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					Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                            Page 1 of 32




                         Attachment to Ortho Biotech’s ESA NCD Reconsideration Request

                                                           Contents


    1.   New Evidence

    2.   Lack of ESA and blood transfusion comparability

    3.   Legal considerations

    4.   Policy and process issues

    5.   Recommendations

    6.   Material misinterpretations

    7.   References
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                          Page 2 of 32




New Evidence

1.   Data concerning the hemoglobin (Hb) concentrations at which patients receive transfusions.

A FDA Medical Officer report supporting once-weekly epoetin alfa approval, recently published studies, and a
review of data from existing clinical trials help characterize the Hb concentrations at which chemotherapy
induced anemia patients require transfusions.

These data demonstrate that a subset of chemotherapy-treated cancer patients require transfusion support
when their pre-transfusion Hb levels are greater than 10 g/dL, and a substantial number require transfusion
when their Hb concentrations are above 9 g/dL.

Twenty-three percent of the transfusion episodes in Medicare recipients included in an ESA registry occurred
with a pre-transfusion Hb value greater than or equal to 9.0 g/dL. Review of these transfusion events reveals
that the majority have occurred in patients with symptoms of anemia e.g. dyspnea, fatigue, etc and/or co-
morbid conditions confirming the medical necessity for these transfusions.

The NCD states:

         “...Transfusions are not required for hemoglobin levels 10.0 g/dL or greater. There are no definitive data
         regarding transfusion need, and by extension ESA need for patients with hemoglobin levels between 7 and
         10 g/dL.” (NCD p. 21)

While such a statement may be relevant to other populations (e.g., patients in the intensive care unit or postoperative
setting), experience shows that cancer patients receiving chemotherapy have different transfusion support needs and
differing Hb levels at which transfusions are required. This is not unexpected, given malignancy-related and therapy-
related side effects experienced by ambulatory cancer patients who strive to maintain the premorbid functional status.
The FDA Medical Officer Report of the placebo-controlled epoetin alfa weekly dosing trial described patients with pre-
transfusion Hb levels up to 10.7 g/dL prior to study entry (FDA Medical Officer Report p. 16) with a similar finding during
the study (FDA Medical Officer Report p. 27). Two to 3% of transfusion episodes occurred at a pre-transfusion Hb
level > 10 g/dL (FDA Medical Officer Report p.27).

Similar finding have been reported with the published literature and analyses of controlled clinical trials. Dernedde
(2007) reported increases in the transfusion trigger in the oncology population from 2001-2004.

         “...Looking at the hemoglobin levels preceding transfusion (trigger levels) on two separate occasions, the
         mean trigger hemoglobin level rose from 8.53 g/dL in the first year of the audit to 8.86 g/dl in the third year (p<
         0.001, t test)...” (Dernedde 2007)

Additionally, 4% of transfusions were administered for patients with a pre-transfusion Hb level of 10-11.9 g/dL.

Controlled ESA clinical trials have reported similar findings with regard to transfusion trigger including 10-14% of
transfusions with pretransfusion Hb > 9 g/dL as described in the table below (Ortho Biotech data on file) Review of
events prior to transfusion reported anemia-related symptoms including fatigue, shortness of breath, dyspnea on
exertion, and chest palpitations, which provides supporting evidence that the transfusions were medically necessary.
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                          Page 3 of 32




                                      Proportion of transfusion episodes stratified by pretransfusion Hb level
     Published ESA clinical trial                 Hb 9.1-10 g/dL                          Hb > 10 g/dL
           Witzig (2005)                                6.7%                                 3.6%
         Waltzman (2005)                               10.3%                                 1.6%
           Henry (2006)                                10.0%                                 3.8%

Data from an ongoing registry, which reflects real world practice, reported that 19% of transfusion episodes occurred at
a pre-transfusion Hb level of > 9 g/dL. In a subset analysis of the Medicare population from this registry, 23% of
transfusion episodes occurred at a Hb level > 9 g/dL. Review of these transfusion events reveals that the majority have
occurred in patients with symptoms of anemia e.g. dyspnea, fatigue, etc and/or co-morbid conditions confirming the
medical necessity for these transfusions

Pre-transfusion Hb reported from ongoing ESA registry in chemotherapy-treated cancer patients

Transfusion trigger (g/dL)             <7             7-7.9       8-8.9         9-9.9        10-10.9       11-11.9
Total number of transfusions         14 (4%)        96 (31%)    141 (45%)     48 (15%)       14 (4%)       1 (0.3%)
(%) (N=314)
Medicare Patients (n=150)             8 (5%)        47 (31%)     61 (41%)     22 (15%)       12 (8%)        0 (0%)

2.    Data concerning transfusion risks associated with various hemoglobin concentrations at which ESA
      therapy is initiated.

New data from an ongoing ESA registry of patients with chemotherapy-induced anemia demonstrates that a
significantly greater proportion of chemotherapy-treated cancer patients initiated on ESAs at baseline Hb
below 10 g/dL required transfusion compared with those initiated on ESAs at baseline Hb 10-11 g/dL.

Additionally, a recent integrated analysis of patient-level data from three clinical trials reports significantly
greater transfusion requirements in patients initiated at lower Hb levels, including 165% higher transfusion
risk in patients with ESA initiation at Hb < 10 g/dL versusHb 10-11 g/dL.

New medical claims analyses of ESA-treated cancer patients receiving chemotherapy report significantly
greater hospitalization risk, length of hospital stay and transfusion rates in patients whose ESA treatment was
initiated at a Hb ≤10 g/dL compared with those whose ESA treatment was initiated at a Hb >10 g/dL.

The Dosing and Outcomes Study of Erythropoiesis Stimulating Therapies (DOSE) is an ongoing registry of oncology
patients treated in U.S. community clinics and hospital centers. The registry provides observational outcomes data in
oncology patients receiving chemotherapy from over eighty sites that provide a national representation. In a new
analysis of > 960 patients, a significantly greater proportion of chemotherapy-treated cancer patients required
transfusion in those initiated on ESAs at baseline Hb < 10 g/dL compared with baseline Hb 10-11 g/dL. This analysis
also reported significantly greater blood utilization in patients initiated at baseline Hb < 10 g/dL compared with a
baseline Hb of 10-11 g/dL.

Baseline Hb                                                < 10 g/dL        10-11 g/dL             p value
Proportion of patients requiring blood transfusion            31%              14%                 <0.0001
Blood utilization (Units/study patient)                       0.89             0.44                < 0.0001

Similar findings have been reported in clinical trial analyses in data previously reported to CMS (June 13th submission)
comparing patients initiated at a Hb < 10 g/dL compared with those with ESA initiation of 10-11 g/dL. The table below
summarizes clinical trial data that reported a higher proportion of patients requiring blood transfusion in the groups with
Hb levels at ESA initiation of < 10 g/dL compared with Hb levels of 10-11 g/dL.

Proportion of patients requiring blood transfusion stratified by baseline Hb
                                          Proportion of patients transfused stratified by Hb at ESA
               Author
                                                                   initiation
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                            Page 4 of 32




                                                           < 10 g/dL                        10-11 g/dL
           Vadhan-Raj (2003)                              39% (33,34)                      16% (14,19)
          Vansteenkiste (2004)                            31% (17,45)                       15% (8,22)
              Boccia (2006)                               28% (24,32)                       12% (9,14)
             Szczudlo (2007)                              36% (24,48)                       9% (3,15)
             Szczudlo (2007)                              29% (18,40)                        3% (0,7)

Quirt (2006) evaluated patient level data from three clinical trials to assess transfusion patterns in patients treated with
epoetin alfa based on prior transfusion use and hemoglobin at time of ESA initiation. Baseline Hb was found to be a
significant predictor of transfusion risk. The authors stated:

         “...As anticipated, patients with baseline Hb levels <10 g/dl had a significantly higher risk for
         subsequent transfusion than patients with baseline Hb levels of 10–11 g/dl. When directly
         comparing Hb level strata at which epoetin alfa treatment was initiated, patients were found to
         have a 165% higher risk for transfusion from day 29 to the end of study
         (RR, 2.65; 95% CI, 1.54–4.56) at a baseline Hb level <10 g/dl compared with a baseline Hb level
         of 10–11 g/dl...patients who were treated at a baseline Hb level < 10 g/dl having a higher chance of being
         transfused than patients in whom epoetin alfa was initiated at baseline Hb levels of 10–11 g/dl. In addition,
         when the total units transfused in patients receiving epoetin alfa at different baseline Hb levels were analyzed,
         >85% of the units of blood transfused were received by patients with baseline Hb levels < 10 g/dl...”

This was also demonstrated in modeling of transfusion requirements and baseline Hb. The figure below represents
the number of units transfused per patient based on Hb level at initiation of ESA administration for all patients. The
findings of greater red blood cell utilization with lower Hb levels prior to ESA administration were even greater in those
patients who had a transfusion requirement within 28 days of initiating ESA (baseline pre-transfusion).




An analysis of medical claims and laboratory data in 820 ESA-treated cancer patients receiving chemotherapy stratified
by baseline Hb level (Hb ≤10 g/dL versus Hb >10 g/dL within 28 days of treatment initiation) was conducted.
Treatment groups were similar with regard to age, gender distribution, and mean ESA treatment duration. Outcomes
measures for the analyses included hospitalization rates, hospital length of stay (LOS) and transfusion rates during
ESA treatment. The incidence rates (number of events divided by the person-time of observation) were compared
between the two groups. ESA initiation with lower Hb levels increased the risk of hospitalization by 47% (95% CI: 17%-
85%, p<0.001) compared to initiating treatment at Hb>10 g/dL. The hospital LOS and blood transfusion rates were also
significantly different between groups, revealing a 53% increased in hospital LOS (95% CI: 38%-69%, p < 0.001) and a
3.6-fold increase in the risk of blood transfusion (95% CI: 2.4-5.4, p < 0.001) for patients whose ESA treatment was
initiated at a Hb value ≤10 g/dL compared to those with Hb value >10 g/dL.
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                      Page 5 of 32




3.                    Data correlating maximum Hb limits to achieved Hb concentration.

Observational data from the ESA registry demonstrate that mean Hb levels achieved in ESA-treated cancer
patients are usually 1-1.5 g/dL below the recommended Hb ceiling, i.e. the Hb value at which recommendation
is made to suspend ESA dosing (the FDA-recommended prescribing information recommended a Hb ceiling
of 13 g/dL during the majority of the data collection period).

Modeling Hb changes (+/- SD) over time and applying the potential impact in the downward shift of the Hb
limit to 10 g/dL, indicates that approximately 50% of ESA-treated patients’ Hb values would fall in the range of
8-9 g/dL, a Hb range that is seen in 41% of patients who receive blood transfusions in the same registry.

The graph below reported the data from 1257 patients treated in oncology clinics between 2004-2007. During this
time, FDA-approved prescribing information recommended a Hb cap of 13 g/dL during the majority of the data
collection period. As illustrated, mean Hb levels approximated 11 g/dL however evaluation of the standard deviation
(vertical bars) reported excursions to Hb > 12 g/dL during ESA treatment. Prescribing information now clearly articulate
the recommendations to stop ESA administration for Hb > 12 g/dL


                      13

                      12
  Hemoglobin (g/dL)




                      11

                      10

                       9

                       8

                       7
                           0                   4                      8                  12                   16
                                                             ESA treatment week



The following graph describes the estimated mean Hb values and standard deviations with Hb cap of 12 g/dL which
suggest minimal Hb values > 12 g/dL and modest number of Hb values in the Hb range of 8-9 g/dL, where the
transfusion risk is greater.


                      13

                      12
 Hemoglobin (g/dL)




                      11

                      10

                       9

                       8
                           0                    4                         8                   12                   16
                                                              ESA Treatment Week
      Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                     Page 6 of 32




      Estimated Hb values and standard deviation with Hb cap of 11 g/dL, which suggests a large number of patients in the
      Hb range of 8-9 g/dL, where the transfusion risk is greatest.



                    13

                    12
Hemoglobin (g/dL)




                    11

                    10

                    9

                    8

                    7
                         0                          4                          8                         12                            16
                                                                     ESA treatment week



      4.             Recent product labeling reviews in the EMEA and in the United States.

      Following an exhaustive review of available data, the EMEA’s Committee for Medicinal Products for Human
      Use (CHMP) and its Pharmacovigilance Working Party (PhVWP) concluded that the benefits of these
      products continue to outweigh their risks in the approved indications, but recommended the following
      changes to the product information:

                             (1) Changes to the ‘Indication’ section (section 4.1), saying that epoetins should be used in the
                                 treatment of anaemia only if associated with symptoms and

                             (2) Changes, stipulating a uniform target haemoglobin range for all epoetins of 10 g/dL to 12 g/dL
                                 with a warning not to exceed a concentration of 12 g/dL. (European Medicines Agency press
                                 release, October 23, 2007).

      The updated FDA-approved erythropoietic stimulating agent (ESA) prescribing information (November 2007)
      maintains a Hb upper safety limit of 12 g/dL, permitting appropriate flexibility of ESA dosing based on
      individual patient need and response for various clinical scenarios. The updated label does not restrict ESA
      initiation or maintenance to Hb limits of < 10 g/dL.

      As described in the October 2007 EMEA press release:

                             “The European Medicines Agency (EMEA) has recently reviewed the safety of epoetins. These medicines
                             are used for the treatment of anaemia in patients with chronic renal failure and for the treatment of patients
                             with non-myeloid malignancies receiving chemotherapy. The safety review was initiated because data from
                             recent clinical trials show a consistent unexplained excess mortality in patients with anaemia associated with
                             cancer who have been treated with epoetins.
                             In addition, the results of two studies and a meta-analysis have recently been published suggest
                             that treatment of anaemia with epoetins in patients with chronic kidney disease to achieve
                             relatively high target haemoglobin concentrations may be associated with an increase in the risk
                             of mortality and cardiovascular morbidity...”
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                      Page 7 of 32



Johnson & Johnson has been in close collaboration with the FDA regarding new clinical trial evidence and
recommendations of the May 2007 Oncology Drug Advisory Committee meeting regarding ESAs. The prescribing
information was updated in March 2007 with the following dosing recommendations for cancer chemotherapy patients.

March 2007 Epoetin alfa prescribing information

         TIW Dosing Starting Dose: Adults 150 Units/kg SC TIW; Reduce Dose by 25% when: 1. Hgb approaches 12
         g/dL or, 2. Hgb increases > 1 g/dL in any 2-week period Withhold Dose if: Hgb exceeds 12 g/dL, until the
         hemoglobin falls below 11 g/dL, and restart dose at 25% below the previous dose. Increase Dose to 300
         Units/kg TIW if: response is not satisfactory (no reduction in transfusion requirements or rise in hemoglobin)
         after 8 weeks to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for RBC
         transfusion and not to exceed 12 g/dL

         Weekly Dosing Starting Dose: Adults 40,000 Units SC; Pediatrics 600 Units/kg IV (maximum 40,000 Units);
         Reduce Dose by 25% when: Hgb approaches 12 g/dL or increases > 1 g/dL in any 2 weeks Withhold Dose if:
         Hgb exceeds 12 g/dL, until the hemoglobin falls below 11 g/dL, and restart dose at 25% below the previous
         dose Increase Dose if: response is not satisfactory (no increase in hemoglobin by ≥1g/dL after 4 weeks of
         therapy, in the absence of a RBC transfusion) to achieve and maintain the lowest hemoglobin level sufficient
         to avoid the need for RBC transfusion and not to exceed 12 g/dL: Adults: 60,000 Units SC Weekly Pediatrics:
         900 Units/kg IV (maximum 60,000 Units)

The FDA-approved ESA prescribing information, updated in October 2007, continued recommendations to avoid ESA
administration for Hb levels > 12 g/dL, however, no recommendations or clinical data were incorporated to initiate or
maintain Hb levels at <10 g/dL during ESA treatment.

November 2007 Epoetin alfa prescribing information

         TIW Dosing
         Starting Dose: Adults 150 Units/kg SC TIW; Reduce Dose by 25% when: Hemoglobin reaches a level
         needed to avoid transfusion or increases > 1 g/dL in any 2-week period; Withhold Dose if: Hemoglobin
         exceeds 12 g/dL and restart at 25% below the previous dose when the hemoglobin approaches a level where
         transfusions may be required; Increase Dose to 300 Units/kg TIW if: Response is not satisfactory (no
         reduction in transfusion requirements or rise in hemoglobin) after 8 weeks to achieve and maintain the lowest
         hemoglobin level sufficient to avoid the need for RBC transfusion and not to exceed the upper safety limit of
         12 g/dL

         Weekly Dosing
         Starting Dose: Adults 40,000 Units SC; Pediatrics 600 Units/kg IV (maximum 40,000 Units) Reduce Dose by
         25% when: Hemoglobin reaches a level needed to avoid transfusion or increases > 1 g/dL in any 2-weeks
         Withhold Dose if: Hemoglobin exceeds 12 g/dL and restart at 25% below the previous dose when the
         hemoglobin approaches a level where transfusions may be required Increase Dose if: For Adults: 60,000
         Units SC Weekly For Pediatrics: 900 Units/kg IV (maximum 60,000 Units) if: Response is not satisfactory (no
         increase in hemoglobin by ≥ 1 g/dL after 4 weeks of therapy, in the absence of a RBC transfusion) to achieve
         and maintain the lowest hemoglobin level sufficient to avoid the need for RBC transfusion and not to exceed
         the upper safety limit of 12 g/dL

5.   New National Practice Guidelines.

October 2007 evidence-based anemia treatment guidelines, issued by the American Society of
Hematology/American Society of Clinical Oncology (ASH/ASCO) support ESA initiation at Hb< 10 g/dL or 10-
12 g/dL in special populations (“including but not limited to elderly individuals with limited cardiopulmonary
reserve, those with underlying coronary artery disease or symptomatic angina, or substantially reduced
exercise capacity, energy, or ability to carry out activities of daily living)”, treatment to hemoglobin
concentration to (or near) 12 g/dL, and dose adjustments consistent with prescribing information.
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                       Page 8 of 32



Updated ASH/ASCO recommendations are consistent with 2007 National Comprehensive Cancer Network
(NCCN) anemia treatment guidelines.

The American Society of Hematology and American Society of Clinical Oncology established a joint committee to
update the clinical practice guidelines on the use of the erythropoietic stimulating agents. The committee reviewed
clinical literature available through July 2007, which included clinical trials, systematic reviews and meta-analyses
including the 2006 Cochrane Review and the 2006 Agency for Healthcare Research and Quality-sponsored
comparative effectiveness systematic review. Additionally discussions/publications of the 2004 and 2007 Oncology
Drug Advisory Committee meeting regarding ESAs and FDA-approved prescribing information were considered.

The 2007 ASH/ASCO ESA guidelines (Rizzo 2007) included the following:

         Hb initiation
         “...The use of epoetin or darbepoetin is recommended as a treatment option for patients with chemotherapy-
         associated anemia and a Hb concentration that is approaching, or has fallen below, 10 g/dL to increase Hb
         and decrease transfusion...For patients with declining Hb levels but less severe anemia (those with Hb
         concentration < 12 g/dL, but who have never fallen near 10 g/dL), the decision of whether to use epoetin or
         darbepoetin immediately or wait until the H levels fall close to 10 g/dL, should be determined by clinical
         circumstances (including but not limited to elderly individuals with limited cardiopulmonary reserved, those
         with underlying coronary artery disease or symptomatic angina, or substantially reduced exercise capacity,
         energy, or ability to carry out activities of daily living [ADLS])...”

         Hb target
         “...Hb can be raised to (or near) a concentration of 12 g/dL, at which time the dosage of epoetin and
         darbepoetin should be titrated to maintain that level...”

         Dose adjustment
         “...Dose escalation should follow FDA recommendations...Dose reductions are also recommended when Hb
         rise exceeds 1 g/dl in any 2 wk period or when Hb exceeds 11 g/dL....”

It is relevant to note that the NCD (p. 21 of 61) quoted the 2002 American Society of Hematology/American Society of
Clinical Oncology (ASH/ASCO) guidelines; however, only a portion of the guidelines was included. The NCD stated:

         “...ASCO and ASH guidelines recommended evaluating patients for the need for ESA therapy when the
         hemoglobin is at or below 10 g/dL…”

It is unclear why the second portion of this guideline was not mentioned in the CMS NCD, as it includes information
relevant to the Medicare population. They specifically recommend ESA initiation at an Hb of 10-12 g/dL in certain
clinical conditions, such as the elderly.

         “...The guideline panel found good evidence to recommend use of epoetin as a treatment option for patients
         with chemotherapy-associated anemia with a hemoglobin level less than 10 g/dL. Use of epoetin for patients
         with less severe anemia (hemoglobin < 12 g/dL but never below 10 g/dL) should be determined by clinical
         circumstances... Examples of patients at this higher degree of absolute risk, who may be considered
         reasonable candidates for this agent, based on clinical judgment, include but are not limited to elderly
         individuals with limited cardiopulmonary reserve or patients with underlying coronary artery disease and
         symptomatic angina...” (Rizzo 2002)

The NCD reference list included the NCCN anemia treatment guidelines (accessed 4/5/07), however such guidelines
are not mentioned in the evidence section describing ESA intervention (NCD p. 21 of 61). It is unclear why such
anemia guidelines were not explicitly considered in the evidence supporting the NCD. Additionally, updated NCCN
anemia treatment guidelines were issued since the version referenced in the NCD document. The more recent NCCN
anemia treatment guidelines (v. 3.2007, dated 4/10/07) recommended ESA initiation at a hemoglobin level of < 11 g/dL
for cancer patients with chemotherapy-induced anemia:
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                       Page 9 of 32



         “Following the identification of anemia (defined for the purpose of considering intervention as hemoglobin
         levels equal to or less than 11 g/dL) and the evaluation for anemia specific causes, an initial risk assessment
         should be completed...The history should assess whether accompanying symptoms are present, such as
         chest pain or dyspnea. Comorbidities such as cardiac disease or underlying pulmonary disease must be
         considered...Observation or erythropoietic therapy should be considered for asymptomatic patients with risk
         factors for developing anemia. The decision of whether to use epoetin immediately or to wait until hemoglobin
         levels fall closer to 10 g/dL should be determined by clinical circumstances. For symptomatic patients,
         transfusion and/or erythropoietic therapy are recommended. If the patient's hemoglobin level is between 10-
         11 g/dL, the panel recommends the consideration of erythropoietic therapy with or without transfusion. If the
         patient's hemoglobin level is <10 g/dL, the panel strongly recommends erythropoietic therapy...” (NCCN
         anemia treatment guidelines v.3.2007)

The updated NCCN anemia treatment guidelines highlighted changes from previous versions, which included the
following:

         “.... The target hemoglobin was changed from 12 g/dL to 11-12 g/dL throughout the guidelines. The
         recommendation threshold for holding therapy was changed from 13 g/dL to 12 g/dL...” (NCCN anemia
         treatment guidelines v.3.2007

6.   Further information concerning ESA U.S. registration trials.

The FDA Medical Officer Report regarding weekly epoetin alfa dosing in cancer chemotherapy patients was
recently (September 27, 2007) posted to FDA’s website and provides new data for CMS’s consideration,
including comments on safety and efficacy of once weekly epoetin alfa dosing and comparable safety of TIW
and QW epoetin alfa dosing.

Additionally, the Johnson & Johnson Pharmaceutical Research and Development clinical study report of
once weekly epoetin alfa in the oncology population has been made available to CMS as part of this
reconsideration request (The information contained within this study report includes commercial
trade secret information and is proprietary and confidential. This information should not be
disclosed to any third party without the prior written consent of Ortho Biotech Products, LP. The
trade secrets and commercial proprietary and confidential information herein are exempt from
disclosure under 20 CFR § 402.90 and 5 USC 552(b)(4).

The Center for Drug Evaluation and Research FDA Medical Officer Report provided new insights regarding the clinical
data supporting the FDA-approved use of once-weekly dosing for epoetin alfa. The report summarized the data
evaluated by the FDA review team. The recommendation of clinical approvability included the following:
         “...Results demonstrated that Epogen/Procrit therapy reduce the proportion of patients transfused in day 29
         through week 16 of the study as compared to placebo. Twenty-five patients (14%) in the Epogen/Procrit
         group received transfusion compared to 48 patients (28%) in the placebo group (p=-.0010) between day 29
         and week 16 or the last day on study. The safety data from this study were comparable between the placebo
         and the treatment arm study...” (FDA Medical Officer review p. 5)
Additionally, reviewers commented on safety data from the EPO-PHI-377 trial that compared epoetin alfa TIW and QW
dosing. The reviewers stated,
         “...As can be seen, the adverse events profile in this small study showed comparability between the two study
         arms...” (FDA Medical Officer review p. 66)
7.   Placebo-controlled trial data from an unplanned interim analysis reported similar tumor-related and
     survival outcomes in Hodgkin’s lymphoma patients in ESA- and placebo-treated groups

An unplanned interim analysis of a placebo-controlled trial (planned N=1,500) that included data from 688 patients with
advanced stage Hodgkin’s lymphoma receiving chemotherapy was reported in November 2007. The trial was
conducted to evaluate safety and efficacy of three different dose/schedules of BEACOPP combination chemotherapy.
A second randomization assigned patients to epoetin alfa 40,000 Units weekly or placebo. ESA administered when the
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                     Page 10 of 32



Hb level was < 14 g/dL and dose hold for Hb > 14 g/dL. The Hb level of ESA initiation was changed to Hb level < 13
g/dL following protocol amendment in February 2004. For a maximum of six weeks following chemotherapy
completion, Hb levels were targeted to 12 g/dL This analysis at 30 month follow-up (mean) reported no significant
difference between epoetin alfa and placebo groups in tumor response rate, freedom from treatment failure, or overall
survival. Compared to placebo, epoetin alfa treatment significantly reduced the number of RBC units transfused.

Preliminary results of this Hodgkin’s lymphoma placebo-controlled ESA trial were consistent with multiple randomized,
controlled trials of ESAs in tumor-specific clinical trials (lung cancer, head and neck cancer, breast cancer, cervical
cancer). These trials reported similar tumor-related and/or survival outcomes in the ESA- and placebo-treated groups.
Such findings were reported to CMS in the June 13th Ortho Biotech clinical white paper and described in the table
below.
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                                     Page 11 of 32



       Epoetin alfa Pharmacovigilance Program Evaluating Safety in Epoetin alfa Safety in Patients with Chemotherapy-induced Anemia
STUDY #         Tumor Type                      Primary         Secondary                     Safety Results                                        Status
   (n,                                          Endpoint         Endpoint
accrual/
planned)
                                                    Tumor
                                                  response
                                               (designed to                   Objective Tumor response: EPO 72% (95%CI:
                                                 exclude an                   64-81%), placebo 67% (95% CI: 58-76%). No
                 Lung cancer, treated with         absolute                   more than a 6% difference in RR between the 2      Stopped in agreement with FDA due to slow
 N93-004                                                          Overall
                 chemotherapy, Target Hb        reduction of                  groups was ruled out therefore primary endpoint    accrual secondary to changing standard of
(224/400)                                                         survival
                       14-16 g/dL                15% in RR                    was met.                                           care ; Manuscript published (Grote 2005)
                                               between the                    Overall survival (months): EPO 10.5, control
                                                  EPO and                     10.4, (p=0.264)
                                                    control
                                                   groups)
                Lung cancer, Target Hb 12-                                    Significant difference in the median survival in
      EPO-                                                                                                                       Terminated November 2003 based on
                14 g/dL (anemia of cancer;    Quality of life   Hemoglobin    favor of the patients on the placebo arm of the
    CAN-20                                                                                                                       unplanned interim analysis; Manuscript
                 not candidates for further                       change      trial (EPO 63 v placebo 129 days; hazard ratio,
    (70/300)                                                                                                                     published (Wright 2007)
                      chemotherapy)                                           1.84; P .04)
                                                                              No survival disadvantage for EPO group;            Closed to accrual December 2005;
                 Lung cancer treated with
 Ger-22                                       2 year survival   Local tumor   Interim analysis, median survival                  2-year survival data mature 4Q07(Debus
                 chemotherapy, target 12-
(389/612)                                          rate           control     EPO 338 days (95% CI 242-434)                      2006)
                        14 g/dL1
                                                                              Control 299 (95% CI 234-364)
                                                                                                                                 Closed in November 2003 based on
RTOG 99-           Head and neck cancer       Local-regional      Overall     1 yr local-regional control HR 1.18 (95% CI
                                                                                                                                 unplanned interim analysis; Abstract
   03             receiving RT; Target Hb        failure          survival    0.67-2.09);
                                                                                                                                 published (Machtay 2004); Manuscript
(148/372)                14-16 g/dL                                           1 yr overall survival HR 1.57 (95% CI 0.76-3.27)
                                                                                                                                 submitted

  EPO-                                                                                                                           Closed to accrual April 2002 due to slow
                   Head and neck cancer        2 year local                   No effect on local tumor control
 GBR-7                                                            Overall                                                        accrual; 5 year follow-up ongoing; Last patient
                  receiving RT; Target Hb      disease free                   1 year survival EPO 77.3%, control 79.9%
(301/800)                                                         survival                                                       out 2Q07 (Data on file #9, JJPRD; FDA
                        12.5-15 g/dL              survival                    (p=0.867)
                                                                                                                                 ODAC Briefing Information, May 10, 2007)

KEY: Hb, hemoglobin; EPO, epoetin alfa RT,radiation therapy; HR, Hazard Ratio,
1
    Protocol amended in October 2003 to target Hb range of 12-13 g/dL
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                                        Page 12 of 32



Epoetin alfa Pharmacovigilance Program Evaluating Safety in Epoetin alfa Safety in Patients with Chemotherapy-induced Anemia

 STUDY #        Tumor Type                    Primary           Secondary                            Safety Results                                          Status
(n, accrual/                                  Endpoint           Endpoint
 planned)
                                                                                                                                               Closed to accrual October 2002; 5
                                                                 5 yr DFS,     5yr disease free survival: EPO 72%, control 71% (p=0.86)
                     Breast cancer;         2 year disease                                                                                     yr survival data mature 2Q2008;
  Moebus                                                        5 yr Overall   overall survival as of Apr. ‘07: EPO 81%, control 83%
                 Target Hb 12.5 -13 g/dl     free survival                                                                                     Abstract published (Data on file #7,
                                                                  survival     (p=0.89)
                                                                                                                                               JJPRD; Moebus 2007)
                                                                                                                                               Accrual ongoing (JJPRD trial
                    Breast cancer
 EPO-ANE-                                   Progression-         Overall                                                                       available at
                Target Hb not to exceed                                        Patient accrual ongoing
   3010
                        12 g/dl
                                            free survival        survival                                                                      www.clinicaltrials.gov - ID
                                                                                                                                               NCT00338286)
 EPO-CAN-        Breast cancer, treated                                        A total of 55 subjects died (27 in the epoetin alfa group and   Closed to accrual May 2003;
                                                                2 yr Overall
     17           with chemotherapy         Quality of life                    28 in the SOC group). Kaplan-Meier estimates of the             Clinical Study Report Submitted to
                                                                  survival
  (354/350)      Target Hb 12-14 g/dL                                          survival curves were similar (log rank test, p=0.82)            FDA (Chang 2005)
                                                                               Interim analyses
                                                                               Recurrence rate: EPO 11%, control 22% (p=0.04),
    AGO/         Cervical cancer, treated
                                            5 year relapse                     Median observation time: 64 weeks                               Closed to accrual March 2001;
  NOGGO           with chemotherapy                              Overall
                                             free survival                                                                                     Follow-up ongoing, 5 yr relapse
  (264/264)        Target Hb 13 g/dL                             survival
                                                                        The difference in recurrence between the groups at the                 free survival data available 3Q’07
                                                                        105-week observation was less (25% versus 17% for the                  (Blohmer 2003)
                                                                        control and epoetin alfa groups, respectively), but trended
                                                                        toward significance (p=0.074)
KEY: Hb, hemoglobin; EPO, epoetin alfa; JJPRD: Johnson & Johnson Pharmaceutical Research & Development, L.L.C; RT, radiation therapy;
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                        Page 13 of 32



Lack of ESA and transfusion comparability
The NCD assumes incorrectly that transfusions and ESA treatment are interchangeable.

Clinical studies reported inferior cancer-related and mortality outcomes in transfused patients
compared with non-transfused patients.

CMS’ national coverage policy for ESAs positions ESAs and transfusions as interchangeable substitutes for
one other. In their communications, CMS has even suggested that transfusions are at best preferred, or at
worst “not a big deal” for cancer patients with chemotherapy-induced anemia (CIA). This approach ignores
the fundamental differences between the therapeutic goals, patient experience, timing, effects, and known
and theorized risks of each. The NCD forces a singular and substituted judgment on all Medicare
beneficiaries with chemotherapy-induced anemia (CIA). This judgment is levied in the presence of
incomplete evidence of differential harm, yet tangible differences, in why the treatments are used, and how
they are perceived by and delivered to patients. In addition, the potential for unintended and harmful
consequences for other patients -- those who urgently require blood or time in an infusion chair/hospital bed --
appear to have been ignored.

ESAs are pharmacologic treatments whose primary therapeutic goal is to reduce the risks of transfusion, with
a secondary goal of reducing the signs and symptoms of anemia. The decision of when to treat with ESAs is
driven by the primary therapeutic goal, and a Hb trigger of 10g/dL is not uncommon because ESA treatment
effects are not seen until 2-6 weeks after treatment initiation, during which time hematopoietic stimulation and
the production of red blood cells occurs. The onset of action has been well described in the FDA Medical
Officer report of weekly epoetin alfa in this population:

         “...Following exogenous erythropoietin administration, a clinically significant increase in hemoglobin is
         usually not observed in less than 2 weeks and may require up to 6 weeks because of the length of
         time required for erythropoiesis-several days for erythroid progenitors to mature and be released in
         the circulation...” (FDA Medical Officer report, p. 9)

Evidence in randomized controlled trials shows that transfusion avoidance is maintained with continuous
treatment and a hemoglobin target of 10-12g/dL (Abels 1996, Witzig 2005, Vansteenkiste 2002, Canon
2006). There is no evidence that intermittent ESA treatment or limiting ESA administration to Hb levels <10
g/dL following the initial four weeks of ESA treatment is effective or safe in avoiding blood transfusions.

There are data on the inability of blood transfusions to sustain Hb levels over time. The chart below depicts
Hb levels over time in 11 multiple myeloma patients treated with either 150 IU/kg TIW epoetin alfa or blood
transfusion. The vertical arrows indicate time points of allogeneic blood transfusion. The ‘without epoetin alfa’
line shows patients not receiving epoetin alfa who are repeatedly subjected to allogeneic red blood cell
transfusions. (Couture 2005). It is apparent that blood transfusions provide only transient relief and fail to
maintain Hb levels compared to continuous epoetin alfa therapy.
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                      Page 14 of 32



ESAs are readily available, and their use can spare blood consumption in cancer chemotherapy patients in
whom transfusion can be avoided. ESA treatment is typically delivered at a doctor’s office 2-4 times a month
via subcutaneous injection, during a visit that is routinely scheduled for physician consultation, therapeutic
treatment or diagnostic monitoring. Known risks include thrombovascular events (TVEs) when patients are
treated to Hb levels above 12g/dL in clinical trials. In those trials, higher mortality has been observed. While
that outcome is partially attributable to TVEs, it is also hypothesized to be the result of tumor proliferation.

Blood transfusion is a medical procedure with therapeutic goals of hemodynamic stability and alleviation of
anemia-related signs and symptoms. The decision to intervene with transfusion is usually driven by the
patient’s clinical condition, inclusive of tumor- and treatment-related side effects, comorbidities, and the
severity/rapidity of anemia onset. A Hb trigger of 8-10 g/dL is not uncommon in the cancer chemotherapy
population, as seen in clinical trials and observational studies. Treatment effects are seen immediately, with
response rate and duration dictated by the clinical scenario and alloimmunization from previous blood
transfusions. Blood is a very limited resource, most of which is consumed in urgent settings such as trauma
and surgery. Transfusion for CIA requires patients to wait for scheduling availability, travel to the hospital,
provide informed consent, undergo multiple tests, experience venous access, occupy one of a limited number
of infusion chairs or beds while receiving blood, spend from 12-24 hours in the hospital, and occasionally be
admitted. From a humanistic perspective, patient perceptions of blood transfusion elicit intermediate ratings of
dread and severity similar to reactions of genetically modified food, nuclear reactors, and pesticides (Lee
2006). Known risks of blood transfusion include blood type mismatches, infection, thrombovascular events,
immunomodulation, transfusion-related acute lung injury (TRALI), and fluid or iron overload as described in
                              th
the Ortho Biotech June 13 clinical white paper submitted to CMS.

Adverse patient outcomes have been associated with transfusion in multiple patient populations, including
increased cancer recurrence rates in colorectal cancer patients, and increased morality in patients with acute
lung injury and trauma patients.

In a Cochrane meta-analysis, Amato et al (2006) reported increased cancer recurrence rate in patients that
received perioperative transfusion.

         “...Thirty-six studies on 12,127 patients were included: 23 showed a detrimental effect of
         PBT (perioperative blood transfusion); 22 used also multivariable analyses, and 14 found
         PBT to be an independent prognostic factor. Pooled estimates of PBT effect on colorectal
         cancer recurrence yielded overall OR of 1.42 (95% CI, 1.20 to 1.67) against transfused
         patients in randomized controlled studies. Stratified meta-analyses confirmed these
         findings, also when stratifying patients by site and stage of disease. The PBT effect was
         observed regardless of timing, type, and in a dose-related fashion, although
         heterogeneity was detected...” (Amato 2006)

Netzer (2007) reported transfused of red blood cells in patients with acute lung injury was associated with
increased hospitalization.

         “...RBC transfusion was evaluated as a risk factor using several methods, all of which revealed an
         association with mortality. As a dichotomous variable, the transfusion of any RBCs (> 1 U) was
         associated with an unadjusted OR for mortality of 2.90 (95% confidence interval [CI], 1.32 to 6.35; p
         = 0.008) compared to those never receiving RBCs. This increased OR remained significant (3.12;
         95% CI, 1.28 to 7.58; p= 0.012) when adjusted for age, gender, APACHE III score, and precipitating
         event in a logistic regression model....” (Netzer 2007)

Malone (2003) reported blood transfusion as an independent predictor of mortality, ICU admission, ICU length
of stay, and hospital length of stay in a study of > 15,000 trauma patients.

         “...Logistic regression analysis documented a significantly increased risk for mortality in Blood
         Transfusion patients (OR, 2.83; 95% CI, 1.82–4.40) (Table 5) after controlling for all other
         confounding variables that affect trauma mortality (including ISS, GCS score, age, and race) and all
         available shock variables (including lactate, base deficit, and shock index). Blood transfusion was
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                  Page 15 of 32



         therefore confirmed as a significant independent predictor of adverse trauma outcome, characterized
         by increased mortality...” (Malone 2003)

The pathophysiology of the adverse outcomes in patients requiring transfusion is under investigation;
however, may be due in part to red blood cell changes that occur during storage. (Bennett-Guerrero 2007,
Reynolds 2007)

ESA manufacturers have studies underway to determine if there is an increased risk of tumor
proliferation caused by ESAs compared with transfusion. In contrast, there is no parallel research
program to determine the excess risk of tumor proliferation caused by transfusion compared to
patients who undergo no transfusion. It is often the case when drug and procedure treatments
are being compared, even if incorrectly, that there is less high quality evidence available on the
risks and benefits of the procedure. However, it is important to recognize that this does not mean
that the procedure is a superior choice.

Legal Considerations

The NCD conflicts with CMS’s obligations under the Social Security Act

The NCD conflicts with the plain language of the Social Security Act (“SSA”), 42 U.S.C. §§ 1395d,
1395k, and 1395x. In 1993, Congress amended the SSA to mandate that Medicare must provide
coverage for drugs used in connection with an “anticancer chemotherapeutic regimen for a
medically accepted indication,” including “any use which has been approved by the [FDA].” 42
U.S.C. § 1395x(t)(2) (emphasis added). Despite Congress’ mandate, the NCD bans Medicare
coverage for FDA-approved uses of ESAs in circumstances where they previously were eligible
for coverage.

Medicare Parts A and B both provide coverage for “drugs” and “biologicals.” E.g., 42 U.S.C.
§§ 1395d(a)(1); 1395x(b)(2) (covering “drugs” and “biologicals” under Part A); 42 U.S.C. §
1395x(s)(2)(A)-(B) (covering “drugs and biologicals” under Part B). “Drugs” and “biologicals” are
defined to include “any drugs or biologicals used in an anticancer chemotherapeutic regimen for a
medically accepted indication.” 42 U.S.C. § 1395x(t)(2)(A). Congress amended the statute in
1993 to define the term “medically accepted indication” to include “any use which has been
approved by the [FDA].” Id. § 1395x(t)(2)(B) (emphasis added).

Prior to 1993, the SSA’s definition of “drugs” and “biologicals” included only drugs and biologicals
listed in specified compendia. See 42 U.S.C. § 1395x(t) (1990); SSA, Pub. L. No. 89-97, § 102,
79 Stat. 286, 322 (1965) (amended 1993). Congress amended the definition in 1993 to mandate
that Medicare cover all FDA-approved drugs for all FDA-approved (and certain off-label) uses in
an anticancer chemotherapeutic regimen. See 42 U.S.C. § 1395x(t)(2). In introducing a bill that
included the provision that was codified with no material change at 42 U.S.C. § 1395x(t)(2), the
sponsors explained that “the bill would establish a uniform policy by requiring Medicare to cover
any use of an FDA-approved drug in an anticancer therapeutic regimen that . . . appears in the
drug’s labeling” Testimony of Sander M. Levin, Congressional Record, Extension of Remarks,
139 Cong. Rec. E992-04, E993-94 (Apr. 21, 1993) (emphasis added). The sponsors further
explained that the legislation would ensure that “[a]ny use of an FDA-approved anticancer drug
that is approved by FDA . . . is considered a medically accepted indication and must be covered.”
Id. (emphasis added).

In the NCD, CMS contends that it has authority to restrict coverage of FDA-approved uses of
ESAs under 42 U.S.C. § 1395y(a)(1)(A), which states that “no payment may be made under part
A or part B for any expenses incurred for items or services” unless they are “reasonable and
necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a
malformed body member.” 42 U.S.C. § 1395y(a)(1)(A). CMS is in error. CMS’ assertion that it
retains discretion to determine that certain FDA-approved uses of cancer drugs it deems not
“reasonable and necessary,” renders Section 1395x(t)(2) meaningless. If the plain language of
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                           Page 16 of 32



§ 1395x(t)(2) does not cabin CMS’s discretion with respect to coverage determinations for
approved and off-label uses of cancer drugs, it accomplishes nothing at all. CMS’s interpretation
thus conflicts with the “‘cardinal principle of statutory construction “that ‘a statute ought, upon the
whole, to be so construed that, if it can be prevented, no clause, sentence, or word shall be
superfluous, void, or insignificant.” TRW v. Andrews, 534 U.S. 19, 31 (2001) (quoting Duncan v.
Walker, 533 U.S. 167, 174 (2001)); see also New York v. EPA, 443 F.3d 880, 887 (D.C. Cir.
2006). Because Congress must have intended its reference to “medically accepted indications”
of cancer drugs to have significance, CMS’s interpretation of § 1395y(a)(1)(A) as permitting it to
restrict coverage of uses that meet the definition of medically accepted indications is in error.

In short, the plain language and legislative history make irrefutably clear that Section 1395x(t)(2)
restrains CMS’s discretion to deny coverage of an FDA-approved use of an anticancer drug on
the basis of safety and effectiveness. Congress left that determination exclusively to the FDA.
Congress’ desire for uniform coverage of anticancer drugs -- and its considered judgment that
“any use that has been approved by the Food and Drug Administration” for such drugs must be
covered by Medicare -- would be wholly inconsistent with an interpretation of
Section 1395y(a)(1)(A) that allows CMS to deny or restrict coverage of anticancer drugs on the
basis of safety and effectiveness.

The NCD’s failure to cover the FDA-approved use

In 2007, following the release of results from additional clinical studies, the FDA required that the
Procrit label be changed to strengthen warnings of health risks associated with ESAs when used
to treat patients with Hb levels above 12 g/dL. 1 The revised label directs prescribers to use the
lowest doses of Procrit necessary to avoid the need for transfusions so long as the Hb is not
elevated above 12 g/dL. The revisions to the label did not limit the approved use of the product to
instances in which the Hb is below 10 g/dL but, instead, expressly permits use of ESAs when the
Hb does not exceed 12 g/dL. Since that time, FDA has confirmed repeatedly that ESAs are safe
and effective as long as they are not administered to target Hb of greater than 12 g/dL. In recent
testimony to the United States House of Representatives Committee on Ways and Means
Subcommittee on Health, for example, John K. Jenkins, M.D.,Director of the Office of New Drugs
Center for Drug Evaluation and Research at the FDA, confirmed that the “FDA continues to
believe that ESAs are safe and effective when used according to the recently revised product
labeling, at the recommended dose and approved indication”,” (June 26, 2007), available at
http://www.fda.gov/ola/2007/esa062607.html (hereinafter, “Jenkins Testimony”).

The NCD conflicts and is inconsistent with FDA-approved uses of Procrit in many respects:

         (1)            The NCD does not permit a patient to be initiated on Procrit until the patient’s Hb level
                        falls below 10 g/dL, despite the fact that the FDA-approved label permits initiating
                        Procrit any time an individual patient’s Hb is below 12 g/dL if treatment is necessary to
                        avoid transfusion.

         (2)            Once a patient has received an initial ESA regimen, use of Procrit must be withdrawn
                        each time the patient’s Hb level exceeds 10 g/dL, despite the fact that the FDA
                        approves use of Procrit allows for treatment until the patient’s Hb level reaches 12g/dL.



1
  In late 2006 and early 2007, the results of several studies regarding investigational uses of ESAs were released
(hereinafter, the “Investigational-Use Studies”). According to the FDA, these “studies were evaluating an unapproved
dosing regimen, a patient population for which ESAs are not approved, or a new unapproved ESA.” FDA Alert
(11/16/2006, Updated 2/16/2007 and 3/9/2007), available at http://www.fda.gov/cder/drug/infopage/RHE/default.htm.
(emphasis added). None of the studies reviewed -- or even addressed -- the safety and effectiveness of ESA treatments
used only when an chemotherapy-induced anemic cancer patient’s hemoglobin level falls below 10 g/dL. The FDA
reviewed the results of these studies and issued revised warnings regarding possible health risks associated with ESA
treatment. The FDA did not alter the approved uses for ESAs used in connection with a chemotherapy regimen.
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                          Page 17 of 32



         (3)            The NCD establishes dose adjustments for Procrit that are different from and
                        inconsistent with FDA-approved dosage adjustments.

         (4)            The NCD prohibits continued use of Procrit where a patient’s Hb levels increase by less
                        than 1 g/dL after eight weeks of treatment, despite the fact that continued use in such
                        circumstances is consistent with FDA-approved uses.

         (5)            When Procrit is withdrawn because a patient’s Hb level exceeds 12 g/dL, as the FDA
                        Label instructs, the NCD prevents resumption of Procrit treatment until the patient’s Hb
                        level falls below 10 g/dL, despite the fact that the FDA approves resumption of
                        treatment when a patient’s Hb level falls below 11 g/dL.

The NCD conflicts with CMS’ obligations under the Administrative and Procedure Act

The NCD is also in error under the Administrative Procedure Act (“APA”), 5 U.S.C. § 706(2)(A). CMS has
restricted coverage for ESAs to uses that have never been clinically tested and that are contrary to scientific
evidence and oncology standards of care confirmed by FDA to be safe and effective. CMS has established
no evidentiary record supporting the clinical limitations on ESA coverage in the NCD that are not also
contained in the FDA-approved labeling for ESAs. CMS action is therefore arbitrary, capricious, and an
abuse of discretion and, as a consequence, must be set aside.

A national coverage determination, like other final agency actions, may not be arbitrary, capricious, or an
abuse of discretion. See 5 U.S.C. § 706(2)(A). Although a court will not substitute its own judgment for that of
the agency, the agency must articulate “a satisfactory explanation for its action including a ‘rational connection
between the facts found and the choice made.’” Motor Vehicle Mfrs. Ass’n v. State Farm Mut. Auto. Ins. Co.,
463 U.S. 29, 43 (1983) (quoting Burlington Truck Lines v. United States, 371 U.S. 156, 168 (1962)); PPL
Wallingford Energy LLC v. FERC, 419 F.3d 1194, 1198 (D.C. Cir. 2005).

In accord with the APA, an agency “must cogently explain why it has exercised its discretion in a given
manner,” State Farm, 463 U.S. at 48–49, so that a reviewing court is able “to conclude that the agency’s
action was the product of reasoned decision-making,” id. at 52. If the agency does not cogently explain its
decision, or if it omits consideration of important factors or considers inappropriate factors, its decision must be
set aside. Id. at 43, 48; A.L. Pharma v. Shalala, 62 F.3d 1484, 1492 (D.C. Cir. 1995).

CMS has failed to articulate an adequate explanation for the NCD’s curtailment of coverage of FDA-approved
uses of ESAs. CMS’ decision departs from the standard of care recognized by thousands of oncologists and
hematologists, from existing clinical studies, and from FDA’s reasoned and expert conclusion that Procrit is
safe and effective for the uses specified in the FDA-approved label. The NCD results in an arbitrary treatment
regimen that has not been shown to be safe or effective, which prevents Medicare beneficiaries from
receiving treatment consistent with well-established standards of care for the treatment of seriously ill cancer
patients. CMS’ action is thus arbitrary and capricious, and CMS should suspend the NCD and reconsider it.

CMS has been down this path before. In Estate of Aitken, Medicare beneficiaries and a physician
organization challenged a national coverage determination issued by the Health Care Financing
Administration (now CMS), arguing that the national coverage determination was arbitrary and capricious
because the scientific study upon which it was based did not support the agency’s decision. 986 F. Supp. 57,
61-66 (D. Mass. 1997). The district court agreed, issued a preliminary injunction prohibiting enforcement of
the national coverage determination, and remanded the matter to the agency. Estate of Aitken, 986 F. Supp.
57, 61-66 (D. Mass 1997).

Here, as in Estate of Aitken, the purported scientific studies underlying the NCD do not provide support for the
limitations on coverage imposed in the NCD. Here, as there, the record lacks “‘adequate information to
support the validity of the determination’” and runs “‘counter to the evidence before the agency.’” Estate of
Aitken, 986 F. Supp. at 64. There is one material difference between the two cases. In the case of ESAs, the
NCD provides coverage in circumstances that have never been proven safe and effective. Conversely,
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                       Page 18 of 32



whereas the published studies that did not adequately support the agency decision in Estate of Aitken
supported a conclusion that the treatment at issue was “about as effective as ‘conventional’ therapy.” 986 F.
Supp. at 64. Just as in that case, CMS’ NCD on ESAs is arbitrary and capricious, and should be suspended
and reconsidered.

Additionally, the NCD is impermissibly arbitrary and capricious because it departs from CMS’ longstanding
policy of deferring to FDA on determinations of whether a drug is safe and effective. In fact, CMS’ ill-
considered decision that many uses of ESAs are not safe, marks a radical departure from prior Agency policy.
CMS has recognized repeatedly that it is the FDA that “must determine that a product is safe and effective.”
As the Agency has recognized in the past, Congress charted a different role for CMS: “CMS must determine
that the product is reasonable and necessary.” 68 Fed. Reg. 55634, 55636 (Sept. 26, 2003). FDA -- and not
CMS -- is the appropriate agency to determine whether a drug is safe and effective: “Drugs or biologicals
approved for marketing by the Food and Drug Administration (FDA) are considered safe and effective . . .
when used for indications specified on the labeling. Medicare Benefit Policy Manual, Chapter 15, Section
50.4.1. CMS’ departure from its longstanding (and sound) policy of deference to FDA on matters of safety
and effectiveness is erroneous, and a proper basis on which to suspend application of the NCD and
reconsider it.

Policies and Process

In addition to the case for reopening the ESA NCD based on new data and material misinterpretations of
data, we believe that CMS should consider issues of the fairness and transparency of the process, as well as
the unprecedented policy changes the NCD represents, which have not been subject to public comment.

Unprecedented Restriction in Coverage for an FDA-approved drug

This is the first case where CMS is more restrictive in its coverage policy for a drug than the FDA-approved
label. CMS’ coverage policy is based on statutory language stating that Medicare should not cover and
reimburse for items and services which “are not reasonable and necessary for the diagnosis or treatment of
illness or injury or to improve the functioning of a malformed body member…” The agency’s longstanding
drug coverage policy has been to cover Part B drugs for the FDA approved use but to leave to local carriers
and intermediaries review and coverage of off-label uses. In the ESA NCD, CMS has restricted coverage in
an unprecedented way for previously covered drugs and has done so without clinical evidence to support its
more restrictive coverage. The agency has migrated from not covering items and services that are proven
harmful to asserting theoretical harm and requiring that sponsors and clinicians prove that no harm exists.

We strongly urge CMS to continue to give FDA-approved labeling appropriate weight in reaching coverage
decisions. In this case, the FDA Oncologic Drug Advisory Committee recently reviewed the issue of Hb
treatment limits and chose not to recommend that FDA reduce the limit below 12 g/dL.

Restriction in Coverage that Departs from Benefit/Risk Considerations and “Reasonable and
Necessary” Requirements

In approving drugs, FDA weighs evidence of safety and efficacy and makes a regulatory decision that reflects
both the benefits and risks of those drugs. CMS’s rationale for setting a coverage limit when the patient’s Hb
reaches 10 g/dL is that such a limit will diminish the risks associated with tumor progression, though CMS has
no evidence of tumor progression in the range of 10-12 g/dL. So, unlike other drugs covered by Medicare
under both Parts B and D, CMS is imposing with ESAs a limit based on theoretical harm and limiting
clinicians’ ability to judge when ESAs are beneficial for individual patients beyond Hb levels of 10g/dL. This
approach, considering only potential risk without regard to individual patient benefit is also unprecedented with
regard to drugs covered by Medicare. CMS is judging that ESA treatment is not medically necessary above
the limit, though the agency does not have evidence to substantiate this position.

Absence of Public Comment on the Hb Cap
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                        Page 19 of 32



The proposed NCD did not propose a Hb cap. Rather, it proposed that beneficiaries would be eligible for
ESA initiation only when their Hb levels were below 9 g/dL. While we understand CMS received many
comments critical of such an initiation level, the oncology community had no reason to provide comments on
a Hb cap, since none was clearly proposed. As such, the agency reached its conclusion without a full and
meaningful discussion of relevant information, such as that contained in the attached Cochrane analysis.
(Bohlius 2007)

Although CMS did not solicit information on the topic, we know from the pharmacodynamics of ESAs that
withholding treatment for Hb values greater than 10 g/dL in the setting of concomitant myelosuppressive
chemotherapy will result in wider Hb fluctuations and an increased transfusion frequency for a substantial
proportion of patients whose Hb will continue to fall while waiting for the beneficial effect of ESA re-treatment.
Multiple interruptions of ESA treatment are likely to compromise the clinical benefit of these agents for
Medicare beneficiaries with chemotherapy-induced anemia.

Absence of Public Comment on Dose Escalation

Likewise, the proposed coverage memorandum contained no discussion of allowing only a onetime
escalation of 25% of the starting dose as was included in the final NCD. Had the agency sought such
comment, CMS likely would have received evidence relating to the clinical trials that established the dose
escalation algorithms contained in the approved product labeling for all ESAs. In fact, we have not been able
to determine on what evidence CMS based this limitation. We would suggest that if CMS reached this
conclusion it was based on the dose escalation required as part of the label for ESAs used in chronic renal
failure, which is directed at patients with very different underlying conditions and responses.

Lack of Transparency

Johnson & Johnson and many others have commended CMS for advancing “coverage with evidence
development,” as a way to provide expedited access to important new treatments with additional data
collection, to increase the evidence for refining and improving coverage policy over time. Just as CMS is
requiring more data and transparency of results to guide coverage policy, CMS should hold itself accountable
to the same standard. The agency should demonstrate in a scientifically appropriate format that the ESA
NCD is evidence-based and should not simply list, as justification for its conclusions, an 800-article
bibliography. AHRQ’s Evidence-based Practice Centers specify individual studies that were examined and
the conclusions that may or may not be reached. Both the United States Preventive Services Task Force and
the Cochrane Collaboration use a similar format. We request that CMS provide such an analysis, at a
minimum, of the studies used to support the Hb treatment cap of 10 g/dL and the one-time dose escalation
algorithm of 25%.

Failure to Consult with Clinical Oncologists and other Experts on the Final NCD

The safety and efficacy of ESAs is well established in treating chemotherapy-induced anemia. Considering
the use in large numbers of cancer patients, the clinical guidelines of the two principal physician specialty
societies – the American Society for Clinical Oncology and the American Society for Hematology -- and the
impact on patient care, CMS should have included input from clinical oncologists in the review and
consideration of the final NCD. The agency’s own Medicare Evidence and Coverage Advisory Committee,
(MedCAC) which includes oncologists, would have been an appropriate body with which to consult on a final
NCD of this significance. While CMS received public comments from oncologists, public comment is no
substitute for having oncologists participate in the data analysis and direct deliberations about the appropriate
parameters for ESA coverage.

Further, the Agency for Healthcare Research and Quality of HHS completed a comprehensive assessment of
ESAs in May 2006. AHRQ’s assessment raised questions about thromboembolic complications, but
concluded that the evidence was not sufficient for conclusions on thresholds for initiating treatment or criteria
for discontinuing therapy, quality of life, tumor response and progression, survival, or adverse outcomes other
than thromboembolic events. Given their recent assessment and expertise in weighing evidence, at a
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                     Page 20 of 32



minimum, CMS should have consulted AHRQ in developing the final NCD. AHRQ has conducted many
technology assessments for CMS and was well -suited to provide advice on this NCD.

Process Concerns
While CMS has adhered rigidly to its interpretation of the MMA statutory language regarding issuance of
NCDs, including the “immediate” effective date, timeframes, etc., the agency does not have a process
governing the issuance of clarifying instructions, even after having a series of calls with stakeholders, where
clarifying information was provided. The prescribed timeframe or any obligation to respond to a request for
reconsideration are also unclear. Rather than responses to their specific requests for reconsideration, earlier
requesters received a letter restating the basis for reopening the NCD and asking specific questions.

Following the issuance of the final NCD, concerned stakeholders were told, “if we have made a mistake, we
want to fix it.” We are proposing reopening the NCD as a critical first step in doing that. Although the agency
leadership has said repeatedly that the NCD policies are not driven by cost considerations, since those
policies have not specifically been tied to evidence, CMS leaves the impression that cost containment is a
major consideration in formulating this decision.


Recommendations

     1.       CMS should immediately suspend the ESA National Coverage Decision and reconsider the
              issues of an upper hemoglobin limit of 10 g/dL; the hemoglobin level threshold for initiation
              therapy; the dose reduction approach; and the one-time 25% dose escalation following the initial
              4 week treatment period for patients who do not achieve at least a 1 g/dL rise in hemoglobin
              concentration.

     2.       The NCD as currently formulated is likely to result in avoidable transfusions for some Medicare
              beneficiaries who receive ESAs. Therefore, the agency should immediately suspend the
              implementation of the NCD. We have previously indicated that CMS has the flexibility to take
              this course of action.

     3.       CMS should convene MedCAC, or an oncology subset of MedCAC, to consider the evidence,
              comments, and formulate the final NCD policy.

     4.       CMS should revise the final NCD format so that the evidence base for the final coverage policy
              is clear. Similar to AHRQ, USPSTF, and the Cochrane Collaboration, the agency should
              provide linkage from conclusions that may be reached from the studies on which it relied.

     5.       During its reconsideration process, CMS should solicit recommendations from stakeholders
              regarding dosing strategies that would encourage providers to use the lowest dose of ESAs to
              avoid transfusions, without materially increasing the number of Medicare beneficiaries requiring
              blood transfusions due to chemotherapy-induced anemia.

NCD Material Misinterpretations or Lack of Considération of Evidence

We agree with the use of erythropoietic stimulating agents (ESAs) supports quality care for Medicare
beneficiaries; however, the current ESA NCD represents fundamental misinterpretations of existing evidence
regarding safe and effective ESA use. This appendix will highlight areas where CMS has materially
misinterpreted the evidence.

1.   The totality of evidence regarding ESA safety has been misinterpreted.

FDA, EMEA, and the Cochrane Collaboration have all looked at the totality of public data and reached
the conclusion that existing evidence establishes an upper safety limit for Hb of 12 g/dL when ESAs
are used to treat chemotherapy induced anemia, rather than 10 g/dL.
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                     Page 21 of 32




EMEA recently reviewed the data in light of the safety concerns and came to the conclusion that an
appropriate target Hb concentration is 10-12 g/dL, with an upper Hb limit of 12 g/dL.

This view of the totality of data is consistent with the view of nearly every source of expert review
cited by CMS as a source of expert opinion. These conclusions are supported by a variety of
published clinical trials, including the Cochrane Collaboration meta-analysis (Bohlius 2007)
demonstrating that the signal of decreased survival in ESA-treated patients is coming exclusively
from “correction beyond anemia studies” i.e. those studies with baseline Hb levels > 12 g/dL.

Whereas it is true that a subset of patients never achieve the high target hemoglobin
levels in these studies, there is no evidence of adverse survival outcomes in this
responding subgroup, nor is it statistically valid to use the findings from the “non-
responding” subgroup, which is confounded by numerous comorbidities, as the basis for
policy development.

Investigational studies have demonstrated adverse safety signals when ESA were initiated and maintained to
a Hb > 12 g/dL (Leyland-Jones 2005, DHANCA 2007) or in the anemia of cancer population (Wright 2007,
Amgen anemia of cancer study). There is agreement that ESA should not be used in such investigational
circumstances. These findings have been discussed with the FDA, which led to a boxed warning
contraindicating this use.

CMS extrapolated these investigational findings and applied them to all ESA use in the cancer chemotherapy
population. This is a material misinterpretation of the evidence. Additionally, speculation of patient outcomes
in subsets those dosed in accordance with present FDA-prescribing information may be uninformative as
such conclusions are impaired by the use of post hoc subset analyses that was not the primary or secondary
objective of the clinical trials.

An extensive body of evidence supports that ESA use is safe and effective when used in accordance with the
FDA-approved label. (Abels 1993, Witzig 2005, Vansteenkiste 2002, Canon 2006). Witzig (2005) reported the
results of a placebo-controlled trial of epoetin alfa in cancer patients receiving chemotherapy. This study was
used for FDA registration purposes of weekly epoetin alfa dosing and found no survival differences between
epoetin alfa and placebo.

         “...When the entire group of 330 patients was analyzed, the median overall survival (OS) was 11.2
         months for placebo-treated patients compared with 10.4 months for the epoetin alfa group (P= not
         significant; Fig 4 [below])...”

It did demonstrate significantly fewer transfusion requirements and better Hb changes in the epoetin alfa-
treated group compared with the placebo group.
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                        Page 22 of 32



Fig 4. Overall survival of the 330 patients by treatment group (EPO, epoetin alfa)




These findings were corroborated by the FDA Medical officer review of epoetin alfa once weekly submission,
which stated the following:

         “...The survival curves are similar, with median survival times of 10.9 months (where 1 month=30
         days) in the placebo group and 10.6 months in the epoetin alfa group. The difference was not
         statistically significant via the logrank test (p=0.429). An updated survival analysis was performed
         when the 4-month safety data became available...Overall, 119 subjects (70%) in the placebo group
         and 121 subjects (70%) in the epoetin alfa group died. The median survival times were similar
         between the placebo and epoetin alf groups (10.9 months and 10.8 months, respectively). (FDA
         Medical Officer report p. 33)

Vansteenkiste (2002), another ESA FDA registration trial, reported the findings of a placebo-controlled
darbepoetin alfa clinical trial (baseline Hb < 11 g/dL) that also reported significantly fewer transfusions in the
ESA-treated group. No difference in survival was noted as the authors describe in the following:

         “...All 314 patients who received study drug were included in the analyses of progression-free
         survival and overall survival. One hundred twenty-nine patients (83%) in the darbepoetin alfa group
         and 141 patients (89%) in the placebo group had disease progression or died either during the study
         or during the follow-up period. The median duration of progression-free survival was 22 weeks (95%
         CI=18 to 31 weeks) in the darbepoetin alfa group and 20 weeks (95% CI = 17 to 23 weeks) in the
         placebo group (Fig. 5). Ninety-two patients (59%) in the darbepoetin alfa group and 109 patients
         (69%) in the placebo group died either on study or during the follow-up period. The median duration
         of survival was 46 weeks (95% CI= 39 to 53 weeks) in the darbepoetin alfa group and 34 weeks
         (95% CI= 29 to 39 weeks) in the placebo group...” (Vansteenkiste 2002)

Grote (2006) reported resulted of a placebo-controlled study of ESA use in lung cancer patients. Survival
outcomes were similar between groups as described by the authors.

          “...A total of 201 of the 224 enrolled patients died before the end of the 3-year follow-up period. The
         overall mortality rate was 91.7% (100 of 109 patients) in the epoetin alfa group and 87.8% (101 of
         115 patients) in the placebo group (hazard ratio, 1.172; 95% CI, 0.887 to 1.549; P _ .264); median
         survival times (based on Kaplan-Meier estimates) were 10.5 months and 10.4 months,
         respectively...” (Grote 2006)

The above findings are further supported by the independent meta analyses conducted by the Cochrane
Group (Bohlius 2006 Cochrane) including all ESAs in which analysis of subgroups of studies found different
mortality signals depending on study baseline Hb entry criteria. The hazard ratio for studies with baseline Hb
less than 10 g/dL was 1.01 (95% CI: 0.89 to 1.15; 20 studies and 3,765 subjects). For studies with baseline
Hb of 10 to 12 g/dL, the hazard ratio was 0.98 (95% CI: 0.82 to 1.16; 8 studies, 1,712 subjects). For studies
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                         Page 23 of 32



with baseline Hb greater than 12 g/dL, the hazard ratio for death in the ESA group was 1.27 (95% CI: 1.07 to
2.49, 7 studies, 994 subjects).

Baseline Hb at ESA initiation                                            Survival odds ratio (95% CI)
Hemoglobin < 10 g/dl                                                            1.01 (0.89, 1.15)
Hemoglobin 10-12 g/dl                                                           0.98 (0.82, 1.16)
Hemoglobin > 12 g/dl                                                            1.27 (1.05, 1.54)

At the May 2007 FDA Oncologic Drugs Advisory Committee (ODAC) meeting, the committee reviewed the
evidence surrounding the adverse safety signals and recommended to maintain the current FDA approved
label which sets the upper limit of 12 g/dL for Hb in ESA-treated patients. The current NCD is in direct conflict
with this in that it restricts use of ESAs to Hb not to exceed 10 g/dL for initiation and maintenance. In recent
testimony to the United States House of Representatives Committee on Ways and Means Subcommittee on
Health, for example, John K. Jenkins, M.D., Director of the Office of New Drugs Center for Drug Evaluation
and Research at the FDA, confirmed that the “FDA continues to believe that ESAs are safe and effective
when used according to the recently revised product labeling, at the recommended dose and approved
indication”,” (June 26, 2007), available at http://www.fda.gov/ola/2007/esa062607.html

Following review of all available data, the EMEA’s Committee for Medicinal Products for Human
Use (CHMP) and its Pharmacovigilance Working Party (PhVWP) concluded that the benefits of
these products continue to outweigh their risks in the approved indications, but recommended the
following changes to the product information:

               (1) Changes to the ‘Indication’ section (section 4.1), saying that epoetins should be
                   used in the treatment of anaemia only if associated with symptoms and
               (2) Changes, stipulating a uniform target haemoglobin range for all epoetins of 10
                   g/dL to 12 g/dL with a warning not to exceed a concentration of 12 g/dL.
                   (European Medicines Agency press release, October 23, 2007)


2.   Neither the evidence nor the precision of medical practice support a dosing strategy in which
     ESAs are uniformly initiated and maintained at a Hb level of 10 g/dL.

All of the registration trials for the ESAs currently marketed initiated therapy when Hb fell below a
concentration of 10.5 or greater, and none required withholding of therapy when a Hb level of 10 g/dL
was exceeded.

There is no published literature providing evidence that uniformly withholding ESA therapy until Hb
concentrations fall below 10 g/dL will permit successful avoidance of blood transfusion. Indeed,
observational studies suggest that across populations more blood transfusions will be avoided
when therapy is ordinarily initiated before Hb falls below 10 g/dL.

CMS has materially misinterpreted the evidence by setting the initiation and maintenance at Hb 10 g/dL. A
review of the current literature and references cited in the NCD fails to show evidence where Hb initiation and
maintenance of 10 g/dL is either safe or effective. The clinical studies supporting FDA approval of ESAs did
not involve stopping administration of ESAs when a patient’s Hb exceeded 10 g/dL. The pivotal trials that led
to FDA approval of ESAs in patients with chemotherapy-induced anemia studied baseline Hb at ESA initiation
of 10.5-11.5 g/dL, including FDA approval of one ESA regimen as recently as March 2006.

FDA-approved ESA regimen*              Year of FDA approval          Baseline Hb in FDA-approved registration trial
Aranesp 500 mcg Q3W                             2006                                      < 11 g/dL
Aranesp 2.25 mcg/kg QW                          2002                                      ≤ 11 g/dL
PROCRIT 40,000 U QW                             2004                         < 10.5 g/dL females, < 11.5 males
PROCRIT 150 U/kg TIW                            1993                                    ≤ 10.5 g/dL
* PROCRIT Prescribing Information [3/07], Aranesp Prescribing Information [4/07]
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                       Page 24 of 32




It is unknown what the risks and benefits of an initiation and maintenance at Hb 10 g/dL may have for
Medicare beneficiaries, since it has never been studied and there is no evidence to support this dosing
schema.

Additionally, there are no practice guidelines supporting use of ESAs in the manner described in the NCD.
The National Comprehensive Cancer Network (NCCN) anemia treatment guidelines provide
recommendations regarding ESA initiation at a Hb level of < 11 g/dL for cancer patients with chemotherapy-
induced anemia:

         “Following the identification of anemia (defined for the purpose of considering intervention as
         hemoglobin levels equal to or less than 11 g/dL) and the evaluation for anemia specific causes, an
         initial risk assessment should be completed...The history should assess whether accompanying
         symptoms are present, such as chest pain or dyspnea. Comorbidities such as cardiac disease or
         underlying pulmonary disease must be considered...Observation or erythropoietic therapy should be
         considered for asymptomatic patients with risk factors for developing anemia. The decision of
         whether to use epoetin immediately or to wait until hemoglobin levels fall closer to 10 g/dL should be
         determined by clinical circumstances. For symptomatic patients, transfusion and/or erythropoietic
         therapy are recommended. If the patient's hemoglobin level is between 10-11 g/dL, the panel
         recommends the consideration of erythropoietic therapy with or without transfusion. If the patient's
         hemoglobin level is <10 g/dL, the panel strongly recommends erythropoietic therapy...” (NCCN
         anemia treatment guidelines v.3.2007)

The NCD (p. 21 of 61) quoted the American Society of Hematology/American Society of Clinical Oncology
guidelines; however, only a portion of the guidelines was included. The NCD stated:

         “...ASCO and ASH guidelines recommended evaluating patients for the need for ESA therapy when
         the hemoglobin is at or below 10 g/dL...”

It is unclear why the full guideline was not referenced; as it includes information relevant to the Medicare
population as the American Society of Hematology/American Society of Clinical Oncology (ASH/ASCO)
published anemia treatment guidelines recommend ESA initiation at an Hb of 10-12 g/dL in certain clinical
conditions, such as the elderly.

         “...The guideline panel found good evidence to recommend use of epoetin as a treatment option for
         patients with chemotherapy-associated anemia with a hemoglobin level less than 10 g/dL. Use of
         epoetin for patients with less severe anemia (hemoglobin < 12 g/dL but never below 10 g/dL) should
         be determined by clinical circumstances... Examples of patients at this higher degree of absolute risk,
         who may be considered reasonable candidates for this agent, based on clinical judgment, include
         but are not limited to elderly individuals with limited cardiopulmonary reserve or patients with
         underlying coronary artery disease and symptomatic angina...” (Rizzo 2002)

The narrow Hb target range of 10 g/dL mandated in the ESA NCD does not allow for clinical flexibility in
treating patients. Inter-patient variability and response to medications is well established. In order to provide
the best medical care, physicians need discretion to determine the optimal care for each individual patient
based on that patient’s specific needs. The NCD as written does not allow for that flexibility and hinders the
ability for physicians to safely and effectively tailor ESA use.

The FDA-approved prescribing information for ESAs recommends using the lowest dose possible to avoid
red blood cell transfusions. This statement allows for flexibility in dosing based on patient differences and
physician discretion. It does not dictate Hb initiation or maintenance of 10 g/dL. Practice guidelines also
recognize the importance of inter-patient variability and the need to tailor usage based on specific patient
needs and physician judgment. This is evidenced in suggesting a target range for Hb of 10-12 g/dL based on
patient needs.
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                      Page 25 of 32



CMS has also fundamentally misinterpreted the difference between Hb target and Hb ceiling (i.e. the Hb value
above which ESA treatment should be held). If, as CMS suggests, the optimal benefit of ESAs with respect to
transfusion reduction is achieved by targeting Hb levels around 10 g/dL in patients receiving
myelosuppressive chemotherapy, then that Hb target can never be achieved by implementing a Hb ceiling of
10 g/dL. Again, this is also counter to ODAC's recommendation that a Hb ceiling not to exceed 12 g/dL was
acceptable. It is recognized and understood that 12 g/dL is the upper safety limit that should not be
exceeded,; however, setting the level at 10 g/dL is arbitrary and not founded in scientific evidence.
CMS categorically misinterpreted the clinical trial evidence and the FDA approved prescribing information by
setting the initiation and ceiling for ESAs at Hb 10 g/dL and failed to allow for inter-patient variability when
dosing ESAs.

3.   The dose escalation and reduction schedules in the NCD are inconsistent with the data
     referenced by CMS, which described some of the same data relied upon by FDA to approve the
     labeling for ESAs.

No publications or evidence in the ESA NCD call into question the conclusions reached by FDA with
respect to dose modifications.

CMS materially misinterpreted the data by restricting ESA dose escalation to 25% if the Hb rise is < 1 g/dL.
FDA-approved prescribing information and anemia treatment guidelines recommend a dose escalation of
50% [in the PROCRIT (epoetin alfa) weekly dosing regimen] or 100% in the three times weekly PROCRIT
(epoetin alfa) dosing regimen. The FDA-approved dose escalation for darbepoetin alfa calls for 100% dose
escalation in the once-weekly regimen and no dose escalation is recommended for the 500 mcg every 3-
week regimen.

As written, the ESA dose adjustments described in the NCD encourages use of ESAs that is contrary to the
FDA label and does not preclude a 25% dose escalation for the darbepoetin alfa 500 mcg every 3 week
regimen. This would translate to 625 mcg every 3 weeks, a dose higher than what is recommended in the
FDA label. The FDA label for darbepoetin has no allowance for dose escalation in this particular regimen.
It is unclear what evidence CMS used to recommend a 25% dose escalation for all ESAs. A review of the
literature, the studies cited in the NCD and all published clinical guidelines fail to provide evidence for this
restriction in the oncology population. A 25% dose escalation has not been studied and it is unknown if such
a dosing regimen is safe or effective for Medicare beneficiaries.

For dose reduction, the NCD calls for a 25% reduction if there is greater than a 1 g/dL rise in Hb over a two-
week period. While this is consistent with the prescribing information for epoetin alfa, it is contrary to the
darbepoetin alfa FDA-approved label, which calls for a 40% reduction in dose. The NCD again recommends
higher ESA doses than recommended by the FDA. This discrepancy is not supported by clinical evidence
and it is unclear why CMS is recommending higher doses that could potentially be harmful to Medicare
beneficiaries. It is a clear misinterpretation of the data.

4.   Transfusion triggers used in non-mobile ICU patients are not an appropriate basis for predicting
     transfusion triggers in ambulatory cancer patients receiving chemotherapy. Because the
     reasoning of the NCD relies heavily upon this prediction, it is a material misinterpretation of the
     data.

Blood transfusion patterns in the chemotherapy-treated cancer population are unique from transfusion
patterns in other settings (e.g., critical care) because of the ambulatory status of this population and the
ongoing myelosuppression induced with continued chemotherapy. CMS misinterpreted the evidence when it
extrapolated transfusion Hb triggers used in non-mobile ICU patients to ambulatory cancer patients.
Transfusion needs may vary based on patient age, co-morbid conditions, underlying malignancy, and
chronicity of chemotherapy regimen selected. Barrett-Lee et al. (2000) reported that if the Hb was <10 g/dL
prior to chemotherapy initiation, the probability of at least one transfusion at some point was markedly
increased compared to higher initial Hb levels, with approximately 70% of patents requiring transfusion.
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                           Page 26 of 32



Similar findings have been reported in analyses comparing patients initiated at a Hb < 10 g/dL compared with
those with ESA initiation of 10-11 g/dL. In clinical trials and observation studies, data have reported a higher
proportion of patients requiring blood transfusion in the Hb < 10 g/dL versus Hb 10-11 g/dL. In most trials,
patients had a two-fold increase in transfusions when they were initiated at a Hb < 10 g/dL compared to those
initiation at a Hb 10-11 g/dL.

            Study                       Study Type              Proportion of patients transfusedHb at ESA initiation

                                                                        < 10 g/dL                   10-11 g/dL
Vansteenkiste (2004)                    Clinical trial                    31%                          15%
Boccia (2006)                           Clinical trial                    28%                         12 %
Szczudlo (2007)                         Clinical trial                    36%                           9%
Szczudlo (2007)                         Clinical trial                    29%                           3%
Wang (2007)                            Observational                      31%                          13%

Lyman (2005) also showed in a systematic review of five controlled trials that the proportion of randomized
patients requiring transfusion in the early ESA treatment group (Hb > 10 g/dL) was 14.3% (11.4 – 17.7%)
compared to 25.6% (22.2 – 29.2%) in those patients receiving late ESA treatment. This combined analysis
provides evidence that patients who are initiated on ESAs when their Hb is <10 g/dL have significantly more
transfusions than those who are initiated at higher Hb levels (10 –11 g/dL).

As the NCD is written, CMS misinterpreted the evidence when they stated that the NCD would not affect the
nation’s blood supply. The evidence shown above supports the fact that transfusions do increase when
ESAs are started at lower Hb levels mandated by the NCD.

Ortho Biotech performed a modeling simulation to estimate the impact that limiting the use of ESAs in
chemotherapy-induced anemia would have on the U.S. blood supply. The excess number of units that would
be required if treated patients were not treated with ESAs was compared with the available marginal supply
using 2004 data (the most recently available). Model inputs were drawn from the published literature or expert
opinion where evidence was lacking. Estimates were developed for a range of scenarios and incorporated
into appropriate sensitivity analyses.

The model predicts that up to a third of the marginal U.S. blood supply would be required to cover the
incremental demand for blood that would arise from a 25% decrease in the use of ESAs. Nearly two-thirds of
the marginal blood supply could be compromised with a 50% reduction of ESA use in patients with
chemotherapy-induced anemia. Recent Wall Street Analysts report that the CMS Proposed Decision Memo
on ESAs as written may decrease ESA sales from 25% to 70% (Porges 2007, Werber 2007, Ende 2007,
Hopkins 2007). Such changes in ESA utilization are associated an incremental demand of 118,000-237,000
units of blood. (Data on file, Ortho Biotech) This added pressure on the blood supply could be even greater
due to regional variation in the number of available units and the variable frequency of donation.

The Association of Community Cancer Centers (ACCC) recently conducted a survey that was sent to 650
ACCC member hospitals. One hundred and fifteen sites responded, including rural (20%), urban (39%), and
suburban (41%) hospitals. The survey showed that 40.9% of respondents indicated that a 30% increase in
demand would cause problems in carrying out normal transfusion services. Another 16.5% said even a 10%
or less increase in demand for blood transfusions would cause problems, and 21.7% said any increase would
result in problems.

It is clear from the randomized controlled studies that transfusions do occur in patients with Hb greater than 10
g/dL, and that those patients who are initiated at Hb lower than 10 g/dL compared to those initiated at Hb
greater than 10 are more likely to get transfused. Based on these data and the new data cited in this paper,
transfusion use will increase due to the NCD restrictions and the NCD therefore will have an impact on the
nation’s blood supply.
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                      Page 27 of 32



5.   CMS may have misunderstood the relationship between transfusions and subsequent Hb levels
     as reported in trials comparing ESA to placebo.

A review of the Witzig (2005) publication revealed that hemoglobin values were inclusive of
transfusion effect and transfusion intervention was physician-determined rather than protocol-
specified.

CMS has commented that cancer chemotherapy patients treated with transfusion alone will increase Hb
levels over the treatment course. However, clinical trials in cancer chemotherapy patients treated with
transfusion alone have reported decreases in Hb levels during placebo treatment. A single clinical trial (Witzig
2005) reported Hb increases in placebo group (based on monthly Hb levels inclusive of transfusion), but two
other placebo-controlled ESA trials (Pirker 2002, Grote 2005) reported significant Hb level reduction in
placebo-treated patients.

Witzig (2005) showed a significantly greater proportion of transfusions in the placebo-treated group.
Transfusions were administered at the discretion of the treating physician and Hb values obtained subsequent
to RBC transfusions were not excluded. While there were significantly greater transfusions and inferior Hb
changes in the placebo-treated group, an increase in the Hb concentration was observed in the placebo
group, as shown in the figure below. Hb levels inclusive of transfusion impacted the Hb change of the
placebo group as noted by the FDA Medical Office Review.

         “...Because the transfusion rate was higher in the placebo group than in the epoetin alfa group, the
         effect of transfusion would contribute to Hgb increase to a great degree in the placebo group than in
         the epoetin alfa group...” (FDA Medical officer report p. 28)




Pirker et al (2002) reported a placebo-controlled trial of darbepoetin alfa in lung cancer patients. Inferior
outcomes with regard to transfusion frequency and Hb changes were reported in the placebo group
compared to the darbepoetin alfa-treated group. Additionally, weekly Hb levels which were controlled for
transfusion (Hb values set to missing for 28 days following blood transfusion) reported decrease over baseline
in the placebo-treated patients as shown in the figure below
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                   Page 28 of 32




Grote (2005) reported a double-blind placebo-controlled study of epoetin alfa in lung cancer patients.
Significantly inferior transfusion and Hb changes were reported in the placebo group compared to the epoetin
alfa-treated group. Hb change in the placebo group decreased over the course of the study as shown in the
figure below.

         “...Over all chemotherapy cycles, fewer epoetin alfa patients (26 of 109 patients; 24%) than placebo
         patients (42 of 115 patients; 37%) required RBC transfusions (hazard ratio, 0.597; 95% CI, 0.365 to
         0.977)...Mean baseline hemoglobin levels (epoetin alfa group, 12.8 g/dL; placebo group, 13.0 g/dL)
         were maintained in the epoetin alfa group during the first 22 weeks of study (mean weekly
         hemoglobin range, 11.3 g/dL to 12.7 g/dL), whereas the mean hemoglobin decreased in the placebo
         group to a minimum of 9.9 g/dL at week 14 (Fig 2). At the time of median exposure to study drug (13
         weeks), mean change in hemoglobin was - 0.2 g/dL in the epoetin alfa group and - 2.9 g/dL in the
         placebo group. Mean hemoglobin at the end of cycle 3 was 12.5 g/dL and 10.6 g/dL in the epoetin
         alfa group and placebo groups, respectively, and mean final hemoglobin was 12.2 g/dL and 10.3
         g/dL, respectively (mean difference in hemoglobin between groups at both timepoints, 1.9 g/dL; 95%
         CI, 1.4 to 2.4)...”
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                       Page 29 of 32




These data also illustrate that blood transfusions are an inferior substitute to ESAs for Hb maintenance. While
blood transfusions readily correct the symptoms of anemia, this effect is transient. ESAs typically require 3-4
weeks of dosing to stimulate sustained erythropoiesis, and patients should be appropriately maintained on
ESAs if chemotherapy is ongoing to avoid the cumulative myelosuppressive effects of cancer regimens.
Accordingly, withholding ESA treatment because an Hb may transiently fluctuate above 10 g/dL during
chemotherapy could result in Hb levels decreasing to the point where a patient would require transfusion
support while waiting for resumption of ESA treatment and a sustained erythropoiesis response.

Conclusion
CMS has fundamentally misinterpreted the evidence in several key areas. In many instances these
misinterpretations are putting Medicare beneficiaries at risk because the safety and efficacy of the restrictions
are unknown and have never been tested in clinical trials.
Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                       Page 30 of 32



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Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                        Page 31 of 32



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Attachment to Ortho Biotech’s ESA NCD Reconsideration Request                                                      Page 32 of 32



PROCRIT (Epoetin alfa) Prescribing Information. Distributed by Ortho Biotech Products, L.P., Raritan, NJ.
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