent to a hemoglobin between 10 and 12 g/dL. 
 
Effective January 1, 2008, CMS modified its policy for monitoring ESA claims and payments in 
response to emerging scientific data and the boxed warning on ESAs labels.  Dialysis facilities 
are required to report patient hemoglobin or hematocrit levels on all ESA claims.13  CMSs 
monitoring policy is based on these reported hemoglobin or hematocrit levels and establishes a 
threshold at which CMS reduces the reported ESA dosage upon which an ESA claim is paid.14   
 
For all patients whose hemoglobin levels exceed 13 g/dL for less than 3 months and for whom a 
reduction in the ESA dosage has not been reported, CMS will pay only for a dosage which 
represents a 25-percent reduction of the dosage reported on the claim.15  For ESA claims with 
reported hemoglobin levels that exceed 13 g/dL for 3 or more consecutive months, CMS will pay 
for a dosage that represents a 50-percent reduction from the dosage reported on a claim.16 
 
METHODOLOGY 
 
Scope 
We reviewed current protocols for administering ESAs from a stratified random sample of 
Medicare-certified dialysis facilities.  We compared information contained in these protocols to 
(1) the boxed warning and selected dosage guidelines on ESAs labels, and (2) Medicares 
benefit policy for ESAs and monitoring policy for ESA claims.  We did not review Medicare 
claims for ESAs.  We did not collect ESRD patients records to review documentation, such as 
physician orders, that may support ESA claims. 
 
                                                 
12 FDA, Information on Erythropoeisis-Stimulating Agents Epoetin alfa (marketed as Procrit, Epogen) and 
Darbepoetin alfa (marketed as Aranesp).  Available online at 
http://www.fda.gov/cder/drug/infopage/RHE/default.htm.  Accessed on June 3, 2009. 
13 CMS, Medicare Claims Processing Manual,  60.4 (epoetin alfa) and 60.7 (darbepoetin alfa).  
14 Although CMSs monitoring policy refers to both hemoglobin and hematocrit levels, and each of these measures 
will be applied during the study as appropriate, hereinafter, we will refer only to hemoglobin levels. 
15 CMS, Medicare Claims Processing Manual, loc. cit. 
16 Ibid. 
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Sample Design 
We selected a stratified random sample of 400 dialysis facilities from CMSs October 2008 
Dialysis Facility Compare database, which contains all Medicare-certified dialysis facilities.17  
The total number of facilities in the sample was reduced from 400 to 399 because one facility 
responded that it is an inpatient hospital unit that does not provide outpatient dialysis services. 
 
As shown in Table 1, we stratified the population of dialysis facilities by profit status to ensure 
that our sample would contain a sufficient number of both for-profit and nonprofit facilities. 
 
Table 1:  Sample of Dialysis Facilities 
Facilities in  Facilities in  Responding 
Stratum  Description of Stratum 
Population  Sample  Facilities 
1  For-profit dialysis facilities                 4,120                   200                       190 
2  Nonprofit dialysis facilities                    993                   199                       176 
Total                 5,113                   399                       366 
Source:  Office of Inspector General (OIG) sample design and CMS Dialysis Facility Compare Database, October 2008. 
 
Data Collection 
We obtained business name and address information for each dialysis facility in the sample from 
the Dialysis Facility Compare database.  In January 2009, we requested by mail the sample 
facilities protocols for administering ESAs.  We asked all facilities to complete a one-page 
request form indicating whether they have a protocol in place and providing general information 
about the characteristics of the facility.  We received responses to our request from 366 of 399 
sample dialysis facilitiesa 92-percent response rate. 
 
Some facilities did not have protocols in place.  Fourteen facilities in our sample had more than 
one ESA protocol in place at the time of our request.  These 14 facilities submitted multiple 
protocols for administering ESAs.  For example, a facility may have a protocol in place for the 
administration of epoetin alfa, in addition to a separate protocol for the administration of 
darbepoetin alfa. 
 
We received a total of 357 protocols from the 366 responding facilities.  Eighty-four percent of 
protocols were specific to epoetin alfa and 16 percent were specific to darbepoetin alfa. 
 
We created a structured data collection instrument to guide our review of each ESA protocol we 
received from sample facilities.  We collected information on the type of ESA protocol, target 
hemoglobin levels presented in the protocol, and starting dose and dose adjustment information 
presented in the protocol. 
 
                                                 
17 Medicare Dialysis Facility Compare Database.  Available online at 
http://www.medicare.gov/Download/DownloadDB.asp.  Accessed on December 18, 2008.  
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Data Analysis 
We determined the number of dialysis facilities that have ESA protocols in place.  We analyzed 
the protocol review data to determine the percentage of protocols that are consistent with the 
boxed warning on ESA labels and the Medicare benefit policy for ESAs.  The boxed warning 
and benefit policy specify that the target hemoglobin level for patients with chronic kidney 
failure should be in the range of 10 to 12 g/dL.  We reviewed protocols to determine whether 
they specified an explicit target hemoglobin range.  Of protocols that specified an explicit target 
range, we considered those in which the upper limit of the range was equal to or less than         
12 g/dL to be consistent with both the boxed warning and the benefit policy.18  We used the 
upper limit of the target range to determine consistency because the boxed warning on ESA 
labels states that health risks increase with higher hemoglobin levels. 
 
We analyzed the protocol review data regarding starting doses and dose adjustments.19  We 
compared this information to selected dosage and administration guidelines on the               
FDA-approved labeling for ESAs.  The selected guidelines are presented in Table 2. 
 
Table 2:  Selected ESA Dosage and Administration Guidelines for Patients With Chronic 
Kidney Failure 
Starting Dose Guidelines 
Epoetin alfa starting dose for adults is 50 to 100 units per kilogram, 3 times per week. 
Darbepoetin alfa starting dose for adults is 0.45 micrograms per kilogram, weekly. 
Dose Adjustment Guidelines 
Increase epoetin alfa dose when hemoglobin level is less than 10 g/dL. 
Decrease epoetin alfa and darbepoetin alfa dose when hemoglobin approaches 12 g/dL. 
Withhold epoetin alfa and darbepoetin alfa dose when hemoglobin continues to rise after a dose decrease. 
Source:  Epogen, Procrit, and Aranesp labels, approved by FDA on November 19, 2008. 
 
We also determined whether dialysis facilities protocols conform with the hemoglobin threshold 
specified in CMSs monitoring policy for ESA claims.  We considered protocols with target 
hemoglobin levels that do not exceed 13 g/dL to conform with the monitoring policy.  In 
addition, we compared protocol review data regarding dose increases to the monitoring policy. 
 
Facilities that responded to our request for ESA protocols indicated their profit status, whether 
the facility is part of a chain, whether the facility is hospital-based or freestanding, and the size 
of the facility (number of dialysis stations).  We examined whether the percentage of protocols 
                                                 
18 Three protocols specified a single target hemoglobin level, rather than a target range.  We considered the target 
hemoglobin level to be the upper limit of the target range for these protocols. 
19 Some ESA protocols include starting dose information that we cannot compare to the guidelines on the ESAs 
labels.  Therefore, we did not include these protocols in our starting dose analysis.  For example, some protocols 
include starting dose amounts, but do not specify how many times per week the dose should be administered.   
OEI-03-09-00010       Renal Dialysis Facilities Dosage Protocols for Administering ESAs 
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that are consistent with the boxed warning differs based on dialysis facilities self-reported 
characteristics.  We tested for statistically significant differences. 
 
We used SUDAAN software to produce weighted estimates of protocol review data percentages.  
These estimates reflect our stratified sample design and are provided in Appendix A.  The results 
of our statistical significance tests are provided in Appendix B. 
 
Standards   
This study was conducted in accordance with the Quality Standards for Inspections approved 
by the Council of the Inspectors General on Integrity and Efficiency. 
 
RESULTS 
 
Ninety-Three Percent of Medicare-Certified Dialysis Facilities Had Protocols in Place for 
Administering ESAs, But Only 56 Percent of the Protocols Explicitly State a Target 
Hemoglobin Range   
Based on responses we received from the Medicare-certified dialysis facilities in our sample, we 
estimate that 93 percent of all facilities had protocols in place for administering ESAs at the time 
of our request.  Seven percent of facilities did not have ESA protocols in place.  Point estimates 
and confidence intervals for all statistics presented in the findings of this memorandum report are 
provided in Appendix A. 
 
Table 3 displays selected types of information included in the protocols for administering ESAs, 
such as target hemoglobin range and dosage and administration guidelines.  Fifty-six percent of 
protocols include a target hemoglobin range and ESA starting dose information.  More than        
90 percent of protocols include information about when to increase, decrease, and withhold ESA 
doses. 
 
Table 3:  Selected Types of Information Included in ESA Protocols 
Percentage of Protocols That  Percentage of Protocols That Do 
Type of Information 
Include This Information  Not Include This Information 
Target hemoglobin range  56%  44% 
Starting dose instructions  56%  44% 
Specific hemoglobin level at which to increase dose 
95%  5% 
(epoetin alfa protocols only) 
Specific hemoglobin level at which to decrease dose  91%  9% 
Specific hemoglobin level at which to withhold dose  95%  5% 
Source:  OIG analysis of dialysis facilities protocols for administering ESAs, 2009. 
 
 
 
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Ninety-Four Percent of Protocols That Include a Target Hemoglobin Range Are Consistent 
With the Boxed Warning on ESAs Labels and the Medicare Benefit Policy for ESAs 
The boxed warning on ESA labels states that providers should administer the drugs to achieve 
and maintain hemoglobin levels within the range of 10 to 12 g/dL for patients with chronic 
kidney failure.20  The Medicare benefit policy for ESAs reflects the target hemoglobin range 
specified in the boxed warning.  Fifty-six percent of protocols explicitly state a target 
hemoglobin range.  We could not determine whether the remaining 44 percent of protocols in our 
review are consistent with the boxed warning or Medicare benefit policy because they do not 
specify a target hemoglobin range. 
 
Of protocols that include a target hemoglobin range, 94 percent are consistent with the boxed 
warning on the FDA-approved labels and the Medicare benefit policy for ESAs.  These protocols 
include a target hemoglobin range in which the upper limit of the target range is equal to or less 
than 12 g/dL.  For the remaining 6 percent of protocols that include a target hemoglobin range, 
the upper limit of the target range exceeds 12 g/dL.  The upper limits in these protocols range 
from 12.1 g/dL to 13 g/dL with a median of 12.5 g/dL. 
 
More chain facilities are consistent with the warning than nonchain facilities.  We detected no 
statistically significant difference between the percentage of protocols that are consistent with the 
boxed warning based on facilities profit status, whether the facility is freestanding or      
hospital-based, or on facility size.  However, we detected a statistically significant difference at 
the 95-percent confidence level based on whether the facility is part of a chain.  Protocols from 
chain facilities are more likely to be consistent with the boxed warning than protocols from 
nonchain facilities.  Specifically, 97 percent of protocols from chain facilities are consistent with 
the warning, compared to 87 percent of protocols from nonchain facilities. 
 
For protocols that specify a target hemoglobin range, the lower limit of the target range is 
typically 11 g/dL.  The lower limit of the target range is equal to 10 g/dL for only 16 percent of 
protocols that include a target hemoglobin range.  The remaining 84 percent of protocols include 
a target hemoglobin range with a lower limit that is greater than 10 g/dL.  Almost all of these 
protocols (97 percent) report a lower limit of 11 g/dL.  The lower limit of the hemoglobin target 
range for these protocols exceeds the lower limit of the target range on the boxed warning and in 
the Medicare benefit policy.  However, it is consistent with a March 2007 National Kidney 
Foundation clinical practice recommendation that, for patients with chronic kidney disease 
receiving ESA therapy, the selected hemoglobin target should generally be in the range of 11 to 
12 g/dL.21 
 
                                                 
20 FDA, Information on Erythropoeisis-Stimulating Agents, loc. cit.   
21 National Kidney Foundation, Kidney Disease Outcomes Quality Initiatives Guidelines.  Available online at 
http://www.kidney.org/professionals/KDOQI/guidelines_anemia/cpr21message.htm.  Accessed on May 11, 2009. 
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Some Dialysis Facilities Protocols Contain Information That Differs From Selected 
Guidelines on ESAs Labels 
The percentage of dialysis facilities protocols that addressed each of the selected ESA dosage 
and administration guidelines ranged from 56 percent to 95 percent.  However, some of these 
protocols include information that differs from the guidelines outlined on the FDA-approved 
labels for ESAs.   
 
Sixteen percent of protocols that include instructions regarding starting doses instruct providers 
to administer a higher starting dose than is recommended.  The FDA-approved epoetin alfa label 
states that the starting dose for adults should be 50 to 100 units per kilogram, three times per 
week.  The FDA-approved darbepoetin alfa label states that the starting dose for adults should be 
0.45 micrograms per kilogram, once per week.  As shown in Table 3, 56 percent of protocols 
include instructions regarding starting doses.  Of these protocols, 16 percent instruct providers to 
administer a higher maximum starting dose than is recommended on ESAs labels.  All but two 
of these protocols are specific to epoetin alfa.  The maximum starting doses for these epoetin alfa 
protocols range from 125 to 200 units per kilogram, three times per week. 
 
Ninety-four percent of protocols that specify a hemoglobin level at which to increase patients 
dosages instruct providers to increase dosages when hemoglobin levels are already within the 
target range on the boxed warning.  The FDA-approved label for epoetin alfa states that 
providers should increase the dose if a patients hemoglobin level falls below 10 g/dL.22   
Ninety-five percent of epoetin alfa protocols specify a hemoglobin level at which to increase 
patients dosages.  Of these protocols, 94 percent instruct providers to increase the dose when a 
patients hemoglobin level is within the recommended target range of 10 to 12 g/dL.  Most of 
these protocols instruct providers to increase the dose when a patients hemoglobin level is 
within the range of 11 to 12 g/dL. 
 
For 62 percent of the epoetin alfa protocols that specify a hemoglobin level at which to increase 
patients dosages, providers are also instructed to ensure that additional conditions are met before 
increasing the dose.  For example, some protocols instruct providers to increase the dose when a 
patients hemoglobin level is equal to 12 g/dL, but only if the patients hemoglobin level is 
decreasing over time.  Other protocols instruct providers to increase the dose when a patients 
hemoglobin level is 12 g/dL, but the patients hemoglobin level must be decreasing over time 
and the previous dose must have been below a specified amount. 
 
More than 40 percent of protocols that specify a hemoglobin level at which to decrease patients 
ESA dosages do not instruct providers to decrease dosages until hemoglobin levels are 12 g/dL 
or higher.  The FDA-approved labels for ESAs state that providers should reduce the ESA dose 
if a patients hemoglobin level is approaching 12 g/dL.  Ninety-one percent of protocols 
specify a hemoglobin level at which to decrease patients ESA dosages.  Of these protocols,     
43 percent do not instruct providers to decrease a patients ESA dose until the patients 
hemoglobin level is 12 g/dL or higher.  The remaining 57 percent of protocols that specify a 
                                                 
22 The darbepoetin alfa label does not include this guideline for increasing patients ESA dosages. 
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hemoglobin level at which to decrease patients ESA dosages instruct providers to reduce the 
ESA dose when a patients hemoglobin level is less than 12 g/dL. 
 
Ninety percent of protocols that specify a hemoglobin level at which to withhold patients ESA 
dosages do not instruct providers to withhold dosages until hemoglobin levels are 13 g/dL or 
higher.  ESAs labels state that the dose should be temporarily withheld if the dose has been 
reduced because a patients hemoglobin level is approaching 12 g/dL and the hemoglobin level 
continues to increase despite the dose reduction.  Ninety-five percent of protocols specify a 
hemoglobin level at which to withhold patients ESA dosages.  Of these protocols, 81 percent do 
not instruct providers to withhold the dose until a patients hemoglobin level is in the range of  
13 to 13.4 g/dL.  Whether the dose is withheld depends on additional conditions for two-thirds of 
these protocols.  For example, many protocols that instruct providers to withhold ESA doses 
when hemoglobin levels are greater than 13 g/dL state that hemoglobin must exceed 13 g/dL for 
3 or more consecutive months before withholding the dose. 
 
An additional 9 percent of dialysis facilities protocols that specify a hemoglobin level at which 
to withhold patients ESA doses do not instruct providers to withhold the dose until a patients 
hemoglobin level is 13.5 to 15 g/dL. 
 
All Protocols That Include a Target Hemoglobin Range or Level at Which To Increase the 
Dose Conform With CMSs Monitoring Policy for ESA Claims 
CMS initiates its ESA payment monitoring policy when the hemoglobin level reported on an 
ESA claim exceeds 13 g/dL.  For hemoglobin levels that exceed 13 g/dL for less than 3 months, 
CMS instructs providers to report ESA dose reductions.  If providers do not report dose 
reductions, CMS will pay only for a dosage which represents a 25-percent reduction of the 
dosage reported on the claim.  For claims that report hemoglobin levels that exceed 13 g/dL for  
3 or more consecutive months, CMS reimburses providers for an ESA dose that represents a     
50-percent reduction of the dose reported on the claim.23 
 
None of the dialysis facilities protocols that include a target hemoglobin range report a target 
range that exceeds 13 g/dL.  Six percent of protocols include a target range with an upper limit 
that is between 12.1 and 13 g/dL.  For the epoetin alfa protocols that specify a hemoglobin level 
at which to increase patients ESA dosages, no protocol instructs providers to increase the dose 
when a patients hemoglobin level is equal to or greater than 13 g/dL. 
 
CONCLUSION 
 
Almost all dialysis facilities that responded to our request had protocols in place for 
administering ESAs.  Fifty-six percent of protocols explicitly state a target hemoglobin range 
that is, with few exceptions, consistent with the boxed warning that states ESAs should be 
administered to achieve and maintain hemoglobin levels in the range of 10 to 12 g/dL.  These 
target hemoglobin ranges are also consistent with the Medicare benefit policy for ESAs.  
                                                 
23 CMS, Medicare Claims Processing Manual,  60.4 and 60.7. 
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However, we could not determine whether the remaining 44 percent of protocols were consistent 
with the boxed warning and Medicares benefit policy because they did not specify a target 
hemoglobin range. 
 
In addition, some protocols contain instructions regarding starting doses, dose adjustments, and 
withholding ESA doses that differ from selected guidelines on ESAs labels.  For example, the 
epoetin alfa label states that providers should increase the ESA dose if a patients hemoglobin 
level falls below 10 g/dL.  Of protocols that specify a hemoglobin level at which to increase 
dosages, 94 percent instruct providers to increase ESA dosages when patients hemoglobin levels 
are already within the target range of 10 to 12 g/dL. 
 
Finally, all protocols that include a target hemoglobin range or guidelines regarding dose 
increases conform with the hemoglobin threshold of 13 g/dL specified in CMSs monitoring 
policy for ESA claims. 
 
Although our review does not address the amount of ESAs providers actually administer to 
patients at their dialysis facilities, it does demonstrate that just over half of facilities had 
protocols for administering ESAs that are consistent with the boxed warning and Medicares 
benefit policy for ESAs.  However, since almost half of the dialysis facilities either did not have 
protocols or did not specify a target hemoglobin range in their protocols, we cannot determine 
whether these facilities policies target the hemoglobin range outlined in the boxed warning that 
FDA requires on ESA labels to alert physicians and patients with chronic kidney failure about 
the increased risks associated with higher hemoglobin levels.  
 
This report is being issued directly in final form because it contains no recommendations.  If you 
have comments or questions about this report, please provide them within 60 days.  Please refer 
to report number OEI-03-09-00010 in all correspondence. 
OEI-03-09-00010       Renal Dialysis Facilities Dosage Protocols for Administering ESAs 
  Page 13  Charlene Frizzera and Margaret A. Hamburg, M.D. 
 
APPENDIX A 
 
Confidence Intervals for Selected Estimates 
Estimate Description  n  Point Estimate1  95-Percent Confidence Interval 
Percentage of dialysis facilities that have protocols  366 93.2% 90.3%96.1% 
Percentage of dialysis facilities that do not have 
366 6.7% 3.8%9.6% 
protocols 
Percentage of protocols that include an explicit target 
357 55.9% 49.8%62.0% 
hemoglobin range 
Percentage of protocols that do not include an explicit  
357 44.0% 37.9%50.1% 
target hemoglobin range 
Of protocols that include a target hemoglobin range, 
percentage that include an upper target limit equal to   209 94.3% 90.8%97.7% 
or less than 12 grams per deciliter (g/dL) 
Of protocols that include a target hemoglobin range, 
percentage that include an upper target limit greater   209 5.6% 2.2%9.1% 
than 12 g/dL 
Of protocols that include a target hemoglobin range, 
percentage that include a lower target limit equal to       206 15.7% 10.1%21.2% 
10 g/dL 
Of protocols that include a target hemoglobin range, 
percentage that include a lower target limit greater     206 84.3% 78.7%89.8% 
than 10 g/dL 
Percentage of protocols that include a lower target     
limit greater than 10 g/dL where the lower target limit    162 97.2% 95.0%99.4% 
equals 11 g/dL 
Percentage of protocols that include starting dose 
357 56.2% 50.3%62.1% 
information 
Percentage of protocols that do not include starting  
357 43.7% 37.8%49.6% 
dose information 
Of protocols that include starting dose information, 
percentage that include a starting dose higher than   202 16.0% 10.9%21.1% 
labels' guidelines 
Percentage of epoetin alfa protocols that specify a 
299 95.1% 92.6%97.6% 
hemoglobin level at which to increase dose 
Percentage of epoetin alfa protocols that do not     
299 4.8% 2.3%7.3% 
specify a hemoglobin level at which to increase dose 
                                                                                                                                                                                                 continued on next page 
OEI-03-09-00010       Renal Dialysis Facilities Dosage Protocols for Administering ESAs 
  Page 14  Charlene Frizzera and Margaret A. Hamburg, M.D. 
 
Confidence Intervals for Selected Estimates (continued) 
Estimate Description  n  Point Estimate1  95-Percent Confidence Interval 
Of epoetin alfa protocols that specify a hemoglobin     
level at which to increase dose, percentage that      
279 26.3% 20.6%31.9% 
instruct providers to increase dose when hemoglobin    
is 10 to 10.9 g/dL 
Of epoetin alfa protocols that specify a hemoglobin     
level at which to increase dose, percentage that      
279 67.8% 61.7%73.8% 
instruct providers to increase dose when hemoglobin    
is 11 to 12 g/dL 
Of epoetin alfa protocols that specify a hemoglobin     
level at which to increase dose, percentage that       279 61.6% 55.4%67.8% 
include additional conditions for increasing dose 
Percentage of protocols that specify a hemoglobin      
357 90.6% 87.4%93.8% 
level at which to decrease dose 
Percentage of protocols that do not specify a   
357 9.3% 6.1%12.5% 
hemoglobin level at which to decrease dose 
Of protocols that specify a hemoglobin level at which    
to decrease dose, percentage that instruct providers to  307 42.5% 36.3%48.8% 
decrease dose when hemoglobin is 12 g/dL or higher 
Of protocols that specify a hemoglobin level at which    
to decrease dose, percentage that instruct providers to  307 57.4% 51.2%63.6% 
decrease dose when hemoglobin is less than 12 g/dL 
Percentage of protocols that specify a hemoglobin      
357 94.9% 92.8%96.9% 
level at which to withhold dose 
Percentage of protocols that do not specify a   
357 5.1% 3.0%7.1% 
hemoglobin level at which to withhold dose 
Of protocols that specify a hemoglobin level at which    
to withhold dose, percentage where specified   325 81.0% 76.4%85.5% 
hemoglobin equals 13 to 13.4 g/dL 
Of protocols that specify a hemoglobin level at which    
to withhold dose, percentage where specified   325 9.4% 5.9%13.0% 
hemoglobin equals 13.5 to 15 g/dL 
Of protocols that specify a hemoglobin level at which    
to withhold dose, percentage where specified  
238 66.9% 60.7%73.1% 
hemoglobin equals 13 to 13.4 g/dL that include   
additional conditions for withholding dose 
Source:  Office of Inspector General analysis of dialysis facilities protocols for administering erythropoiesis-stimulating agents, 2009. 
1Point estimates are weighted to reflect our stratified sample design.
OEI-03-09-00010       Renal Dialysis Facilities Dosage Protocols for Administering ESAs 
  Page 15  Charlene Frizzera and Margaret A. Hamburg, M.D. 
 
APPENDIX B 
 
Results of Statistical Significance Tests 
 
Weighted Chi-Square Tests Comparing Percentages of Protocols That Were 
Consistent With the Boxed Warning Based on Dialysis Facility Characteristics 
Percentage of Protocols in 
P-Value for 
Which Upper Limit of Target 
Dialysis Facility Characteristic    Difference in 
Hemoglobin Range Was Less 
Than or Equal to 12 g/dL1  Percentages 
For-profit facilities  95.6% 
Profit status  0.3655 
Nonprofit facilities 92.9% 
Hospital-based facilities 89.4% 
Type of setting  0.1367 
Freestanding facilities 95.0% 
Chain facilities 96.7% 
Chain status  0.04892 
Nonchain facilities 87.3% 
1g/dL is grams per deciliter. 
2The difference between the percentage of protocols from chain facilities that were consistent with the boxed warning and the 
percentage of protocols from nonchain facilities that were consistent with the warning was statistically significant at the 95-percent 
confidence level. 
Source:  Office of Inspector General (OIG) analysis of dialysis facilities protocols for administering erythropoiesis-stimulating agents, 
2009. 
 
Weighted T-Test Comparing Protocols That Were Consistent With the Boxed 
Warning to Protocols That Were Not Consistent With the Boxed Warning Based on 
Dialysis Facility Size 
Mean Number of  P-Value for 
Difference in 
  Dialysis Stations as  Difference in 
Means 
Proxy for Facility Size  Means 
Facilities protocols in which upper limit of target 
18.9
hemoglobin range was less than or equal to 12 g/dL1    
1.7  0.2752 
Facilities protocols in which upper limit of target 
17.2
hemoglobin range was greater than 12 g/dL 
1g/dL is grams per deciliter. 
Source:  OIG analysis of dialysis facilities protocols for administering erythropoiesis-stimulating agents, 2009. 
 
 
OEI-03-09-00010       Renal Dialysis Facilities Dosage Protocols for Administering ESAs