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| **Johnson & Johnson Pharmaceutical Research & Development, L.L.C.\    |
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| **BACKGROUND INFORMATION**                                            |
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| **FOR**                                                               |
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| **Oncologic Drugs Advisory Committee Meeting**                        |
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| **May 4, 2004**                                                       |
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| **Gaithersburg, MD**                                                  |
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| **Safety of Erythropoietin Receptor Agonists (ERAs) in Patients With  |
| Cancer**                                                              |
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| **available for public disclosure without redaction**                 |
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**Issue/Report Date:** 30 MARCH 2004

**Department:** Drug Development

**Document No.:** EDMS- USRA-9005967:2.0

This Advisory Committee Meeting background package is prepared for the
Oncologic Drugs Advisory Committee (ODAC) meeting, to be held on May 4,
2004. This document provides a summary of the relevant findings of the
Company's ongoing evaluation of PROCRIT^®^ safety, including evaluation
of questions that have arisen from recently published studies of other
Erythropoietin Receptor Agonist (ERA) product formulations. Evaluation
of the available data from clinical studies and post-marketing
experience continues to support the safety and effectiveness of PROCRIT,
when used as directed for the approved indications.

TABLE OF CONTENTS

[LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
5](#list-of-abbreviations-and-definitions-of-terms)[1. EXECUTIVE SUMMARY
7](#executive-summary)[2. INTRODUCTION 12](#introduction)[2.1.
Erythropoietin Receptor Agonists, Overview and History
12](#__RefHeading___Toc68427411)[2.2. Clinical Benefits and Safety in
Approved Indications
13](#clinical-benefits-and-safety-in-approved-indications)[2.3. Safety
in Investigational Use 14](#safety-in-investigational-use)[3. SAFETY OF
CURRENT LABELED INDICATION - TREATMENT OF ANEMIA IN CANCER PATIENTS ON
CHEMOTHERAPY
16](#safety-of-current-labeled-indication---treatment-of-anemia-in-cancer-patients-on-chemotherapy)[3.1.
Adverse Events, Including Thrombotic Vascular Events
17](#adverse-events-including-thrombotic-vascular-events)[3.2. Patient
Outcomes 19](#patient-outcomes)[3.2.1. Survival 19](#survival)

[3.2.2. Tumor Response/Disease Progression
22](#tumor-responsedisease-progression)

[3.2.3. Post-Marketing Surveillance 22](#post-marketing-surveillance)

[3.2.4. Conclusion 23](#conclusion)

[4. INVESTIGATIONAL CLINICAL STUDIES -- TREATMENT BEYOND CORRECTION OF
ANEMIA
23](#investigational-clinical-studies-treatment-beyond-correction-of-anemia)[4.1.
Study EPO-INT-76 25](#study-epo-int-76-9)[4.1.1. Study Design
25](#study-design)

[4.1.2. Patient Demographics 26](#__RefHeading___Toc68427424)

[4.1.3. Patient Treatment 27](#__RefHeading___Toc68427425)

[4.1.4. Early Discontinuation of Study Drug Treatment
29](#early-discontinuation-of-study-drug-treatment)

[4.1.5. Data Sets Analyzed 30](#__RefHeading___Toc68427427)

[4.1.6. Survival -- Final Analysis of 12-Month Survival Rate
30](#__RefHeading___Toc68427428)

[4.1.7. Survival -- Deaths Within 4 Months After Randomization
32](#survival-deaths-within-4-months-after-randomization)

[4.1.7.1. Patient Demographics in Patients Who Died Within 4 Months
32](#patient-demographics-in-patients-who-died-within-4-months)

[4.1.7.2. Causes of Death 33](#causes-of-death)

[4.1.8. Tumor Response 35](#__RefHeading___Toc68427432)

[4.1.8.1. Optimal Tumor Response to First‑Line Chemotherapy
35](#__RefHeading___Toc68427433)

[4.1.8.2. Tumor Response at the End of First‑Line Chemotherapy
36](#__RefHeading___Toc68427434)

[4.1.8.3. Tumor Response at Individual Subject Study End
37](#tumor-response-at-individual-subject-study-end)

[4.1.9. Time to Disease Progression 38](#time-to-disease-progression)

[4.1.10. Conclusion 40](#__RefHeading___Toc68427437)

[4.2. Study of Henke M, et al. 40](#study-of-henke-m-et-al.-2)[4.2.1.
Study Design 41](#__RefHeading___Toc68427439)

[4.2.2. Reported Study Results 41](#reported-study-results)

[4.3. Ongoing Study in Follow-Up Phase: Study AGO/NOGGO
42](#ongoing-study-in-follow-up-phase-study-agonoggo10)[4.3.1. Study
Design 42](#study-design-2)

[4.3.2. Preliminary Analysis 43](#preliminary-analysis)

[4.4. Ongoing Study in Follow-Up Phase: EPO-GBR-7
44](#ongoing-study-in-follow-up-phase-epo-gbr-711)[4.4.1. Study Design
45](#__RefHeading___Toc68427445)

[4.4.2. Preliminary Analysis 45](#preliminary-analysis-1)

[4.4.3. Demographic and Baseline Characteristics
46](#__RefHeading___Toc68427447)

[4.4.4. Tumor Response 47](#__RefHeading___Toc68427448)

[4.4.5. Disease Progression 48](#__RefHeading___Toc68427449)

[4.4.5.1. Local Tumor Evidence 48](#__RefHeading___Toc68427450)

[4.4.6. Survival 50](#__RefHeading___Toc68427451)

[4.5. Study N93‑004 52](#study-n9300412)[4.5.1. Tumor Response to
Chemotherapy / Disease Progression 53](#__RefHeading___Toc68427453)

[4.5.2. Overall Survival 56](#__RefHeading___Toc68427454)

[4.6. Other Relevant Information from Clinical Trials
58](#other-relevant-information-from-clinical-trials)[4.6.1. Overall
Incidence of TVEs in Prior Epoetin Alfa Studies
58](#__RefHeading___Toc68427456)

[4.6.2. Recently Discontinued Studies With Imbalances in Thrombotic
Vascular Events and/or Survival
59](#recently-discontinued-studies-with-imbalances-in-thrombotic-vascular-events-andor-survival)

[4.7. Conclusion 62](#__RefHeading___Toc68427458)[5. BENEFIT AND RISK
ASSESSMENT OF ERAs IN PATIENTS WITH CANCER
63](#benefit-and-risk-assessment-of-eras-in-patients-with-cancer)[6.
CONCLUSION 67](#conclusion-3)[7. REFERENCES 68](#references)[APPENDIX
70](#appendix)[**Attachment 1:** Package Insert
71](#__RefHeading___Toc68427463)

[**Attachment 2:** Lancet Letter to the Editor on EPO-INT-76
104](#__RefHeading___Toc68427464)

[**Attachment 3:** Henke Lancet Article
106](#__RefHeading___Toc68427465)

[**Attachment 4:** Overview and Design of PROCRIT and EPREX Clinical
Studies in Oncology 113](#__RefHeading___Toc68427466)

[**Attachment 5**: Preclinical Data on Epoetins and Tumor Proliferation
122](#__RefHeading___Toc68427467)

# LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS {#list-of-abbreviations-and-definitions-of-terms .unnumbered}

**[Abbreviations]{.underline}**

CAC Cvitkovic et Associés Consultants

CI confidence interval

CR complete remission

CRF case report form

DSMB Data Safety Monitoring Board

DVT deep vein thrombsis

ECOG Eastern Cooperative Oncology Group

EpoR erythropoietin receptor

ERA erythropoietin receptor agonist

FIGO International Federation of Gynecology and Obstetrics

HNC head and neck cancer

HUVECs human umbilical vein endothelial cells

IDMC Independent Data Monitoring Committee

LRPFS locoregional progression‑free survival

MI myocardial infarction

PE pulmonary embolism

pNi peri lymph node metastases

PR partial remission

RT radiotherapy

RT-PCR reverse transcriptase polymerase chain reaction

SCLC small cell lung cancer

TIA transient ischemic attack

TVE thrombotic vascular event

**[Definitions of Terms]{.underline}**

Beyond the correction of anemia initiation of ERA treatment in cancer
patients who had a hemoglobin concentration of 13 g/dL or higher, or
continued treatment of patients after anemia was corrected

epoetin alfa recombinant human erythropoietin (r-HuEPO)

LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS (CONTINUED)

**[Definitions of Terms (Continued)]{.underline}**

EPREX^^ Ex-U.S. trade name of epoetin alfa manufactured by Cilag AG,
Division of Johnson and Johnson (Schaffhausen, Switzerland), and
distributed in Europe and other countries. The active substance epoetin
alfa for EPREX is supplied by Ortho Biologics, L.L.C. (Manati, Puerto
Rico).

PROCRIT^^ U.S. trade name of epoetin alfa manufactured by Amgen, Inc.
(Thousand Oaks, CA) and distributed by Ortho Biotech Products, L.P.
(Bridgewater, NJ).

the Sponsor Johnson & Johnson Pharmaceutical Research & Development,
L.L.C. (Sponsor) and affiliates

## EXECUTIVE SUMMARY

Erythropoietin Receptor Agonists (ERAs) are medications that are very
similar to human erythropoietin, both in structure and in biological
activities. The first ERA produced for human use, epoetin alfa, was
introduced in the US in 1989, and has an amino acid sequence identical
to that of natural human urinary erythropoietin. Two different epoetin
alfa formulations are marketed by the Sponsor including EPREX (ex-US)
and PROCRIT (US). These products have provided important benefits to
over 3 million patients with anemia due to renal disease or due to
cancer chemotherapy. In addition to these indications, extensive ongoing
research has led to the identification of additional approved
indications for epoetin alfa, including use for anemia related to
antiviral therapy (azidothymidine, AZT) for HIV infection, or to reduce
the need for transfusions for perisurgical blood loss. The Sponsor is
committed to supporting scientifically appropriate development
activities investigating potential additional benefits that ERAs may
offer patients in existing and future indications.

Other ERAs, introduced more recently, include epoetin beta
(NeoRecormon^®^, ex-US) and darbepoetin alfa (Aranesp^®^, ex-US and
available in the US since 2001). These more recent ERAs share a close
homology with epoetin alfa and endogenous human erythropoietin. The
products in this class of medications act on the same cellular target
(the erythropoietin receptor) on erythroid precursor cells, to produce
their benefits by increasing red blood cell (RBC) production. They also
share similar side effect profiles, including thrombotic vascular events
(TVEs) and hypertension. These recognized side effects are described in
product labels for all medications in the ERA class.

Erythropoietin receptors are expressed on other cell lines besides
erythroid precursor cells. These include vascular endothelial cells and
some tumor cell lines. Whether these receptors have any functional
activity when exposed to clinically relevant concentrations of ERAs is
doubtful, however the theoretical possibility that ERAs could act as
growth factors for tumor cells is reflected in the labeling of products
in this class.

ERAs have been extensively investigated in clinical trials and are
widely used to provide important benefits in terms of treatment of
anemia. The symptoms of anemia include tiredness, shortness of breath,
weakness and fatigue (weariness from labor or exertion). In addition to
correcting anemia, ERAs have proven benefits in reducing the needs for
RBC transfusions, in their approved indications.

Recent investigational studies of ERAs have focused on additional
potential benefits for patients with cancer, including benefits on tumor
response to radiotherapy and improved survival. This research was
prompted by observations that cancer patients with anemia may have
decreased survival. Additionally, a trend towards improved survival was
noted in two prospective studies with different ERAs. Those studies were
not designed to test this hypothesis, but were powered for other
end-points. Subsequently studies have been performed to specifically
evaluate potential effects on survival. The design of these studies
included treatment with ERAs beyond the correction of anemia, with the
intent of maximizing any benefit on survival.

Published findings from two studies evaluating survival, however, have
indicated that there may be increased risks associated with treatment of
non-anemic cancer patients. Treatment beyond the correction of anemia is
defined for the purposes of the Sponsor's evaluation as: initiation of
ERA treatment in cancer patients who are not anemic, or continued ERA
treatment after correction of anemia.

One of these studies, EPO-INT-76, conducted by the Sponsor, investigated
the effects of prolonged treatment of EPREX (epoetin alfa ex-US product)
and maintenance of non-anemic target hemoglobin levels in patients
starting on chemotherapy for metastatic breast cancer. The other study,
conducted by Henke and colleagues, investigated the effects of treatment
with NeoRecormon^®^ (epoetin beta) to high target hemoglobin levels
during radiation therapy for head and neck cancer.

Both studies reported adverse survival outcomes associated with ERA
treatment. These findings were unexpected and not representative of the
Sponsor's prior safety experience in clinical trials. These findings
occurred in the setting of new uses of ERAs in studies conducted outside
of the US, and did not utilize US-marketed formulations of ERAs.
However, the findings of these studies are relevant to all ERAs
including PROCRIT, given the close homology of ERAs in structure and
mechanism of action.

The Sponsor has evaluated the findings of both of these studies as
extensively as possible, has communicated with the FDA regarding the
questions raised by these studies, and has taken appropriate actions
based on the information available to ensure the ongoing safe and
effective use of epoetin alfa products in clinical studies and actual
practice. This included examination of our ongoing oncology clinical
research programs. Study protocols were modified, where necessary, to
reduce entry and target hemoglobin levels to more closely reflect
treatment to correct anemia. Most of the sponsor's studies of epoetin
alfa in oncology have demonstrated no evidence of safety concerns, and
are continuing. A small number of studies, with investigational uses
beyond the correction of anemia, were discontinued due to potential
safety signals relating to adverse experiences and/or survival
imbalances. The data from these studies are preliminary, and, as patient
enrollment was terminated at an early stage, limited conclusions can be
drawn from these studies except for the potential hazards posed by
treating patients beyond the correction of anemia.

To address the important question about the appropriate investigational
use of ERAs, and to assess the safety of these products when used for
approved indications, the Sponsor has undertaken an extensive evaluation
of data from prior clinical studies and data from current studies,
including EPO-INT-76. In addition, the Sponsor's review of the available
data on the study by Henke et al., published in the literature was
considered in this evaluation. The data for this evaluation are derived
from controlled studies to ensure inclusion of the most reliable
information, as follows:

-   12 completed, randomized, double-blind, placebo-controlled studies
    that included over 3,000 patients (10 which focused on treatment of
    anemia, and 2 that evaluated treatment beyond the correction of
    anemia); and

-   2 randomized, double-blind, placebo-controlled studies, and 11
    randomized, open-label, controlled studies, for which only limited
    mortality data are available.

The analyses discussed in this document focus on the 12 completed,
randomized, double-blind, placebo-controlled studies, as these were most
rigorous data available to address these issues. These data were
evaluated with respect to the following key variables; survival, tumor
response/tumor progression and TVEs. A summary of the evaluations from
each section follows.

Clinical studies involving use of epoetin alfa for the treatment of
anemia in patients with cancer who are receiving chemotherapy (the
current approved oncology indication) have shown no signal of an adverse
impact on survival. Data are more limited regarding tumor response and
disease progression, but available data from clinical studies where
these parameters can be evaluated have not revealed any indications of
an adverse effect of epoetin alfa.

Labels for all ERA products describe the association of TVEs with use of
these products. Experience in clinical trials of epoetin alfa in
treatment of anemia in cancer patients receiving chemotherapy, and
information obtained from post-marketing surveillance, is consistent
with this product labeling.

The results of the EPO-INT-76 and Henke et al. studies raised concerns
regarding shortened survival, possibly mediated by enhanced disease
progression. However, other clinical data have provided little support
for an adverse effect on tumor growth or disease progression. Similarly,
preclinical data regarding tumor proliferative effects of ERAs are
viewed as inconclusive. Alternative explanations for the survival
observations of the EPO-INT-76 and Henke studies must also be
considered. In this regard, while ERAs generally have a limited spectrum
of adverse effects, TVEs are described in the labels for all ERAs, and
are potentially more likely to occur when ERA use is extended beyond the
treatment of anemia.

The evaluation of the Sponsor's clinical program did not demonstrate
that the survival questions generated from EPO-INT-76 and the study by
Henke et al., are relevant to other studies or clinical settings where
ERAs are used to correct anemia. This evaluation is supported by the
Sponsor's ongoing post-marketing surveillance program, which
continuously monitors the safety of products in the approved indications
through evaluation and assessment of spontaneous reports. The
post-marketing data confirm the recognized association of epoetin alfa
use with TVE occurrence, but do not suggest any new survival or tumor
proliferation signal in the marketed indications of epoetin alfa.
Although post-marketing surveillance is an imprecise and insensitive
tool for detecting subtle safety signals, and is no substitute for data
from randomized studies, this provided supportive evidence for the more
robust clinical trial data presented in this document.

In addition, the Sponsor's review of data from EPO-INT-76, did not
support that the survival signal was related to effects of ERA on tumor
response or tumor progression. An excess of TVEs, including fatal TVEs,
was observed on the EPREX arm. These TVEs account for some of the
differences in survival noted, and a blinded chart review of other
deaths in this study support that death due to TVE may be misdiagnosed
as tumor progression and could account for more of the observed effect
on mortality in this study. Patients with cancer have an increased risk
for TVEs, and ERAs are also associated with an increased risk for these
events (as described in the labels for ERAs). Patients should be
appropriately managed to reduce such risk when clinically indicated.
Response to ERA therapy should be closely monitored and dose adjustments
made as appropriate to maximize patient benefit and minimize risk.

In summary, in some investigational studies, ERA treatment of patients
beyond the correction of anemia has resulted in decreased survival or
increased side effects. These specific investigational designs should be
avoided in future development programs. The available data also support
the conclusion that, when used for approved indications and within
established guidelines for baseline and target hemoglobin
concentrations, the benefits of ERA therapy continue to be supported by
a well-defined and acceptable risk profile.

This document provides a detailed discussion of the safety of ERAs in
patients with cancer. For this purpose, the document is divided into the
following key sections:

-   an introduction and overview of ERAs including the clinical
    benefits, safety and a discussion of the current safety question
    raised by the survival findings from a small number of
    investigations studying benefits of ERAs beyond the correction of
    anemia;

-   analyses supporting the safety of the current labeled indication-
    treatment of anemia in cancer patients on chemotherapy;

-   a detailed review of the key data from the investigational studies
    exploring benefits beyond correction of anemia, including data on
    survival, tumor progression/ tumor response and TVEs;

-   an assessment of Benefit-Risk of ERAs in patients with cancer; and

-   the Sponsor\'s conclusion about the safe and effective use of ERAs
    in patients with cancer.

## INTRODUCTION

### Erythropoietin Receptor Agonists, Overview and History

Erythropoietin is a glycoprotein hormone produced primarily by the
kidney in response to hypoxia and is the key regulator of RBC
production. It is involved in all phases of erythroid development, and
has its principal effect at the level of erythroid precursors.
Erythropoietin exerts its biological effect by binding to its cell
surface receptor, which results in concomitant tyrosine phosphorylation
of the receptor and other intracellular proteins. After erythropoietin
binds to its receptor (the erythropoietin receptor, EpoR), it activates
signal transduction pathways that interfere with apoptosis and stimulate
erythroid cell proliferation. These pathways are operative in
nonhematopoietic as well as hematopoietic cells.

Anemia is a common feature of kidney disease, when the production of
erythropoietin by the kidneys is reduced and levels of
endogenously‑produced erythropoietin are no longer sufficient to
maintain normal levels of erythroid cell production. The development and
commercialization of a recombinant version of erythropoietin (epoetin
alfa), manufactured using recombinant DNA technology to introduce the
human erythropoietin gene into cultured mammalian cells, was completed
in the late 1980's and provided an important new alternative for the
treatment of anemia in patients with kidney disease. Subsequently, it
has been shown that recombinant erythropoietins have value for treating
anemia associated with cancer chemotherapy and with certain other human
illnesses as well. Additional recombinant erythropoietins have been
developed.

Erythropoietin receptors are known to be expressed on cells other than
erythroid precursor cells, including vascular endothelial cells and
certain tumor cells. Although the functional role of these receptors on
other cells lines is uncertain, there is a theoretical potential for
erythropoietin to act as a growth factor on cell lines other than
erythroid cells. This potential applies to exogenously administered
erythropoietins produced by recombinant techniques as well as to natural
erythropoietin.

The first ERA marketed in the US, epoetin alfa, was developed by Amgen,
and has been marketed as EPOGEN by Amgen for anemia of kidney disease
since 1989. Under terms of a license agreement with Amgen, epoetin alfa
has also been marketed in the US by Ortho Biotech (an affiliate of the
Sponsor) under the trade name PROCRIT, since April 1993 for use in
treatment of anemia in patients with cancer receiving chemotherapy.
PROCRIT/EPOGEN^®^ solution for injection (recombinant human
erythropoietin, r-HuEPO, epoetin alfa) is a glycoprotein manufactured by
recombinant DNA technology, has an amino acid sequence identical to
human urinary erythropoietin, is indistinguishable from
naturally-occurring human erythropoietin on the basis of biological
erythropoietic effects, and has a molecular weight of 30,400 daltons.

More recently, Amgen has introduced another ERA in the US, Aranesp
(darbepoetin alfa), marketed since 2001 for treatment of anemia in
patients with kidney disease and since 2002 for treatment of anemia in
patients with cancer receiving chemotherapy. This product is closely
homologous with epoetin alfa and differs by 5 amino acids.

ERAs available outside of the US include Aranesp, marketed by Amgen;
EPREX, another formulation of epoetin alfa marketed by the Sponsor under
license from Amgen; and NeoRecormon^^, an epoetin beta product marketed
by Hoffmann -- La Roche.

Products in the ERA class of medication share close structural homology
with naturally occurring human erythropoietin, and differ from each
other by minor amino acid substitutions. Epoetin alfa marketed in the
U.S (PROCRIT and EPOGEN) differs from the epoetin alfa marketed ex-U.S
(EPREX) in the preservative that is used.

  ---------------- -------------- -------------------- --------------------
  PRODUCTS IN ERA                                      
  CLASS                                                

                   Molecule       Homology of Amino    Year Introduced in
                                  Acid sequence to     US for anemia in
                                  human erythropoietin cancer patients on
                                                       chemotherapy\*

  PROCRIT          Epoetin alfa   100%                 1993

  EPREX            Epoetin alfa   100%                 NA

  NeoRecormon^^   Epoetin beta   100%                 NA

  Aranesp          Darbepoetin    97%                  2002
                   alfa                                
  ---------------- -------------- -------------------- --------------------

\* EPOGEN (epoetin alfa) is the same formulation as PROCRIT and is
marketed by Amgen in the US for the dialysis indication.

### Clinical Benefits and Safety in Approved Indications

Over 3 million patients have benefited from EPREX or PROCRIT therapy in
over a decade of clinical experience in multiple indications. With
respect to patients with cancer, EPREX or PROCRIT treatment of anemic
cancer patients receiving cancer chemotherapy has been shown to
significantly ameliorate anemia and to reduce transfusion requirements.
This has provided for the effective treatment of the symptoms of anemia
in these patients, including tiredness, shortness of breath, weakness
and fatigue (weariness from labor or exertion). In addition to
correcting anemia, ERAs have proven benefits in reducing the needs for
RBC transfusions, while reducing potential risks that may accompany
transfusions of allogeneic RBC products, and also reducing utilization
of the limited supplies of blood products. These benefits are supported
by a well-defined safety profile in currently approved indications.

Over the years since the initial US marketing approval of epoetin alfa,
numerous additional clinical studies have been performed by the Sponsor,
both to further evaluate the approved uses for PROCRIT and to explore
potential new therapeutic uses. PROCRIT is thus also approved for the
treatment of anemia in zidovudine (azidothymidine, AZT)-treated patients
who are infected with human immunodeficiency virus (HIV), and to reduce
allogeneic blood transfusion requirements in the perisurgical setting.

In addition to providing demonstrated benefits in their approved
indications, by stimulating the erythropoietin receptor, products in the
ERA class also share well characterized and similar side effect
profiles. Some of the side effects common to this class include
hypertension and thrombotic complications. These ERA class side effects
are reflected in the prescribing information for all products. Other
possible side effects are also common to products in this class.

Although these side effects have the potential to result in serious
outcomes, they need to be considered in the context of the important
benefits this class of medications provides to patients with serious and
terminal illnesses, and as the only therapeutic alternatives to blood
transfusions.

### Safety in Investigational Use

ERAs have been extensively investigated in clinical trials, and safety
data from trials investigating ERAs in the treatment of anemia in
patients with cancer receiving chemotherapy supports the safety and
benefits of these products when used for this indication.

More recently, published findings from two studies evaluating potential
new investigational uses for ERAs in patients with cancer have indicated
that there may be increased risks associated with treatment of
non-anemic patients. These investigational uses were designed to
demonstrate benefits from ERA therapy beyond the reduction in the
requirements for transfusion or treatment of symptoms of anemia. The
intent of these studies is described in this briefing document as
treatment beyond the correction of anemia; this is specifically defined
as initiation of ERA treatment in cancer patients who are not anemic, or
continued ERA treatment after correction of anemia, considering a
hemoglobin level of 13 g/dL as a clearly non-anemic value.

One of these studies, EPO-INT-76^1^, investigated the effects of
prolonged treatment of EPREX (epoetin alfa, formulation marketed ex-US)
and maintenance of non-anemic target hemoglobin levels in patients
starting on chemotherapy for metastatic breast cancer. The other study,
conducted by Henke and colleagues^2^, investigated the effects of
treatment with NeoRecormon (epoetin beta, formulation marketed ex-US) to
high target hemoglobin levels during radiation therapy for head and neck
cancer.

These studies, sponsored by different manufacturers, both independently
reported inferior survival associated with this new investigational use.
These findings were unexpected and did not reflect the Sponsor's prior
safety experience with established marketed uses. Although these
findings occurred in the setting of new uses of ERAs, they raised
questions as to whether the outcomes observed in those settings were
specific to those investigational settings, and stimulated the need to
examine and confirm the ongoing positive benefit-risk profile of these
products when used to correct anemia associated with chemotherapy in
patients with cancer.

The Sponsor has thus undertaken an extensive evaluation of all currently
available data, including data from these investigational studies; has
communicated with the FDA regarding the issues raised by these studies;
and has taken the following actions deemed appropriate based on the
information available:

-   The Sponsor has undertaken an extensive evaluation of data from
    prior clinical studies together with data from current studies,
    including EPO-INT-76 and other investigational studies, to assess
    and re-affirm the favorable benefit-risk profile of EPREX and
    PROCRIT when used as directed in approved indications.

-   The Sponsor took steps to modify or suspend clinical research
    studies involving administration of ERAs beyond the correction of
    anemia in patients with cancer.

-   The Sponsor has communicated its concerns regarding such research
    designs to clinical scientists globally as well as to regulatory
    authorities, and has ensured that all of its ongoing clinical
    research studies incorporate appropriate patient safeguards,
    including avoidance of treatment beyond the correction of anemia,
    and data monitoring by independent Data Safety Monitoring Boards
    (DSMB)s.

-   While the use of the Sponsor's epoetin alfa products in clinical
    practice (outside of research studies) in patients with cancer
    appears to be well-delimited to the approved indication, i.e, the
    treatment of anemia, the Sponsor continues to work in cooperation
    with global regulatory authorities to ensure that prescribing
    information provides all information relevant for making clinical
    decisions regarding beneficial and safe use.

-   The Sponsor also continues to work with global regulatory
    authorities and clinical research consultants to identify any
    additional research that may be needed or desirable to further
    define the optimal use of the Sponsor's ERAs and other products.

These data are presented in detail in this document, and form the basis
for the Sponsor's assessment that ERAs continue to have a favorable
benefit-risk profile when used for approved indications. Data from
randomized controlled studies form the primary database that was used
for the analyses presented in this document (detailed study designs are
found in Attachment 4). These studies were chosen as they represent
robust, reliable data and have information on the variables of interest
(survival, tumor response/tumor progression and TVE).

## SAFETY OF CURRENT LABELED INDICATION - TREATMENT OF ANEMIA IN CANCER PATIENTS ON CHEMOTHERAPY 

Based on the questions arising from the recently-published
investigational studies of ERAs, the Sponsor has undertaken an
examination of data available from clinical trials and from
post-marketing experience. The Sponsor's clinical trials database is
extensive, and there is a large post‑marketing experience with epoetin
alfa products. The analyses summarized here focus on all relevant
information that has been generated in randomized, controlled trials,
particularly trials that were double-blind. Analyses that are most
useful to the evaluation of the current questions are provided.

### Adverse Events, Including Thrombotic Vascular Events

As noted above, ERAs have a long history of use in the treatment of
anemia in patients receiving cancer chemotherapy. Several thousand
patients have been enrolled in PROCRIT controlled clinical studies, and
millions of patients have received PROCRIT for this indication. The
adverse events that have been observed in association with this use are
described in product labeling.

Among the adverse events that have been described in association with
ERA use for anemia in cancer patients receiving chemotherapy, thrombotic
events (also described as thrombotic vascular events, or TVEs) are
events that may occur relatively frequently in cancer patients and can
be serious. Examples of serious TVEs may include such events as deep
venous thrombosis with pulmonary embolism, cardiac ischemia or
infarction, or thrombotic stroke. Other more common but less serious
events such as superficial venous thrombosis may also be considered as
TVEs, depending on the definition used to characterize these events. The
list of general TVEs is the Sponsor's broadest approach for identifying
TVEs, and includes all superficial TVEs, all catheter related TVEs and
events that could, but not necessarily would, be caused by an underlying
thrombovascular event, and where no information was available to prove
the contrary. General TVEs are also subclassified as clinically
relevant, a definition that is still broader than the generally accepted
clinically important TVEs (e.g., DVT, PE, stroke/TIA, and MI).

The Sponsor has performed an analysis of TVEs in 10 double-blind,
randomized, placebo-controlled trials of PROCRIT epoetin alfa or EPREX
epoetin alfa that focused on treatment of anemic cancer patients
receiving chemotherapy. All studies were part of regulatory submissions
or filings made by the Sponsor in support of the oncology indication for
treatment of anemia. Many of the studies enrolled patients with a mix of
tumor types, limiting the possibilities to evaluate any tumor
type-specific effects but expected to still have sensitivity to an
adverse event (e.g., TVE) -- related effect. Some studies utilized
PROCRIT (epoetin alfa), while others utilized EPREX (a different
formulation of epoetin alfa). A list of the studies is provided in Table
1, below.

+----------+---------+---------+-----------+--------------+----------+
| **Table  |         |         |           |              |          |
| 1:**     |         |         |           |              |          |
| Study    |         |         |           |              |          |
| Charact  |         |         |           |              |          |
| eristics |         |         |           |              |          |
| for      |         |         |           |              |          |
| Doubl    |         |         |           |              |          |
| e-Blind, |         |         |           |              |          |
| Pl       |         |         |           |              |          |
| acebo-Co |         |         |           |              |          |
| ntrolled |         |         |           |              |          |
| O        |         |         |           |              |          |
| ncology\ |         |         |           |              |          |
| Studies  |         |         |           |              |          |
| in       |         |         |           |              |          |
| Anemic   |         |         |           |              |          |
| Patients |         |         |           |              |          |
+----------+---------+---------+-----------+--------------+----------+
| Study    | Tumor   | Entry   | Target    | Dose         | Duration |
|          |         |         | (initial) |              |          |
+----------+---------+---------+-----------+--------------+----------+
|          | Type    | Hb      | Hb (g/dL) | of Therapy   |          |
|          |         | (g/dL)  |           |              |          |
+----------+---------+---------+-----------+--------------+----------+
| N        | Mixed   | ≤10.5   | Hct       | 100 IU/kg    | 8 wks    |
| on-Chemo |         |         | 38%-40%   | TIW          |          |
+----------+---------+---------+-----------+--------------+----------+
| Nonc     | Mixed   | ≤10.5   | Hct       | 150 IU/kg    | 12 wks   |
| isplatin |         |         | 38%-40%   | TIW          |          |
+----------+---------+---------+-----------+--------------+----------+
| C        | Mixed   | ≤10.5   | Hct       | 150 IU/kg    | 12 wks   |
| isplatin |         |         | 38%-40%   | TIW          |          |
+----------+---------+---------+-----------+--------------+----------+
| J89-040  | CLL     | Hct     | Hct       | 150 IU/kg    | 12 wks   |
|          |         | \<32%   | 38%-40%   | TIW          |          |
+----------+---------+---------+-----------+--------------+----------+
| P-174    | CLL     | Hct     | Hct       | 150 IU/kg    | 12 wks   |
|          |         | \<32%   | 38%-40%   | TIW          |          |
+----------+---------+---------+-----------+--------------+----------+
| INT-1    | Ovarian | \<11\*  | 12.5-14   | 150/300      | 1 mo     |
|          |         |         |           | IU/kg TIW    | past CTX |
+----------+---------+---------+-----------+--------------+----------+
| INT-2    | MM      | \<11    | 12-14     | 150-300      | 12 wks   |
|          |         |         |           | IU/kg TIW    |          |
+----------+---------+---------+-----------+--------------+----------+
| INT-3    | Mixed   | \<12    | 12-14F,   | 150-300      | 12 wks   |
|          |         |         | 14-16M    | IU/kg TIW    |          |
+----------+---------+---------+-----------+--------------+----------+
| INT-10   | Mixed   | ≤10.5   | 12-15     | 150-300      | 24 wks/6 |
|          |         |         |           | IU/kg TIW    | cycles   |
+----------+---------+---------+-----------+--------------+----------+
| PR9      | Mixed   | ≤11.5/1 | 13-15     | 40,000 IU QW | 16 wks   |
| 8-27-008 |         | 0.5\*\* |           |              |          |
+----------+---------+---------+-----------+--------------+----------+
| \*       |         |         |           |              |          |
| Patients |         |         |           |              |          |
| were     |         |         |           |              |          |
| also     |         |         |           |              |          |
| eligible |         |         |           |              |          |
| if they  |         |         |           |              |          |
| had      |         |         |           |              |          |
| exp      |         |         |           |              |          |
| erienced |         |         |           |              |          |
| a Hb     |         |         |           |              |          |
| decline  |         |         |           |              |          |
| of ≥ 1.5 |         |         |           |              |          |
| g/dL     |         |         |           |              |          |
| (from a  |         |         |           |              |          |
| baseline |         |         |           |              |          |
| of\      |         |         |           |              |          |
| \< 14    |         |         |           |              |          |
| g/dl),   |         |         |           |              |          |
| or if    |         |         |           |              |          |
| they had |         |         |           |              |          |
| exp      |         |         |           |              |          |
| erienced |         |         |           |              |          |
| a Hb     |         |         |           |              |          |
| decline  |         |         |           |              |          |
| of ≥ 2   |         |         |           |              |          |
| g/dL     |         |         |           |              |          |
| (from a  |         |         |           |              |          |
| baseline |         |         |           |              |          |
| of ≥ 14  |         |         |           |              |          |
| g/dL).   |         |         |           |              |          |
|          |         |         |           |              |          |
| \*\*     |         |         |           |              |          |
| ≤11.5    |         |         |           |              |          |
| g/dL for |         |         |           |              |          |
| men;     |         |         |           |              |          |
| ≤10.5    |         |         |           |              |          |
| g/dL for |         |         |           |              |          |
| women    |         |         |           |              |          |
+----------+---------+---------+-----------+--------------+----------+

Figure 1 illustrates the odds ratios for TVEs in these 10 studies.

**Figure 1:** Incidence of Clinically Relevant Thrombotic Vascular
Events Odds Ratios\
and 95% Confidence Intervals\
(10 Double-Blind, Placebo-Controlled, Completed Oncology Studies: Safety
Population).

![](media/image1.png){width="4.959722222222222in"
height="5.711805555555555in"}

For the pooled analysis, the odds ratio was based on Mantel-Haenszel
estimate stratified by study.

In brief, the odds ratios for TVEs were variable in these 10 studies.
The combined analysis of all 10 studies yielded an odds ratio of 1.55
with a 95% CI (0.96, 2.50) suggesting higher incidence of TVEs with
epoetin alfa treatment.

### Patient Outcomes

#### Survival 

The Sponsor also has reanalyzed survival data from its prior clinical
studies of PROCRIT and EPREX in anemic patients receiving cancer
chemotherapy. The analyses (including a combined analysis) presented in
this section of this background document are also based on the same
10 completed, randomized, double-blind, and placebo‑controlled studies
identified in Table 1, above. It should be noted that these studies are
generally of relatively shorter double‑blind duration than the
investigational studies that are presented in Section 4, Investigational
Clinical Studies -- Treatment Beyond Correction of Anemia, of this
background document. As noted previously, many of the studies enrolled
patients with a mix of tumor types, limiting the possibilities to
evaluate any tumor type‑specific effects but expected to still have
sensitivity to adverse event (e.g., TVE) -- related effects. Some
studies utilized PROCRIT (epoetin alfa), while others utilized EPREX
(epoetin alfa).

The results of these analyses are presented in Figure 2.

**Figure 2:** Subject Survival: Hazard Ratios and 95% Confidence
Intervals\
(Up to 30 Days After End of Double-Blind Phase)\
(10 Double-Blind, Placebo-Controlled, Completed Oncology Studies)

![](media/image2.png){width="4.949305555555555in"
height="5.879861111111111in"}

For the pooled analysis, the hazard ratio and its 95% CI were obtained
using Cox's Regression stratified by study.

Combined analyses of survival from the double-blind phase plus 30 day
follow-up for these 10 double-blind, placebo-controlled oncology studies
were similar for the epoetin alfa and placebo groups.

Finally, an abstract recently presented at the annual meeting of the
American Society of Hematology described an independent meta-analysis,
evaluating survival across a number of studies evaluating epoetins in
the treatment of anemia in patients with cancer. There was no evidence
of an impairment of survival among patients receiving epoetins in these
studies.^3^

#### Tumor Response/Disease Progression

Tumor response to chemotherapy, disease progression, or both were
evaluated in five of the completed, double-blind studies listed in Table
1, above, at the end of a double-blind phase that ranged from 12 to 24
weeks. Tumor response data were available for studies EPO-INT-1,
EPO-INT-2, EPO-INT-3, EPO-INT-10, and PR98-27-008. Tumor response was
assessed after the last cycle of chemotherapy, and the assessment of
response did not require a complete radiographic assessment. The method
for assessing tumor response was at the investigator\'s discretion. Of
note, a number of caveats commonly applied to the interpretation of
these studies: 1) tumor response was not a primary or secondary
objective of the study; 2) predesignated times and method or instrument
to evaluate tumor response were not specified; 3) baseline data on the
extent of disease was missing in many patients in some studies; 4) time
to tumor progression or progression-free survival was not a primary or
secondary objective of many studies and the methods to evaluate these
outcomes varied from study to study; and 5) by design, many studies were
of relatively short duration and later-occurring outcomes such as tumor
progression and death were not built into the study design. However,
when data were available, overall or clinically objective tumor response
rates (complete remission plus partial remission) were similar for
subjects treated with epoetin alfa and those who received placebo. Thus,
results from all five of these completed studies for which tumor
response data are available suggest that treatment with epoetin alfa had
no adverse effect on response to chemotherapy.

Disease progression is another important clinical observation that may
be used to determine a subject's response to chemotherapy and any
possible role of ERAs on tumor progression. In Studies EPO-INT-1
(ovarian cancer), EPO-INT-2 (multiple myeloma), and EPO-INT-3 (mixed
tumor types), disease progression was similar for subjects in the
epoetin alfa and placebo groups at the end of the double-blind phase of
the study. In Study EPO-INT-10 (mixed tumor types), disease progression
was reported in 24% of the subjects who received epoetin alfa compared
with 33% of subjects who received placebo. These data suggest that
disease progression was unlikely to be affected by treatment with
epoetin alfa.

#### Post-Marketing Surveillance

Cumulative patient exposure for PROCRIT and EPREX for all marketed
indications is 3.1 million years since their introductions. This
represents a large patient experience, which is continuously monitored.
Although post-marketing surveillance is an imprecise tool for detecting
subtle safety signals, the Sponsor's ongoing post-marketing surveillance
program has not identified any indications of an adverse effect of
PROCRIT or EPREX on tumor response, disease progression, or survival.
Interpretation of these data is constrained by the known limitations of
these reporting systems. TVEs have been reported in association with
PROCRIT and EPREX use. The frequency and nature of these reports is
consistent with the Sponsor's prior experience and is adequately
reflected in product labeling.

#### Conclusion

Clinical studies involving use of epoetin alfa for the treatment of
anemia in patients with cancer who are receiving chemotherapy (the
current approved oncology indication) have shown no signal of an adverse
impact on survival. Data are more limited regarding tumor response and
disease progression, but available data from clinical studies where
these parameters can be evaluated have not revealed any indications of
an adverse effect of epoetin alfa.

Labeling for all ERA products describes the association of TVEs with use
of these products. Experience in clinical trials of epoetin alfa in
treatment of anemia in cancer patients receiving chemotherapy, and
information obtained from post-marketing surveillance, is consistent
with this product labeling.

## INVESTIGATIONAL CLINICAL STUDIES -- TREATMENT BEYOND CORRECTION OF ANEMIA

As noted above, the established, approved use of ERAs in patients with
cancer is to treat anemia in patients receiving chemotherapy. That is,
ERAs are used in the supportive care of patients and are not currently
administered with an expectation of affecting the outcome of anticancer
treatment. However, some preclinical and clinical study findings have
suggested the possibility that ERAs might have a beneficial impact on
treatment outcomes in cancer patients (e.g., a favorable effect on tumor
response and/or patient survival). For example, laboratory and clinical
studies have suggested that tumor hypoxia may reduce the anticancer
effectiveness of radiation therapy and of many chemotherapy drugs; in
theory, use of ERAs to increase hemoglobin levels might enhance tumor
oxygenation and thus might enhance the effectiveness of these treatment
modalities.^4,5^ Also, clinical studies have frequently suggested that
anemic cancer patients do not do as well as non-anemic patients, raising
the question of whether correcting anemia would have a beneficial impact
on patient prognosis.^6^ Finally, limited survival data from two earlier
studies\
(EPO-INT-10 and the study of Vansteenkiste et al.^7,8^) of ERAs in
anemic cancer patients also suggested the possibility of modestly
improved treatment outcomes for patients receiving ERAs. While these
findings and arguments suggested a possibility of benefit, there was no
substantive evidence and further research was needed.

Several investigational studies have subsequently been designed to
examine whether ERA treatment of patients with cancer could lead to
better treatment outcomes. Given the extensive prior use of these
agents, the perceived high degree of safety of treatment, and the desire
to adequately test the hypothesis that higher hemoglobin levels would be
associated with better patient outcomes, the designs of these
investigational studies have commonly provided for the treatment of
patients to higher hemoglobin levels than described in current
prescribing information. Thus, these studies have involved treatment of
cancer patients who were not anemic, or the use of target hemoglobin
levels that were significantly higher than those recommended for the
established use of these agents for treatment of anemia (i.e., treatment
beyond the correction of anemia, as previously noted). In this regard,
these investigational studies differed from prior clinical studies that
had raised the possibility of better treatment outcomes with ERA
treatment; in the prior studies, ERA administration was generally in
accordance with current prescribing information for use of these
products in anemic patients with cancer receiving chemotherapy.

Partial results from two studies evaluating the effects of ERAs on
treatment outcomes in patients with cancer have recently been published.
In the EPO-INT-76 study, patients beginning chemotherapy for metastatic
breast cancer were randomized to receive concomitant EPREX (the epoetin
alfa formulation marketed outside the US) or placebo for one year. In
the study performed by Henke et al.,^2^ patients beginning radiation
therapy for head and neck cancer were randomized to receive concomitant
NeoRecormon^^ (epoetin beta) or placebo prior to and for the duration
of their radiation therapy. In brief, patient survival in these two
studies appeared to be worse, not better, with ERA treatment compared to
placebo. The results of these investigational studies are summarized
below. This section also summarizes available data from three other
studies that have examined the impact of ERAs on treatment outcomes in
cancer patients, and provides information from other clinical trials
relevant to the questions raised by the results of the EPO-INT-76 and
Henke et al. studies.

### Study EPO-INT-76 ^9^

#### Study Design 

EPO-INT-76 was a company-sponsored randomized, double-blind,
placebo-controlled multicenter trial conducted in women with breast
cancer who were receiving first-line chemotherapy for disseminated
disease, and was designed to evaluate the impact on survival and quality
of life of using epoetin alfa to maintain hemoglobin at non-anemic
levels for 12 months. The primary efficacy variable was 12-month
survival. A total of 939 patients were enrolled, and were randomly
assigned to receive either epoetin alfa (EPREX), 40,000 IU s.c. weekly
or placebo in a 1:1 ratio. Study drug was initiated when the hemoglobin
concentration was 13 g/dL or lower and was to be continued thereafter on
a weekly basis, until the end of the 12-month double‑blind phase of the
study; this treatment was intended to continue regardless of any changes
in patients' anticancer treatments.

Subsequent to the double-blind phase of the study, there was an optional
open-label phase, in which all subjects could receive epoetin alfa. In
both phases, study drug was administered with the goal of maintaining
hemoglobin concentrations in the range of 12 to 14 g/dL. The dose of
study drug could be escalated up to a maximum of 60,000 IU per injection
if, after receiving 4 weekly doses, the hemoglobin concentration was
less than 10.5 g/dL and had increased by less than 1 g/dL or the
reticulocyte count had increased by less than 40,000 cells/μL. Treatment
was to be interrupted if the rate of rise in hemoglobin level exceeded
2 g/dL per month or if hemoglobin exceeded 14 g/dL. Randomization was
stratified according to 3 categories: disease restricted to the
skeleton, extraskeletal measurable disease, and extraskeletal
nonmeasurable disease. The choice of chemotherapy and hormonal therapy
was left to the discretion of the investigators, except that
dose-intense chemotherapy for bone marrow or stem cell transplantation
was not allowed. There were no detailed requirements for tumor
assessment at entry nor during the follow-up period.

Subjects included in the study had a confirmed diagnosis of metastatic
breast carcinoma, including histology of the primary tumor. Subjects
were female, at least 18 years of age, were starting first-line
chemotherapy, had an Eastern Cooperative Oncology Group (ECOG)
performance status score of 0, 1, or 2, and were to have an estimated
life expectancy of at least 6 months. Subjects were excluded if they had
brain metastases or leptomeningeal disease at the time of randomization,
if they were receiving dose intensification chemotherapy for bone marrow
or stem cell transplantation, if they had an active second primary
malignancy, if there were causes of anemia known to be unresponsive to
epoetin alfa, or if they had had a prior TVE within 6 months (unlike
prior studies of epoetin alfa, which largely excluded patients with any
prior TVE).

#### Patient Demographics

Demographic and baseline characteristics for the intent-to-treat
population are summarized by treatment group and overall in Table 2a;
baseline tumor-related characteristics are presented in Table 2b.

+--------------------------------------+--------------+----------------+---+
| **Table 2a:** Demographics and       |              |                |   |
| Baseline Characteristics             |              |                |   |
|                                      |              |                |   |
| (Study EPO-INT-76: Intent-to-Treat   |              |                |   |
| Subjects: Metastatic Breast Cancer)  |              |                |   |
+--------------------------------------+--------------+----------------+---+
|                                      | Placebo      | Epoetin Alfa   |   |
+--------------------------------------+--------------+----------------+---+
| Characteristic                       | (N=470)      | (N=469)        |   |
+--------------------------------------+--------------+----------------+---+
| **Age (years)**                      |              |                |   |
+--------------------------------------+--------------+----------------+---+
| N                                    | 470          | 469            |   |
+--------------------------------------+--------------+----------------+---+
| Mean (SD)                            | 55.1 (10.49) | 55.8 (11.13)   |   |
+--------------------------------------+--------------+----------------+---+
| Median                               | 55           | 56             |   |
+--------------------------------------+--------------+----------------+---+
| Range                                | 30-84        | 24-83          |   |
+--------------------------------------+--------------+----------------+---+
| **Age categories (years), no. (%)**  |              |                |   |
+--------------------------------------+--------------+----------------+---+
| \<=35                                | 10 (2%)      | 14 (3%)        |   |
+--------------------------------------+--------------+----------------+---+
| 36-45                                | 65 (14%)     | 66 (14%)       |   |
+--------------------------------------+--------------+----------------+---+
| 46-55                                | 149 (32%)    | 133 (28%)      |   |
+--------------------------------------+--------------+----------------+---+
| 56-65                                | 156 (33%)    | 145 (31%)      |   |
+--------------------------------------+--------------+----------------+---+
| 66-75                                | 75 (16%)     | 86 (18%)       |   |
+--------------------------------------+--------------+----------------+---+
| \>=76                                | 15 (3%)      | 25 (5%)        |   |
+--------------------------------------+--------------+----------------+---+
|                                      |              |                |   |
+--------------------------------------+--------------+----------------+---+
| **Weight (kg)**                      |              |                |   |
+--------------------------------------+--------------+----------------+---+
| N                                    | 470          | 469            |   |
+--------------------------------------+--------------+----------------+---+
| Mean (SD)                            | 70.6 (12.88) | 70.6 (14.10)   |   |
+--------------------------------------+--------------+----------------+---+
| Median                               | 69           | 69             |   |
+--------------------------------------+--------------+----------------+---+
| Range                                | 40-120       | 40-138         |   |
+--------------------------------------+--------------+----------------+---+
| **Body mass index categories         |              |                |   |
| (kg/m^2^), no. (%)**                 |              |                |   |
+--------------------------------------+--------------+----------------+---+
| \< 18.5                              | 9 (2%)       | 11 (2%)        |   |
+--------------------------------------+--------------+----------------+---+
| 18.5-24.9                            | 169 (36%)    | 176 ( 38%      |   |
+--------------------------------------+--------------+----------------+---+
| 24.9-29.9                            | 168 (36%)    | 160 (34%)      |   |
+--------------------------------------+--------------+----------------+---+
| \>=30.0                              | 123 (26%)    | 121 (26%)      |   |
+--------------------------------------+--------------+----------------+---+
| Missing                              | 1 (\<1%)     | 1 (\<1%)       |   |
+--------------------------------------+--------------+----------------+---+
| Reference: EPO-INT-76 CSR^9^         |              |                |   |
+--------------------------------------+--------------+----------------+---+

+---------------------------------------+------+-------+-----+-------+
| **Table 2b:** Baseline Tumor-Related  |      |       |     |       |
| Characteristics                       |      |       |     |       |
|                                       |      |       |     |       |
| (Study EPO-INT-76: Intent-to-Treat    |      |       |     |       |
| Population: Metastatic Breast Cancer) |      |       |     |       |
+---------------------------------------+------+-------+-----+-------+
| Characteristic                        | Plac |       | E   |       |
|                                       | ebo\ |       | poe |       |
|                                       | (N=  |       | tin |       |
|                                       | 470) |       | Al  |       |
|                                       |      |       | fa\ |       |
|                                       |      |       | (   |       |
|                                       |      |       | N=4 |       |
|                                       |      |       | 69) |       |
+---------------------------------------+------+-------+-----+-------+
|                                       |      |       |     |       |
+---------------------------------------+------+-------+-----+-------+
| **Estrogen receptor result, no.(%)**  |      |       |     |       |
+---------------------------------------+------+-------+-----+-------+
| Negative                              | 131  | ( 28) | 126 | ( 27) |
+---------------------------------------+------+-------+-----+-------+
| Positive                              | 232  | ( 49) | 226 | ( 48) |
+---------------------------------------+------+-------+-----+-------+
| Not determined                        | 107  | ( 23) | 117 | ( 25) |
+---------------------------------------+------+-------+-----+-------+
| **ECOG performance status,            |      |       |     |       |
| no.(%)**^a^                           |      |       |     |       |
+---------------------------------------+------+-------+-----+-------+
| 0                                     | 222  | ( 47) | 198 | ( 42) |
+---------------------------------------+------+-------+-----+-------+
| 1                                     | 199  | ( 42) | 216 | ( 46) |
+---------------------------------------+------+-------+-----+-------+
| 2                                     | 49   | ( 10) | 55  | ( 12) |
+---------------------------------------+------+-------+-----+-------+
| ^a^ ECOG performance scores: 0 = able |      |       |     |       |
| to carry out all normal activity      |      |       |     |       |
| without restriction; 1 = restricted   |      |       |     |       |
| in physically strenuous activity but  |      |       |     |       |
| ambulatory and able to do light work; |      |       |     |       |
| 2 = ambulatory and capable of all     |      |       |     |       |
| self-care but unable to carry out any |      |       |     |       |
| work; 3 = capable of only limited     |      |       |     |       |
| self-care, confined to bed or chair   |      |       |     |       |
| more than 50% of waking hours; 4 =    |      |       |     |       |
| completely disabled; cannot carry out |      |       |     |       |
| any self care; totally confined to    |      |       |     |       |
| bed or chair.                         |      |       |     |       |
+---------------------------------------+------+-------+-----+-------+
| Reference: EPO-INT-76 CSR^9^          |      |       |     |       |
+---------------------------------------+------+-------+-----+-------+

#### Patient Treatment

Summary statistics regarding exposure to study drug are provided in
Table 3 for the intent-to-treat population.

Subjects did not have to be anemic to qualify for study entry; any
baseline hemoglobin concentration was acceptable. Following
randomization, however, study drug administration was to not to begin
until the hemoglobin level was 13.0 g/dL or less. The median time from
randomization to study drug start was the same in both treatment groups
(4 days).

+-------------------------------------+----------+----------+----------+
| **Table 3:** Time From              |          |          |          |
| Randomization to Study Drug Start,  |          |          |          |
| Time on\                            |          |          |          |
| Study and Study Drug, and Number of |          |          |          |
| Doses                               |          |          |          |
|                                     |          |          |          |
| (Study EPO-INT-76: Intent-to-Treat  |          |          |          |
| Subjects: Metastatic Breast Cancer) |          |          |          |
+-------------------------------------+----------+----------+----------+
|                                     | Placebo  | Epoetin  |          |
|                                     |          | Alfa     |          |
+-------------------------------------+----------+----------+----------+
| Exposure Parameters                 | (N=470)  | (N=469)  |          |
+-------------------------------------+----------+----------+----------+
| Time from randomization to study    |          |          |          |
| drug start (days)                   |          |          |          |
+-------------------------------------+----------+----------+----------+
| N                                   | 456      | 448      |          |
+-------------------------------------+----------+----------+----------+
| Mean                                | 12.2     | 13.0     |          |
+-------------------------------------+----------+----------+----------+
| Median                              | 4        | 4        |          |
+-------------------------------------+----------+----------+----------+
| Interquartile Range                 | 0-14.0   | 0-12.5   |          |
+-------------------------------------+----------+----------+----------+
| Range                               | 0-265    | 0-286    |          |
+-------------------------------------+----------+----------+----------+
| Time on study drug (weeks)          |          |          |          |
+-------------------------------------+----------+----------+----------+
| N                                   | 456      | 448      |          |
+-------------------------------------+----------+----------+----------+
| Mean (SD)                           | 36.9     | 30.4     |          |
|                                     | (16.34)  | (17.25)  |          |
+-------------------------------------+----------+----------+----------+
| Median                              | 44.1     | 32.1     |          |
+-------------------------------------+----------+----------+----------+
| Range                               | 0.1-59.7 | 0.1-65.4 |          |
+-------------------------------------+----------+----------+----------+
| Number doses per subject            |          |          |          |
+-------------------------------------+----------+----------+----------+
| N                                   | 456      | 448      |          |
+-------------------------------------+----------+----------+----------+
| Mean (SD)                           | 35.2     | 21.4     |          |
|                                     | (15.91)  | (13.50)  |          |
+-------------------------------------+----------+----------+----------+
| Median                              | 40       | 19       |          |
+-------------------------------------+----------+----------+----------+
| Range                               | 1-57     | 1-58     |          |
+-------------------------------------+----------+----------+----------+
| Time on study (weeks)               |          |          |          |
+-------------------------------------+----------+----------+----------+
| N                                   | 470      | 469      |          |
+-------------------------------------+----------+----------+----------+
| Mean (SD)                           | 43.8     | 41.6     |          |
|                                     | (15.18)  | (16.78)  |          |
+-------------------------------------+----------+----------+----------+
| Median                              | 52.0     | 52.0     |          |
+-------------------------------------+----------+----------+----------+
| Range                               | 0-68     | 0-66     |          |
+-------------------------------------+----------+----------+----------+
| Reference: EPO-INT-76 CSR^9^        |          |          |          |
+-------------------------------------+----------+----------+----------+

During the study, study drug was administered to maintain the subject's
hemoglobin concentration in the range of 12 to 14 g/dL, and doses were
to be withheld when the hemoglobin level was increased above 14 g/dL.
Subjects in the epoetin alfa group were on study drug for a shorter
length of time and received fewer doses of study drug per subject
compared with those assigned to the placebo group (Table 3). In both
groups, the majority of subjects in both treatment groups remained in
the double-blind study for the specified 12-month duration (median, 52
weeks).

The mean doses of study drug over time in the epoetin alfa and placebo
group are shown for the intent-to-treat population in Figure 3.

**Figure 3:** Mean Weekly Dose Over Time for Patients Receiving Study
Drug

(Study PRI/EPO-INT-76: Intent-to-Treat Subjects: Metastatic Breast
Cancer)

![](media/image3.png){width="5.067361111111111in"
height="4.352083333333334in"}

Note: Zero weekly doses were excluded from the summary.

Reference: EPO-INT-76^9^

Patients in the placebo arm tended to receive higher doses of study drug
over time, consistent with a lack of pharmacologic effect resulting in
dose escalations. Patients in the active treatment arm tended to receive
lower doses over time consistent with dose adjustments based on
hemoglobin increases or due to adverse events.

#### Early Discontinuation of Study Drug Treatment

In April 2002, the Independent Data Monitoring Committee (IDMC) reviewed
available data on the 939 enrolled subjects. The IDMC recommended
discontinuation of the study because of an unexpected increase in
mortality among subjects in the epoetin alfa‑treated group compared with
the placebo group. Although study drug treatment was terminated, study
participants were to be followed according to the protocol. At the time
of discontinuation of study drug treatment, all study patients had
already been enrolled, 88% of study patients had already completed the
study period or had withdrawn from treatment, and the last patients to
be enrolled had completed 10 months of the planned 12-month treatment
period.

#### Data Sets Analyzed

In general, data and conclusions concerning the analysis of the primary
efficacy end point for the efficacy population (defined as patients who
received at least one dose of study drug; this included 904 of the 939
patients enrolled) were consistent with those for the intent-to-treat
population. Therefore, results for the intent-to-treat population are
discussed in the text of this document.

After study drug treatment was discontinued (follow-up continued and is
ongoing), and the pre-planned primary analysis was completed, the
Sponsor engaged an outside consulting firm (Cvitkovic et Associés
Consultants \[CAC\], Paris, France), staffed by medical oncologists, to
review the subjects' medical charts at all sites. This review was
conducted in an attempt to collect further information to better
understand the efficacy and safety results. The oncologists who
performed the review were blinded to the identity of the study drug
previously administered to each subject. Additional information obtained
from this medical chart review is utilized in some analyses, and is so
identified when used.

#### Survival -- Final Analysis of 12-Month Survival Rate

The intent-to-treat population, which included all subjects randomized,
consisted of 939 subjects with a mean age of 55.5 years. In general,
demographic and baseline characteristics were similar between epoetin
alfa- and placebo-treated subjects. For the intent-to-treat population,
survival rates at 12 months after randomization, based on Kaplan-Meier
estimates, are presented in Table 4. The 12-month survival rate based on
Kaplan-Meier estimates was lower in the epoetin alfa group (70%)
compared with the placebo group (76%). The analysis based on Cox's
proportional hazards model stratified by metastatic category showed that
the difference between the treatment groups was statistically
significant (p=0.012). The Kaplan‑Meier curves for time to death within
12 months after randomization for the intent-to-treat population are
presented in Figure 4.

Table 4 also summarizes the 12-month survival results for the efficacy
population. For this population, the 12-month survival rate, based on
Kaplan-Meier estimates, was also significantly lower in the epoetin alfa
group compared with the placebo group (p=0.019). Similar results were
seen using the survival data as of the date of treatment discontinuation
(hazard ratio=1.33, p=0.024). In this analysis, subjects were censored
at the date the study treatment was discontinued or at 12 months,
whichever occurred first.

+--------------------------+----------+-----------+-------------------+
| **Table 4:** Primary     |          |           |                   |
| Efficacy Variable:       |          |           |                   |
| 12‑Month Survival Rate\  |          |           |                   |
| (Study PRI/EPO-INT-76:   |          |           |                   |
| Intent-to-Treat and      |          |           |                   |
| Efficacy Subjects:       |          |           |                   |
| Metastatic Breast        |          |           |                   |
| Cancer)                  |          |           |                   |
+--------------------------+----------+-----------+-------------------+
|                          | Placebo  | Epoetin   | Hazard Ratio      |
|                          |          | Alfa      | \[95% CI\]        |
|                          |          |           |                   |
|                          |          |           | p value^a^        |
+--------------------------+----------+-----------+-------------------+
| **Intent-to-Treat**      | (N=470)  | (N=469)   |                   |
+--------------------------+----------+-----------+-------------------+
| Died^b^                  | 24%      | 30%       | 1.37 \[ 1.07,     |
|                          |          |           | 1.74\]            |
+--------------------------+----------+-----------+-------------------+
| Survived^b^              | 76%      | 70%       | 0.012             |
+--------------------------+----------+-----------+-------------------+
|                          |          |           |                   |
+--------------------------+----------+-----------+-------------------+
| **Efficacy**^c^          | (N=456)  | (N=448)   |                   |
+--------------------------+----------+-----------+-------------------+
| Died^b^                  | 23%      | 29%       | 1.35 \[ 1.05,     |
|                          |          |           | 1.74\]            |
+--------------------------+----------+-----------+-------------------+
| Survived^b^              | 77%      | 71%       | 0.019             |
+--------------------------+----------+-----------+-------------------+
| Key: CI=confidence       |          |           |                   |
| interval                 |          |           |                   |
|                          |          |           |                   |
| ^a^ Based on Cox's model |          |           |                   |
| stratified by metastatic |          |           |                   |
| category.                |          |           |                   |
|                          |          |           |                   |
| ^b^ reported percentages |          |           |                   |
| are based on             |          |           |                   |
| Kaplan-Meier estimates.  |          |           |                   |
|                          |          |           |                   |
| ^c^ Efficacy population  |          |           |                   |
| comprised only of        |          |           |                   |
| subjects who received    |          |           |                   |
| study drug.              |          |           |                   |
|                          |          |           |                   |
| Reference: EPO-INT-76    |          |           |                   |
| CSR^9^                   |          |           |                   |
+--------------------------+----------+-----------+-------------------+

**Figure 4:** Time to Death Within 12 Months After Randomization\
(Study PRI/EPO-INT-76/EPO‑CA‑489: Intent-to-Treat Subjects: Metastatic
Breast Cancer)

Note: Survival curves for 365 days (+ 2-week window) post-randomization.

![](media/image4.wmf){width="6.0in" height="4.5in"}

Reference: EPO-INT-76 CSR^9^

#### Survival -- Deaths Within 4 Months After Randomization 

The Kaplan-Meier survival curves separated early in the study, with
nearly the maximum difference in mortality already evident after the
first 4 months of the double-blind study. As the excess deaths occurred
largely in the first 4 months, the subset of subjects who died within
the first 4 months of randomization was examined further. This was a
post-hoc analysis, to better understand the data. For the
intent-to-treat population, a total of 57 subjects died within the first
4 months after randomization in the double-blind phase. Of these
57 subjects, 16 were in the placebo group and 41 were in the epoetin
alfa group.

##### Patient Demographics in Patients Who Died Within 4 Months 

No apparent reasons for the observed imbalance in deaths at 4 months
were evident from examination of the selected characteristics of
patients who died at 4 months, compared to the total population. Table 5
is illustrative of the findings of these comparisons.

+-----+---+------------------------+---+----------+--------+---+----------+-------+
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|     | e |                        |   |          |        |   |          |       |
|     | t |                        |   |          |        |   |          |       |
|     | a |                        |   |          |        |   |          |       |
|     | s |                        |   |          |        |   |          |       |
|     | t |                        |   |          |        |   |          |       |
|     | a |                        |   |          |        |   |          |       |
|     | t |                        |   |          |        |   |          |       |
|     | i |                        |   |          |        |   |          |       |
|     | c |                        |   |          |        |   |          |       |
|     | B |                        |   |          |        |   |          |       |
|     | r |                        |   |          |        |   |          |       |
|     | e |                        |   |          |        |   |          |       |
|     | a |                        |   |          |        |   |          |       |
|     | s |                        |   |          |        |   |          |       |
|     | t |                        |   |          |        |   |          |       |
|     | C |                        |   |          |        |   |          |       |
|     | a |                        |   |          |        |   |          |       |
|     | n |                        |   |          |        |   |          |       |
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|     | e |                        |   |          |        |   |          |       |
|     | r |                        |   |          |        |   |          |       |
|     | ) |                        |   |          |        |   |          |       |
+-----+---+------------------------+---+----------+--------+---+----------+-------+
|     |   |                        |   | [Plac    |        |   | [Epoetin |       |
|     |   |                        |   | ebo]{.un |        |   | A        |       |
|     |   |                        |   | derline} |        |   | lfa]{.un |       |
|     |   |                        |   |          |        |   | derline} |       |
+-----+---+------------------------+---+----------+--------+---+----------+-------+
|     |   |                        |   | Early    | Total  |   | Early    | Total |
|     |   |                        |   | Deaths   |        |   | Deaths   |       |
+-----+---+------------------------+---+----------+--------+---+----------+-------+
|     | C |                        |   | (N=16)   | (      |   | (N=41)   | (N    |
|     | h |                        |   |          | N=470) |   |          | =469) |
|     | a |                        |   |          |        |   |          |       |
|     | r |                        |   |          |        |   |          |       |
|     | a |                        |   |          |        |   |          |       |
|     | c |                        |   |          |        |   |          |       |
|     | t |                        |   |          |        |   |          |       |
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|     | r |                        |   |          |        |   |          |       |
|     | i |                        |   |          |        |   |          |       |
|     | s |                        |   |          |        |   |          |       |
|     | t |                        |   |          |        |   |          |       |
|     | i |                        |   |          |        |   |          |       |
|     | c |                        |   |          |        |   |          |       |
+-----+---+------------------------+---+----------+--------+---+----------+-------+
|     | M |                        |   | 56.5     | 55     |   | 58       | 56    |
|     | e |                        |   |          |        |   |          |       |
|     | d |                        |   |          |        |   |          |       |
|     | i |                        |   |          |        |   |          |       |
|     | a |                        |   |          |        |   |          |       |
|     | n |                        |   |          |        |   |          |       |
|     | A |                        |   |          |        |   |          |       |
|     | g |                        |   |          |        |   |          |       |
|     | e |                        |   |          |        |   |          |       |
|     | ( |                        |   |          |        |   |          |       |
|     | y |                        |   |          |        |   |          |       |
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|     | r |                        |   |          |        |   |          |       |
|     | s |                        |   |          |        |   |          |       |
|     | ) |                        |   |          |        |   |          |       |
+-----+---+------------------------+---+----------+--------+---+----------+-------+
|     | \ |                        |   | 31%      | 19%    |   | 41%      | 24%   |
|     | > |                        |   |          |        |   |          |       |
|     | 6 |                        |   |          |        |   |          |       |
|     | 5 |                        |   |          |        |   |          |       |
|     | y |                        |   |          |        |   |          |       |
|     | e |                        |   |          |        |   |          |       |
|     | a |                        |   |          |        |   |          |       |
|     | r |                        |   |          |        |   |          |       |
|     | s |                        |   |          |        |   |          |       |
|     | o |                        |   |          |        |   |          |       |
|     | f |                        |   |          |        |   |          |       |
|     | a |                        |   |          |        |   |          |       |
|     | g |                        |   |          |        |   |          |       |
|     | e |                        |   |          |        |   |          |       |
|     | ( |                        |   |          |        |   |          |       |
|     | % |                        |   |          |        |   |          |       |
|     | ) |                        |   |          |        |   |          |       |
+-----+---+------------------------+---+----------+--------+---+----------+-------+
|     |   | Estrogen Receptor      | 5 |          | 49%    | 3 |          | 48%   |
|     |   | Positive (%)           | 0 |          |        | 7 |          |       |
|     |   |                        | % |          |        | % |          |       |
+-----+---+------------------------+---+----------+--------+---+----------+-------+
|     |   | Hemoglobin ≤ 10.5      | 6 |          | 11%    | 2 |          | 14%   |
|     |   | g/dL, (%)              | % |          |        | 9 |          |       |
|     |   |                        |   |          |        | % |          |       |
+-----+---+------------------------+---+----------+--------+---+----------+-------+
|     |   | ≥3 Indicator lesions   | 0 |          | 21%    | 3 |          | 23%   |
|     |   | at entry (%)           |   |          |        | 7 |          |       |
|     |   |                        |   |          |        | % |          |       |
+-----+---+------------------------+---+----------+--------+---+----------+-------+
|     |   | Reference: EPO-INT-76  | [ |          | []{    | [ |          |       |
|     |   | CSR^9^                 | ] |          | .mark} | ] |          |       |
|     |   |                        | { |          |        | { |          |       |
|     |   |                        | . |          |        | . |          |       |
|     |   |                        | m |          |        | m |          |       |
|     |   |                        | a |          |        | a |          |       |
|     |   |                        | r |          |        | r |          |       |
|     |   |                        | k |          |        | k |          |       |
|     |   |                        | } |          |        | } |          |       |
+-----+---+------------------------+---+----------+--------+---+----------+-------+

There were no notable differences in the prestudy (adjuvant) or on-study
chemotherapy received by patients who died in the first 4 months after
randomization, compared to the total study population.

##### Causes of Death

The causes for all deaths that occurred within 4 months of
randomization, and for all deaths that occurred during the 12-month
double‑blind phase of Study EPO-INT-76, are summarized in Table 6, for
the intent-to-treat population.

As shown in Table 6, a total of 263 (28%) subjects in the
intent-to-treat population died during the 12‑month double‑blind phase,
including 24% of placebo-treated subjects and 32% of epoetin
alfa-treated subjects. During the first 4 months after randomization, 16
placebo-treated subjects died, compared with 41 subjects in the epoetin
alfa group. The most common cause of death at 4 months and at 12 months
post-randomization was reported as disease progression. During the first
4 months after randomization, deaths attributed by the investigator to
disease progression accounted for 13/16 and 28/41 of the deaths in the
placebo and epoetin alfa treatment populations, respectively. This
pattern was still seen at the 12‑month time point, where a large
majority of deaths (91% and 85%) in each of the two treatment groups was
attributed to disease progression.

+---------------------------------+-----------+-----------+-----------+
| **Table 6:** Cause of Deaths    |           |           |           |
| Among Subjects Who Died Within  |           |           |           |
| 4 Months and Within 12 Months   |           |           |           |
| of Randomization as Attributed  |           |           |           |
| by the Investigator\            |           |           |           |
| (Study PRI/EPO-INT-76:          |           |           |           |
| Intent‑to‑Treat Subjects:       |           |           |           |
| Metastatic Breast Cancer)       |           |           |           |
+---------------------------------+-----------+-----------+-----------+
|                                 | Placebo   | Epoetin   | D         |
|                                 |           | Alfa      | ifference |
+---------------------------------+-----------+-----------+-----------+
|                                 | (N=470)   | (N=469)   | EPO-PBO   |
+---------------------------------+-----------+-----------+-----------+
| **No. (%) died within 4         | **16      | **41      | **25**    |
| months**                        | (3)**     | (9)**     |           |
+---------------------------------+-----------+-----------+-----------+
|                                 |           |           |           |
+---------------------------------+-----------+-----------+-----------+
| **Cause of death within 4       |           |           |           |
| months as attributed by         |           |           |           |
| investigator**                  |           |           |           |
+---------------------------------+-----------+-----------+-----------+
| > Chemotherapy toxicity         | 1         | 3         | 2         |
+---------------------------------+-----------+-----------+-----------+
| > Disease progression           | 13        | 28        | 15        |
+---------------------------------+-----------+-----------+-----------+
| > Missing                       | 0         | 1^a^      | 1         |
+---------------------------------+-----------+-----------+-----------+
| > Other^b^                      | 1         | 4         | 3         |
+---------------------------------+-----------+-----------+-----------+
| > Thrombotic vascular event     | 1         | 5         | 4         |
+---------------------------------+-----------+-----------+-----------+
|                                 |           |           |           |
+---------------------------------+-----------+-----------+-----------+
| **No. (%) died during 12        | **115     | **148     | **33**    |
| months**                        | (24)**    | (32)**    |           |
+---------------------------------+-----------+-----------+-----------+
|                                 |           |           |           |
+---------------------------------+-----------+-----------+-----------+
| **Cause of death during 12      |           |           |           |
| months as attributed by         |           |           |           |
| investigator**                  |           |           |           |
+---------------------------------+-----------+-----------+-----------+
| > Chemotherapy toxicity         | 1         | 8         | 7         |
+---------------------------------+-----------+-----------+-----------+
| > Disease progression           | 105       | 126       | 21        |
+---------------------------------+-----------+-----------+-----------+
| > Missing^c^                    | 0         | 2         | 2         |
+---------------------------------+-----------+-----------+-----------+
| > Other^d^                      | 6         | 6         | 0         |
+---------------------------------+-----------+-----------+-----------+
| > Thrombotic vascular event     | 3         | 6         | 3         |
+---------------------------------+-----------+-----------+-----------+
| ^a^ Cause of death was unknown. |           |           |           |
| Subject 3003 died suddenly on   |           |           |           |
| Study Day 36.                   |           |           |           |
|                                 |           |           |           |
| ^b^ Other causes include:       |           |           |           |
|                                 |           |           |           |
| \- fatty embolism, ischemic     |           |           |           |
| colon perforation, pulmonary    |           |           |           |
| edema, unknown                  |           |           |           |
|                                 |           |           |           |
| ^c^ Cause of death not listed   |           |           |           |
| for 2 subjects in the epoetin   |           |           |           |
| alfa treatment group.           |           |           |           |
|                                 |           |           |           |
| ^d^ Other causes of death       |           |           |           |
| included\                       |           |           |           |
| -aspiration of barium --        |           |           |           |
| cardiac arrest, cardiomyopathy  |           |           |           |
| and disease progression\        |           |           |           |
| -cardiomyopathy, circulatory    |           |           |           |
| tract insufficiency\            |           |           |           |
| -euthanasia, fatty embolism\    |           |           |           |
| -heart insufficiency, ischemic  |           |           |           |
| colon perforation\              |           |           |           |
| -died with traffic accident,    |           |           |           |
| pulmonary edema\                |           |           |           |
| -renal insufficiency\           |           |           |           |
| -respiratory/circulatory        |           |           |           |
| insufficiency, serious adverse  |           |           |           |
| event: aspiration of barium\    |           |           |           |
| -traffic accident, unknown.     |           |           |           |
|                                 |           |           |           |
| Reference: EPO-INT-76 CSR^9^    |           |           |           |
+---------------------------------+-----------+-----------+-----------+

It should be noted that the cause of death given for subjects in
Study EPO-INT-76 was based on the assessment of the investigator, and it
was not necessary for the study investigator to provide corroborating
information when he/she checked off "disease progression" as the cause
of death. It is perhaps not surprising that, in this population of
subjects with metastatic cancer, most deaths were attributed to "disease
progression". To help determine whether the observed difference in
mortality reflected a true difference in tumor treatment response /
disease progression, a blinded chart review was undertaken, in which all
available information in individual patient charts regarding indicators
of disease progression was evaluated, including tumor response, time to
disease progression, and progression-free survival. All chart
information on the patients who died in the first 4 months was also
examined to look for any records regarding associated TVEs.

Based on the information generated in this blinded chart review, among
the patients who died in the first 4 months following randomization,
2/16 deaths in the placebo group and 11/41 deaths in the epoetin alfa
group were related to TVEs, compared with 1/16 and 5/41 deaths that had
been attributed to TVEs according to the original report of the study
investigator on the case report form (CRF). Thus, TVEs accounted for
some of the increased mortality in the epoetin alfa group in the 4
months following randomization, and this analysis, together with the
potential for underdiagnosis of fatal TVEs, suggests that these events
may well have accounted for a substantial portion of the observed
increased mortality in the epoetin alfa group.

#### Tumor Response

Study EPO-INT-76 was designed as a survival study with limited data
collection, and there were no detailed requirements for tumor assessment
at entry or during study treatment or follow-up. Further, despite
post-hoc efforts to retrospectively collect additional information via
chart reviews, 26% of placebo-treated subjects and 29% of epoetin
alfa-treated subjects had inadequate tumor assessments before
chemotherapy. This substantial level of missing data clearly constrains
the interpretation of analyses of response rates and time to progression
in this study. However, analyses of tumor response were performed with
findings as described below.

##### Optimal Tumor Response to First‑Line Chemotherapy

> Optimal tumor response rate to first‑line chemotherapy was defined as
> the best overall response noted at any time during first‑line
> chemotherapy. Individual investigators made the determination on the
> basis of tumor measurements obtained during first‑line chemotherapy,
> and the method of determination was at the investigator\'s discretion.
> No detailed requirements were defined for tumor assessment at study
> entry or during the follow‑up period. As noted above, baseline tumor
> assessment data were missing in a substantial proportion of patients
> in each treatment group.

For the intent-to-treat population, the optimal tumor response to
chemotherapy was not statistically different between the treatment
groups (p=0.93). The proportion of patients who had a complete or
partial response to first‑line chemotherapy was similar in the placebo
and the epoetin alfa treatment groups (Table 7). The number of patients
who developed new lesions, as a manifestation of progressive disease,
was also similar in both groups, indicating that epoetin alfa was not
associated with a higher incidence of new metastatic lesions.

+----------------------------------+----------------+----------------+
| **Table 7:** Optimal Tumor       |                |                |
| Response to First‑Line           |                |                |
| Chemotherapy\                    |                |                |
| (Study PRI/EPO-INT-76:           |                |                |
| Intent‑to‑Treat Subjects:        |                |                |
| Metastatic Breast Cancer)        |                |                |
+----------------------------------+----------------+----------------+
|                                  | Placebo        | Epoetin Alfa   |
+----------------------------------+----------------+----------------+
|                                  | (N=470)        | (N=469)        |
+----------------------------------+----------------+----------------+
| Tumor response, n (%)            |                |                |
+----------------------------------+----------------+----------------+
| Complete response                | 45 (10)        | 55 (12)        |
+----------------------------------+----------------+----------------+
| Partial response                 | 170 (36)       | 154 (33)       |
+----------------------------------+----------------+----------------+
| Overall response (CR + PR)       | 215 (46)       | 209 (45)       |
+----------------------------------+----------------+----------------+
| No response (stable disease)     | 156 (33)       | 149 (32)       |
+----------------------------------+----------------+----------------+
| Progressive disease              | 84 (18)        | 87 (19)        |
+----------------------------------+----------------+----------------+
| New lesions                      | 56 (12)        | 43 (9)         |
+----------------------------------+----------------+----------------+
| Unknown                          | 15 (3)         | 24 (5)         |
+----------------------------------+----------------+----------------+
| p value^a^                       | 0.9303         |                |
+----------------------------------+----------------+----------------+
| ^a^ The p‑value was based on a   |                |                |
| stratified                       |                |                |
| Cochran‑Mantel‑Haenszel test.    |                |                |
| Response to chemotherapy         |                |                |
| categories:                      |                |                |
|                                  |                |                |
| [Complete response]{.underline}: |                |                |
| complete absence of detectable   |                |                |
| tumor.                           |                |                |
|                                  |                |                |
| [Partial response]{.underline}:  |                |                |
| reduction in estimated tumor     |                |                |
| mass by ≥50%; \<25% increase in  |                |                |
| the size of any measurable       |                |                |
| malignant lesion; \<25% increase |                |                |
| in the estimated size of any     |                |                |
| evaluable but non‑measurable     |                |                |
| malignant lesion; no new         |                |                |
| lesions.                         |                |                |
|                                  |                |                |
| [No response (stable             |                |                |
| disease)]{.underline}: reduction |                |                |
| of tumor mass by \<50%; \<25%    |                |                |
| increase in the size of any      |                |                |
| measurable malignant lesion;     |                |                |
| \<25% increase in the estimated  |                |                |
| size of any evaluable but        |                |                |
| non‑measurable malignant lesion; |                |                |
| no new lesions.                  |                |                |
|                                  |                |                |
| [Progressive                     |                |                |
| disease]{.underline}: increase   |                |                |
| in estimated tumor mass by ≥25%  |                |                |
| or appearance of new lesion.     |                |                |
|                                  |                |                |
| Reference: EPO-INT-76 CSR^9^     |                |                |
+----------------------------------+----------------+----------------+

##### Tumor Response at the End of First‑Line Chemotherapy

> For the intent-to-treat population, the tumor response at the end of
> first‑line chemotherapy was 35% for subjects in the epoetin alfa
> treatment group and 36% for subjects in the placebo group (Table 8).

+--------------------------------------+---------------+---------------+---+
| **Table 8:** Tumor Response at the   |               |               |   |
| End of First‑Line Chemotherapy\      |               |               |   |
| (Study PRI/EPO-INT-76:               |               |               |   |
| Intent‑to‑Treat Subjects: Metastatic |               |               |   |
| Breast Cancer)                       |               |               |   |
+--------------------------------------+---------------+---------------+---+
|                                      | Placebo       | Epoetin Alfa  |   |
+--------------------------------------+---------------+---------------+---+
|                                      | (N=470)       | (N=469)       |   |
+--------------------------------------+---------------+---------------+---+
| **Tumor response, n (%)**            |               |               |   |
+--------------------------------------+---------------+---------------+---+
| Complete response                    | 41 (9)        | 49 (10)       |   |
+--------------------------------------+---------------+---------------+---+
| Partial response                     | 127 (27)      | 115 (25)      |   |
+--------------------------------------+---------------+---------------+---+
| Overall response (CR + PR)           | 168 (36)      | 164 (35)      |   |
+--------------------------------------+---------------+---------------+---+
| No response (stable disease)         | 124 (26)      | 96 (20)       |   |
+--------------------------------------+---------------+---------------+---+
| Progressive disease                  | 123 (26)      | 125 (27)      |   |
+--------------------------------------+---------------+---------------+---+
| New lesions                          | 101 (21)      | 86 (18)       |   |
+--------------------------------------+---------------+---------------+---+
| Unknown^a^                           | 55 (12)       | 84 (18)       |   |
+--------------------------------------+---------------+---------------+---+
| ^a^ All information on response to   |               |               |   |
| chemotherapy was missing.            |               |               |   |
|                                      |               |               |   |
| Response to Chemotherapy Categories: |               |               |   |
|                                      |               |               |   |
| [Complete response]{.underline}:     |               |               |   |
| complete absence of detectable       |               |               |   |
| tumor.                               |               |               |   |
|                                      |               |               |   |
| [Partial response]{.underline}:      |               |               |   |
| reduction in estimated tumor mass by |               |               |   |
| ≥50%; \<25% increase in the size of  |               |               |   |
| any measurable malignant lesion;     |               |               |   |
| \<25% increase in the estimated size |               |               |   |
| of any evaluable but non‑measurable  |               |               |   |
| malignant lesion; no new lesions.    |               |               |   |
|                                      |               |               |   |
| [No response (stable                 |               |               |   |
| disease)]{.underline}: reduction of  |               |               |   |
| tumor mass by \<50%; \<25% increase  |               |               |   |
| in the size of any measurable        |               |               |   |
| malignant lesion; \<25% increase in  |               |               |   |
| the estimated size of any evaluable  |               |               |   |
| but non‑measurable malignant lesion; |               |               |   |
| no new lesions.                      |               |               |   |
|                                      |               |               |   |
| [Progressive disease]{.underline}:   |               |               |   |
| increase in estimated tumor mass by  |               |               |   |
| ≥25% or appearance of new lesion.    |               |               |   |
|                                      |               |               |   |
| Reference: EPO-INT-76 CSR^9^         |               |               |   |
+--------------------------------------+---------------+---------------+---+

##### Tumor Response at Individual Subject Study End 

> For the intent-to-treat population, tumor response at the last
> assessment for each individual subject during the 12‑month
> double‑blind phase was similar for the two treatment groups (Table 9).
> Slightly more subjects who received placebo showed progressive disease
> than those who received epoetin alfa, with a corresponding finding for
> the occurrence of new lesions. These data do not indicate any effect
> of epoetin alfa on tumor response rate.

+--------+---+-----------------------------+---------------+---------------+
|        | * |                             |               |               |
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|        | ‑ |                             |               |               |
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|        | a |                             |               |               |
|        | t |                             |               |               |
|        | S |                             |               |               |
|        | u |                             |               |               |
|        | b |                             |               |               |
|        | j |                             |               |               |
|        | e |                             |               |               |
|        | c |                             |               |               |
|        | t |                             |               |               |
|        | s |                             |               |               |
|        | : |                             |               |               |
|        | M |                             |               |               |
|        | e |                             |               |               |
|        | t |                             |               |               |
|        | a |                             |               |               |
|        | s |                             |               |               |
|        | t |                             |               |               |
|        | a |                             |               |               |
|        | t |                             |               |               |
|        | i |                             |               |               |
|        | c |                             |               |               |
|        | B |                             |               |               |
|        | r |                             |               |               |
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|        | ) |                             |               |               |
+--------+---+-----------------------------+---------------+---------------+
|        |   |                             | Placebo       | Epoetin Alfa  |
+--------+---+-----------------------------+---------------+---------------+
|        |   |                             | (N=470)       | (N=469)       |
+--------+---+-----------------------------+---------------+---------------+
|        |   | Tumor response, n (%)       |               |               |
+--------+---+-----------------------------+---------------+---------------+
|        |   | Complete response           | 34 (7)        | 44 (9)        |
+--------+---+-----------------------------+---------------+---------------+
|        |   | Partial response            | 66 (14)       | 45 (10)       |
+--------+---+-----------------------------+---------------+---------------+
|        |   | Overall response (CR + PR)  | 100 (21)      | 89 (19)       |
+--------+---+-----------------------------+---------------+---------------+
|        |   | No response (stable         | 88 (19)       | 102 (22)      |
|        |   | disease)                    |               |               |
+--------+---+-----------------------------+---------------+---------------+
|        |   | Progressive disease         | 216 (46)      | 195 (42)      |
+--------+---+-----------------------------+---------------+---------------+
|        |   | New lesions                 | 177 (38)      | 140 (30)      |
+--------+---+-----------------------------+---------------+---------------+
|        |   | Unknown^a^                  | 66 (14)       | 83 (18)       |
+--------+---+-----------------------------+---------------+---------------+
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|        | w |                             |               |               |
|        | l |                             |               |               |
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|        | s |                             |               |               |
|        | i |                             |               |               |
|        | o |                             |               |               |
|        | n |                             |               |               |
|        | . |                             |               |               |
|        |   |                             |               |               |
|        | R |                             |               |               |
|        | e |                             |               |               |
|        | f |                             |               |               |
|        | e |                             |               |               |
|        | r |                             |               |               |
|        | e |                             |               |               |
|        | n |                             |               |               |
|        | c |                             |               |               |
|        | e |                             |               |               |
|        | : |                             |               |               |
|        | E |                             |               |               |
|        | P |                             |               |               |
|        | O |                             |               |               |
|        | - |                             |               |               |
|        | I |                             |               |               |
|        | N |                             |               |               |
|        | T |                             |               |               |
|        | - |                             |               |               |
|        | 7 |                             |               |               |
|        | 6 |                             |               |               |
|        | C |                             |               |               |
|        | S |                             |               |               |
|        | R |                             |               |               |
|        | ^ |                             |               |               |
|        | 9 |                             |               |               |
|        | ^ |                             |               |               |
+--------+---+-----------------------------+---------------+---------------+

If epoetin alfa were interfering with response to chemotherapy or
potentiating tumor growth, a lower objective response rate might have
been observed in patients treated with epoetin alfa, and the number of
patients in the epoetin alfa group with new lesions or disease
progression might have been higher. These findings are not suggestive of
an effect of epoetin alfa on tumor response to treatment, and may
support consideration of other mechanisms, such thrombotic vascular
events (some of which may be occult) and/or other adverse events, to
explain the observed survival differences. This also may suggest that
disease progression was not the true reason for the difference in deaths
in the two treatment groups, despite the attributions assigned in the
case records.

#### Time to Disease Progression 

It is again important to note that Study EPO-INT-76 was designed as a
survival study with limited data collection, and there were no detailed
requirements for tumor assessment at entry or during study treatment or
follow-up. Further, despite efforts to retrospectively collect
additional information via chart reviews, 26% of placebo-treated
subjects and 29% of epoetin alfa-treated subjects had inadequate tumor
assessments before chemotherapy. This substantial level of missing data
clearly constrains the interpretation of analyses of response rates and
time to progression in this study.

For purposes of analysis, the date of disease progression was determined
to be the first time the investigator noted disease progression when
recording evaluation of optimal tumor response to first‑line
chemotherapy, tumor response at the end of first‑line chemotherapy, and
tumor response at completion or withdrawal from the study. If a subject
did not have disease progression reported on study, time to disease
progression was determined by using the following rules:

-   if subject died within 12 months after randomization and death was
    attributed to disease progression, she was considered as having
    disease progression with the time to disease progression equivalent
    to the time to death;

-   if subject died within 12 months after randomization of causes other
    than disease progression, time to disease progression was censored
    at the date of death;

-   if death occurred beyond 12 months after randomization, time to
    disease progression was censored at the date of completion or
    withdrawal.

Forty subjects (24 in the epoetin alfa group, 16 in the placebo group)
were not evaluable for this endpoint, because of early withdrawal from
the study before any tumor assessments were conducted.

For the intent-to-treat population, time to disease progression was
similar between the 2 treatment groups (p=0.71) (Figure 5). On the basis
of Kaplan‑Meier estimates, 43.4% of subjects who received epoetin alfa
and 41.1% of those who received placebo had evidence of disease
progression by Month 12.

**Figure 5:** Time to Disease Progression\
(Study PRI/EPO-INT-76: Intent‑to‑Treat Subjects: Metastatic Breast
Cancer)

![](media/image5.wmf){width="5.697916666666667in"
height="4.283333333333333in"}

> Reference: EPO-INT-76 CSR^9^

#### Conclusion

Study EPO-INT-76 evaluated whether epoetin alfa treatment, administered
weekly for one year to maintain hemoglobin levels at 12-14 g/dL in
patients starting first-line chemotherapy for metastatic breast cancer,
could favorably affect the survival of these patients. Treatment
differed from the common uses of ERAs for chemotherapy-associated anemia
in that target hemoglobins were relatively high and treatment continued
for a year regardless of chemotherapy. The reasons for the observed
outcome of EPO-INT-76 are not clear. An effect on tumor treatment
response / disease progression cannot be excluded, but it also appears
likely that increased adverse effects (TVEs), associated with this use
of ERA treatment of patients beyond the correction of anemia, may have
played a role.

### Study of Henke M, et al. ^2^

It is important to acknowledge that the Sponsor did not have access to
the primary data to evaluate the results of this study. This discussion
of the results is based on data available in the public domain.

#### Study Design

Henke et al. conducted a multicenter, randomized, double‑blind,
placebo‑controlled clinical trial in patients with head and neck cancer,
designed to investigate the effects of epoetin beta (NeoRecormon^^) on
locoregional progression‑free survival (LRPFS) and overall survival,
compared with placebo. The starting dose of epoetin beta was 300 IU/kg
t.i.w. for 7 to 9 weeks, beginning 10-14 days before the start of
radiation therapy (double the starting dose recommended in product
labeling). Study subjects had advanced stage (III/IV) head and neck
cancer (HNC) and were to receive postoperative radiation therapy, or
radiation therapy alone if their disease was inoperable. The entry level
for hemoglobin was \<12.0 g/dL for women and \<13.0 g/dL for men. The
target hemoglobin was ≥14.0 g/dL for women and ≥15.0 g/dL for men . The
study was designed to determine if ERA-induced higher hemoglobin levels
can increase the radiosensitivity of head and neck cancer, and thus
improve the outcome of treatment.

The primary end point of the study was LRPFS. Time to locoregional tumor
progression and survival were also assessed. A total of 351 subjects
were enrolled between March 1997 and April 2001 and were randomly
assigned to either the epoetin beta group or the placebo group.
Randomization was to three strata, based on complete resection;
incompletely resected disease; or not operable (candidates for primary
definitive radiotherapy).

#### Reported Study Results 

Subjects treated with epoetin beta had a robust increase in hemoglobin
concentration that was maintained during treatment, with a reported
median hemoglobin at baseline of 11.7 g/dL, rising to reported mean
hemoglobin values of 14.8 and 15.4 g/dL after 4 weeks and 9 weeks,
respectively. In the intent‑to‑treat population, the median LRPFS was
406 days for subjects in the epoetin beta treatment group and 745 days
for those who received placebo. The stage-adjusted and stratum-adjusted
relative risk for LRPFS was 1.62 (95% CI, 1.22 to 2.14, p=0.0008).
Survival in the intent-to-treat population also favored the placebo
group (p=0.02, RR=1.39 \[95% CI, 1.05 to 1.84\], respectively).
Separation of the LRPFS and survival curves began at about 6 months and
continued for the duration of follow-up.

A total of 89 (52%) subjects in the placebo arm and 109 (61%) subjects
in the epoetin beta arm died. One-third (34%) or 119 subjects in the
2 treatment groups had deaths attributed to cancer. Data on the number
of cancer-related deaths by treatment arm are not available in the
publication. Interestingly, the majority of the 20 excess deaths in the
epoetin beta treatment arm could be accounted for by imbalances in
reported deaths from cardiac disorders (5 placebo versus 10 epoetin beta
deaths) and "general disorders" (1 placebo versus 9 epoetin beta). There
was no difference in the rate of distant metastatic disease in the
2 arms of the study (23% in the placebo group versus 25% in the epoetin
beta group,).

Vascular disorders were reported in 5% of placebo patients and 11% of
epoetin beta patients, and included hypertension, hemorrhage, venous
thrombosis and pulmonary embolism, and cerebrovascular disorders.

These unanticipated results suggested that therapy with epoetin beta in
advanced stage HNC treated with radiotherapy might have exerted an
adverse effect on LRPFS and survival; and the publication raised
concerns that ERAs might be radioprotective or might stimulate tumor
cell proliferation, resulting in disease progression and decreased
survival.

### Ongoing Study in Follow-Up Phase: Study AGO/NOGGO^10^

The study conducted by a German cooperative group AGO/NOGGO, referred to
as Study AGO/NOGGO, is an investigator-sponsored study. It is important
to note that the Sponsor did not have access to the primary data, and
results are presented with the author\'s permission based on a
presentation at ASCO in September 2003 together with a draft manuscript.
This study was initiated in 1999 among patients with cervical cancer
receiving sequential adjuvant chemoradiotherapy (ifosfamide and
carboplatin followed by radiotherapy) and has a primary endpoint of
recurrence-free survival after 5 years. The data presented here are
preliminary, as median follow-up for study participants is currently
approximately two years.

#### Study Design 

The study is a multicenter, randomized, open‑label study conducted
primarily to compare relapse-free survival of patients with high-risk
cervical cancer receiving adjuvant sequential chemotherapy and
radiotherapy with or without epoetin alfa. Secondary endpoints were
change in hemoglobin levels, transfusion requirements, reduction in
anemia, changes in ECOG performance status, toxicity, and overall
survival. Eligible patients had International Federation of Gynecology
and Obstetrics (FIGO) staging scores of IB, IIA, or IIB, and had
undergone radical hysterectomy. Patients in stages IB or IIA were also
required to have one of the following poor prognostic factors: invasion
of the tumor into lymph and/or blood vessels, adenocarcinoma, age less
than 35 years, grading G3, tumor greater than 4 cm in diameter, and pN1
(pelvic lymph node metastases). Patients were centrally randomized using
three prognostic factors as stratification criteria: lymph node
involvement, staging according to FIGO classification system, and
quality of tumor resection. At baseline (after surgery but before
chemotherapy or radiotherapy) patients in the epoetin alfa group began
treatment with 10,000 IU of epoetin alfa subcutaneously 3 times a week.
Administration of epoetin alfa continued until 2 weeks after the end of
radiotherapy to a target hemoglobin of 13.0 g/dL. If hemoglobin at
chemotherapy initiation was \<10.5 g/dL, epoetin alfa dose was increased
to 10,000 IU 6 times weekly. If hemoglobin rose to \>13.0 g/dL, epoetin
alfa dose was reduced to 10,000 IU 2 times weekly; epoetin alfa was
discontinued if hemoglobin reached \>14.0 g/dL.

Patients in the control group received oral iron (Fe++ 200 mg/day) and
blood transfusions for treatment of hemoglobin \<9.0 g/dL. Patients in
the epoetin alfa group whose hemoglobin declined to this level also
received blood transfusions.

#### Preliminary Analysis 

Before the initiation of chemotherapy, 53% of patients who received
epoetin alfa and 43% of patients in the control group had hemoglobin
levels [\>]{.underline}12 g/dL. The respective mean values were 12 g/dL
and 11.8 g/dL. Before radiotherapy, mean hemoglobin levels were 12.5
g/dL for the epoetin alfa group and 10.8 g/dL for the control group.
Mean hemoglobin at the end of radiotherapy was 12.9 g/dL for the epoetin
alfa group and 12.1 g/dL for the control group. Two weeks after
radiotherapy mean hemoglobin levels increased to 13.1 g/dL for the
epoetin alfa group and 12.4 g/dL for the control group.

As designed, the study initially had three arms; a chemoradiotherapy
(control) arm, a chemoradiotherapy plus epoetin alfa arm, and a
radiation therapy alone arm. The third arm accrued very few patients and
was closed. Of the 264 patients enrolled, 257 were in the control or
epoetin alfa arms. Evaluable patients who had baseline demographics and
characteristics for the primary intent-to-treat analysis included 122
epoetin alfa and 125 control patients. The relapse-free survival for the
control group and the epoetin alfa group over time is shown in Figure 6.
Table 10 summarizes relapse-free survival at a median observation time
of 105 weeks (mean 102.6 weeks). The difference between the groups
trended towards significance (p = 0.074).

+----------------+--------------------+----------------+--------------+
| **Table 10:**  |                    |                |              |
| Recurrence of  |                    |                |              |
| Malignancy at  |                    |                |              |
| Median of 105  |                    |                |              |
| weeks\*\       |                    |                |              |
| (Study         |                    |                |              |
| AGO/NOGGO:     |                    |                |              |
| Cervical       |                    |                |              |
| Cancer)        |                    |                |              |
+----------------+--------------------+----------------+--------------+
|                | **Epoetin alfa     | **Control      | **Total**    |
|                | group**            | group          |              |
|                |                    | (n=116)**      | **( n=234)** |
|                | **(n=113)**        |                |              |
+----------------+--------------------+----------------+--------------+
| No recurrence  | 94 (83%)           | 87 (75%)       | 185 (79%)    |
+----------------+--------------------+----------------+--------------+
| Recurrence     | 19 (17%)           | 29 (25%)       | 49 (21%)     |
+----------------+--------------------+----------------+--------------+
| \**p* = .074   |                    |                |              |
|                |                    |                |              |
| Note: 5        |                    |                |              |
| patients were  |                    |                |              |
| randomized to  |                    |                |              |
| the            |                    |                |              |
| radiotherapy   |                    |                |              |
| group, which   |                    |                |              |
| are not        |                    |                |              |
| included in    |                    |                |              |
| this table.    |                    |                |              |
|                |                    |                |              |
| Reference:     |                    |                |              |
| Reference #10. |                    |                |              |
+----------------+--------------------+----------------+--------------+

**Figure 6:** Relapse-Free Survival for the Control Group vs the Epoetin
Alfa Group\
(Study AGO/NOGGO: Cervical Cancer)

> ![](media/image6.wmf){width="4.990277777777778in" height="3.75in"}

Reference: Reference #10.

### Ongoing Study in Follow-Up Phase: EPO-GBR-7^11^

Study EPO-GBR-7 was a company-sponsored study conducted in the United
Kingdom with a planned sample size of 800 subjects receiving
radiotherapy for head and neck cancer. The first subject was randomized
in August 1999. Due to slow accrual, enrollment was stopped after 301
subjects had been recruited, with the last subject randomized in April
2002. Based on the study protocol, the study treatment phase has been
completed and the 5-year follow-up phase is ongoing. Subjects who
completed the study were to be followed monthly for 3 months after the
end of radiotherapy and annually thereafter either until death or for
5 years post-radiotherapy, whichever is sooner.

#### Study Design

This was a randomized, open-label, Phase 3, multicenter study. The
primary objective of the study was to evaluate the effect of treatment
with epoetin alfa on the length of local disease-free survival, local
tumor control, and quality of life in subjects receiving radical
radiotherapy with curative intent for head and neck cancer. Subjects
were randomly assigned to receive either standard radiotherapy plus
epoetin alfa (4,000 or 10,000 IU s.c. 3 times per week based on whether
entry hemoglobin concentration was \>12.5 g/dL or ≤12.5 g/dL) or
standard radiotherapy alone. The duration of treatment was through the
end of radiotherapy. Subjects were to have a baseline hemoglobin
concentration of less than or equal to 15 g/dL. Hemoglobin
concentrations during the study were intended to be maintained at
approximately 12.5 g/dL-15 g/dL.

#### Preliminary Analysis

Of the 301 subjects enrolled, no data were available for one subject.
All summaries and analyses presented in this document were based on the
300 subjects (149 in the observation group \[standard radiotherapy
only\] and 151 in the epoetin alfa group) who were randomized and had
data (referred to as "All Subjects Randomized" in this document for
simplicity).

Fifty-seven (38%) subjects in each treatment group were withdrawn from
the study (Table 11). The majority of the withdrawals were due to tumor
recurrence (46 \[31%\] in the observation group and 43 \[28%\] in the
epoetin alfa group).

At the time of the current analysis, a total of 148 (49%) subjects (74
\[50%\] in the observation group and 74 \[49%\] in the epoetin alfa
group) were alive and still being followed in the study.

+----------------------------------------+--------------+--------------+
| **Table 11:** Study                    |              |              |
| Completion/Withdrawal Information\     |              |              |
| (Study EPO-GBR-7: All Subjects         |              |              |
| Randomized: Head and Neck Cancer)      |              |              |
+----------------------------------------+--------------+--------------+
|                                        | Observation  | Epoetin Alfa |
+----------------------------------------+--------------+--------------+
|                                        | (N=149)      | (N=151)      |
+----------------------------------------+--------------+--------------+
|                                        | n (%)        | n (%)        |
+----------------------------------------+--------------+--------------+
| Died before end of RT                  | 0            | 0            |
+----------------------------------------+--------------+--------------+
| Died between end of RT and end of Year | 17 (11)      | 20 (13)      |
| 5^a^                                   |              |              |
+----------------------------------------+--------------+--------------+
| Withdrawal and reasons^b^              | 57 (38)      | 57 (38)      |
+----------------------------------------+--------------+--------------+
| Tumor recurrence                       | 46 (31)      | 43 (28)      |
+----------------------------------------+--------------+--------------+
| Adverse event                          | 1 (1)        | 0            |
+----------------------------------------+--------------+--------------+
| Personal choice                        | 5 (3)        | 3 (2)        |
+----------------------------------------+--------------+--------------+
| Lost to follow-up                      | 1 (1)        | 2 (1)        |
+----------------------------------------+--------------+--------------+
| Other                                  | 5 (3)        | 11 (7)       |
+----------------------------------------+--------------+--------------+
| Alive and being followed in study      | 74 (50)      | 74 (49)      |
+----------------------------------------+--------------+--------------+
| Status unknown                         | 1 (1)        | 0            |
+----------------------------------------+--------------+--------------+
| Key: RT=radiotherapy                   |              |              |
|                                        |              |              |
| ^a^ According to the protocol,         |              |              |
| subjects were considered to have       |              |              |
| completed the study if they either     |              |              |
| completed the 5-year follow-up or died |              |              |
| between the end of radiotherapy and    |              |              |
| Year 5.                                |              |              |
|                                        |              |              |
| ^b^ Each subject could have up to 2    |              |              |
| reasons. Per protocol, subjects could  |              |              |
| withdraw from the 5-year study due to  |              |              |
| any of these reasons. However, vital   |              |              |
| status of withdrawn subjects is still  |              |              |
| being followed to obtain complete,     |              |              |
| long-term survival data.               |              |              |
+----------------------------------------+--------------+--------------+

Reference: EPO-GBR-7 preliminary report.^11^

#### Demographic and Baseline Characteristics

Demographic and baseline characteristics are summarized in Table 12. The
overall population of this study had a median age of 58.5 years and a
77:23 male-to-female ratio. At baseline, 38% of study subjects had
Stage IV tumors, 25% had Stage III, 33% had Stage II, and the remaining
4% had Stage I. The median hemoglobin concentration at baseline for the
overall population was 13.6 g/dL.

Compared with subjects in the observation group, more subjects in the
epoetin alpha group had stage IV disease (39% vs. 36%).

Other demographic and baseline characteristics (age, sex, and hemoglobin
concentration) were generally balanced between the 2 groups.

Among subjects who were randomized into the active treatment group, 25%
had starting dose of 10,000 IU 3 times weekly, and 75% had a starting
dose of 4,000 IU 3 times weekly, which were determined according to the
subjects\' baseline hemoglobin concentrations.

+--------------------------+---------------------+---------------------+
| **Table 12:**            |                     |                     |
| Demographic and Baseline |                     |                     |
| Characteristics\         |                     |                     |
| (Study EPO-GBR-7: All    |                     |                     |
| Subjects Randomized:     |                     |                     |
| Head and Neck Cancer)    |                     |                     |
+--------------------------+---------------------+---------------------+
|                          | Observation         | Epoetin Alfa        |
+--------------------------+---------------------+---------------------+
|                          | (N=149)             | (N=151)             |
+--------------------------+---------------------+---------------------+
| **Age (Years)**          |                     |                     |
+--------------------------+---------------------+---------------------+
| N                        | 149                 | 151                 |
+--------------------------+---------------------+---------------------+
| Mean (SD)                | 60.2 (10.6)         | 59.8 (10.8)         |
+--------------------------+---------------------+---------------------+
| Median                   | 58.0                | 60.0                |
+--------------------------+---------------------+---------------------+
| Range                    | 35 - 84             | 37 - 88             |
+--------------------------+---------------------+---------------------+
|                          |                     |                     |
+--------------------------+---------------------+---------------------+
| **Sex, n (%)**           |                     |                     |
+--------------------------+---------------------+---------------------+
| N                        | 149                 | 151                 |
+--------------------------+---------------------+---------------------+
| Male                     | 118 (79)            | 114 (75)            |
+--------------------------+---------------------+---------------------+
| Female                   | 31 (21)             | 37 (25)             |
+--------------------------+---------------------+---------------------+
|                          |                     |                     |
+--------------------------+---------------------+---------------------+
| **Tumor Stage, n (%)**   |                     |                     |
+--------------------------+---------------------+---------------------+
| N                        | 147                 | 150                 |
+--------------------------+---------------------+---------------------+
| I                        | 5 (3)               | 8 (5)               |
+--------------------------+---------------------+---------------------+
| II                       | 52 (35)             | 45 (30)             |
+--------------------------+---------------------+---------------------+
| III                      | 37 (25)             | 38 (25)             |
+--------------------------+---------------------+---------------------+
| IV                       | 53 (36)             | 59 (39)             |
+--------------------------+---------------------+---------------------+
|                          |                     |                     |
+--------------------------+---------------------+---------------------+
| **Hemoglobin (g/dL)**    |                     |                     |
+--------------------------+---------------------+---------------------+
| N                        | 146                 | 148                 |
+--------------------------+---------------------+---------------------+
| Mean (SD)                | 13.5 (1.3)          | 13.4 (1.2)          |
+--------------------------+---------------------+---------------------+
| Median                   | 13.65               | 13.40               |
+--------------------------+---------------------+---------------------+
| Range                    | 8.9 - 16.7          | 9.3 - 15.5          |
+--------------------------+---------------------+---------------------+
|                          |                     |                     |
+--------------------------+---------------------+---------------------+
| **Hemoglobin Category, n |                     |                     |
| (%)**                    |                     |                     |
+--------------------------+---------------------+---------------------+
| N                        | 146                 | 148                 |
+--------------------------+---------------------+---------------------+
| \<12.5 g/dL              | 30 (21)             | 35 (24)             |
+--------------------------+---------------------+---------------------+
| ≥12.5 g/dL               | 116 (79)            | 113 (76)            |
+--------------------------+---------------------+---------------------+
|                          |                     |                     |
+--------------------------+---------------------+---------------------+
| **Epoetin Alfa Assigned  |                     |                     |
| Dose^a^, n (%)**         |                     |                     |
+--------------------------+---------------------+---------------------+
| N                        |                     | 150                 |
+--------------------------+---------------------+---------------------+
| 10,000 IU t.i.w.         |                     | 37 (25)             |
+--------------------------+---------------------+---------------------+
| 4,000 IU t.i.w.          |                     | 113 (75)            |
+--------------------------+---------------------+---------------------+
| ^a^Not applicable for    |                     |                     |
| observation group.       |                     |                     |
|                          |                     |                     |
| Reference: EPO-GBR-7     |                     |                     |
| preliminary report^11^   |                     |                     |
+--------------------------+---------------------+---------------------+

#### Tumor Response

At the time of this analysis, data on local tumor response at Week 12
were available for approximately three-quarters of the patients in each
treatment group. On the basis of these preliminary data, 99% of the
subjects in both treatment groups had either a complete response or
partial response to radiotherapy at the primary tumor sites (Table 13).

+-----------------------------+-------------------+---------------------+
| **Table 13:** Local Tumor   |                   |                     |
| Response at Week 12 after   |                   |                     |
| Radiotherapy\               |                   |                     |
| (Study EPO‑GBR‑7: All       |                   |                     |
| Subjects Randomized: Head   |                   |                     |
| and Neck Cancer)            |                   |                     |
+-----------------------------+-------------------+---------------------+
|                             | Observation\      | Epoetin Alfa\       |
|                             | (N=149)           | (N=151)             |
+-----------------------------+-------------------+---------------------+
| Primary Tumor, n (%)        |                   |                     |
+-----------------------------+-------------------+---------------------+
| N                           | 111               | 114                 |
+-----------------------------+-------------------+---------------------+
| Complete response           | 106 (95)          | 108 (95)            |
+-----------------------------+-------------------+---------------------+
| Partial response            | 4 (4)             | 5 (4)               |
+-----------------------------+-------------------+---------------------+
| CR and PR                   | 110 (99)          | 113 (99)            |
+-----------------------------+-------------------+---------------------+
| No response (stable         | 0                 | 1 (1)               |
| disease)                    |                   |                     |
+-----------------------------+-------------------+---------------------+
| Progressive Disease         | 1 (1)             | 0                   |
+-----------------------------+-------------------+---------------------+
| Nodes, n (%)                |                   |                     |
+-----------------------------+-------------------+---------------------+
| N                           | 104               | 102                 |
+-----------------------------+-------------------+---------------------+
| Complete Response           | 97 (93)           | 94 (92)             |
+-----------------------------+-------------------+---------------------+
| Partial Response            | 3 (3)             | 4 (4)               |
+-----------------------------+-------------------+---------------------+
| No Response                 | 1 (1)             | 0                   |
+-----------------------------+-------------------+---------------------+
| Study Day of Assessment     |                   |                     |
+-----------------------------+-------------------+---------------------+
| N                           | 113               | 115                 |
+-----------------------------+-------------------+---------------------+
| Mean (SD)                   | 149.03 (17.36)    | 150.09 (16.66)      |
+-----------------------------+-------------------+---------------------+
| Median                      | 149               | 147                 |
+-----------------------------+-------------------+---------------------+
| Range                       | 109 - 220         | 120 - 203           |
+-----------------------------+-------------------+---------------------+
| Note: Response to           |                   |                     |
| chemotherapy categories was |                   |                     |
| based on the                |                   |                     |
| investigator\'s assessment. |                   |                     |
|                             |                   |                     |
| Reference: EPO‑GBR‑7        |                   |                     |
| preliminary report^11^      |                   |                     |
+-----------------------------+-------------------+---------------------+

Response rates were also high in lymph nodes. The median study day when
these assessments were performed was similar for the observation group
(Day 149) and the epoetin alfa group (Day 147). Based on these
preliminary data, there was no apparent effect of epoetin alfa treatment
on local tumor responses assessed 12 weeks after completion of
radiotherapy.

#### Disease Progression

##### Local Tumor Evidence

Local tumor evidence was assessed at Weeks 1, 4, and 8 after
radiotherapy, and Years 1, 2, 3, and 5 during the follow‑up period.
Since study data collection is ongoing, not all subjects have reached
all the assessment time points, relatively few patients have more than 1
year of follow-up data, and no subject has had the Year 5 assessment at
the time of this analysis. Based on the data available at this time,
epoetin alfa treatment appeared to have no effect on the outcomes of
these assessments (Table 14).

+----------------------------+---------------------+-------------------+
| **Table 14:** Local Tumor  |                     |                   |
| Evidence After             |                     |                   |
| Radiotherapy\              |                     |                   |
| Study EPO-GBR-7: All       |                     |                   |
| Subjects Randomized: Head  |                     |                   |
| and Neck Cancer)           |                     |                   |
+----------------------------+---------------------+-------------------+
|                            | Observation         | Epoetin Alfa      |
|                            |                     |                   |
|                            | (N= 149)            | (N=151)           |
+----------------------------+---------------------+-------------------+
| > Week 1 Post RT, n (%)    | > N=142             | > N=142           |
+----------------------------+---------------------+-------------------+
| > Yes                      | > 14 (10)           | > 12 (8)          |
+----------------------------+---------------------+-------------------+
| > No                       | > 86 (61)           | > 98 (69)         |
+----------------------------+---------------------+-------------------+
| > Missing                  | > 42 (30)           | > 32 (23)         |
+----------------------------+---------------------+-------------------+
|                            |                     |                   |
+----------------------------+---------------------+-------------------+
| > Week 4 Post RT, n (%)    | > N=140             | > N=138           |
+----------------------------+---------------------+-------------------+
| > Yes                      | > 14 (10)           | > 12 (9)          |
+----------------------------+---------------------+-------------------+
| > No                       | > 111 (79)          | > 103 (75)        |
+----------------------------+---------------------+-------------------+
| > Missing                  | > 15 (11)           | > 23 (17)         |
+----------------------------+---------------------+-------------------+
|                            |                     |                   |
+----------------------------+---------------------+-------------------+
| > Week 8 Post RT, n (%)    | > N=135             | > N=129           |
+----------------------------+---------------------+-------------------+
| > Yes                      | > 11 (8)            | > 6 (5)           |
+----------------------------+---------------------+-------------------+
| > No                       | > 101 (75)          | > 106 (82)        |
+----------------------------+---------------------+-------------------+
| > Missing                  | > 23 (17)           | > 17 (13)         |
+----------------------------+---------------------+-------------------+
|                            |                     |                   |
+----------------------------+---------------------+-------------------+
| > Year 1, n (%)            | > N=93              | > N=92            |
+----------------------------+---------------------+-------------------+
| > Yes                      | > 4 (4)             | > 6 (7)           |
+----------------------------+---------------------+-------------------+
| > No                       | > 81 (87)           | > 85 (92)         |
+----------------------------+---------------------+-------------------+
| > Missing                  | > 8 (9)             | > 1 (1)           |
+----------------------------+---------------------+-------------------+
|                            |                     |                   |
+----------------------------+---------------------+-------------------+
| > Year 2, n (%)            | > N=53              | > N=56            |
+----------------------------+---------------------+-------------------+
| > Yes                      | > 0                 | > 1 (2)           |
+----------------------------+---------------------+-------------------+
| > No                       | > 45 (85)           | > 52 (93)         |
+----------------------------+---------------------+-------------------+
| > Missing                  | > 8 (15)            | > 3 (5)           |
+----------------------------+---------------------+-------------------+
|                            |                     |                   |
+----------------------------+---------------------+-------------------+
| > Year 3, n (%)            | > N=21              | > N=18            |
+----------------------------+---------------------+-------------------+
| > Yes                      | > 0                 | > 0               |
+----------------------------+---------------------+-------------------+
| > No                       | > 17 (81)           | > 13 (72)         |
+----------------------------+---------------------+-------------------+
| > Missing                  | > 4 (19)            | > 5 (28)          |
+----------------------------+---------------------+-------------------+
| Reference: EPO‑GBR‑7       |                     |                   |
| preliminary report.^11^    |                     |                   |
+----------------------------+---------------------+-------------------+

#### Survival

The protocol did not require survival status follow up after subjects
had withdrawn from the study. In order to have a more complete and
up-to-date mortality assessment, data collection was initiated to update
the survival status of all enrolled subjects, including those who had
withdrawn, as of 01 November 2003 or later wherever possible. At the
time of this analysis, the status of 29 subjects (14 in the observation
group, 15 in the epoetin alfa group) who had withdrawn remained unknown.
Among all subjects who were not known to have died, the median duration
of last follow up was 869 days in the observation group and 896 days in
the epoetin alfa group (Table 15).

+----------------------+-----------------------+----------------------+
| **Table 15:** Day of |                       |                      |
| Last Follow-Up\      |                       |                      |
| (Study EPO-GBR-7:    |                       |                      |
| All Subjects         |                       |                      |
| Randomized: Head and |                       |                      |
| Neck Cancer)         |                       |                      |
+----------------------+-----------------------+----------------------+
|                      | Observation           | Epoetin Alfa         |
+----------------------+-----------------------+----------------------+
|                      | (N=149)               | (N=151)              |
+----------------------+-----------------------+----------------------+
| Day of last          |                       |                      |
| follow-up^a^         |                       |                      |
+----------------------+-----------------------+----------------------+
| N                    | 99                    | 98                   |
+----------------------+-----------------------+----------------------+
| Mean (SD)            | 834 (366)             | 858 (358)            |
+----------------------+-----------------------+----------------------+
| Median               | 869                   | 896                  |
+----------------------+-----------------------+----------------------+
| Range                | 1 -- 1482             | 10 - 1519            |
+----------------------+-----------------------+----------------------+
| .^a^ Follow-up       |                       |                      |
| cut-off was 01       |                       |                      |
| November 2003 or     |                       |                      |
| later. This summary  |                       |                      |
| excluded subjects    |                       |                      |
| who were known to    |                       |                      |
| have died.           |                       |                      |
|                      |                       |                      |
| Reference: EPO-GBR-7 |                       |                      |
| preliminary report   |                       |                      |
| ^11^                 |                       |                      |
+----------------------+-----------------------+----------------------+

As noted above, at the time of this preliminary analysis, no subject had
completed the scheduled 5-year follow-up. Fifty (34%) of the subjects in
the observation group and 52 (34%) of the subjects in the epoetin alfa
group were known to have died during the follow-up period between the
end of radiotherapy and the end of Year 5 (Table 16); these subjects
were considered to have completed the study according to the protocol.

Disease progression was the most frequently reported cause of death (41
\[28%\] in the observation group and 36 \[24%\] in the epoetin alfa
group). The next most frequently reported cause of death as reported on
the CRFs was "Other". Detailed information for such reported causes is
provided in Table 17 for the 8 (5%) subjects in the observation group
and 13 (9%) subjects in the epoetin alfa group.

+------------------------------+-------------------+-------------------+
| **Table 16:** Subject        |                   |                   |
| Deaths\                      |                   |                   |
| (Study EPO-GBR-7: All        |                   |                   |
| Subjects Randomized: Head    |                   |                   |
| and Neck Cancer)             |                   |                   |
+------------------------------+-------------------+-------------------+
|                              | Observation       | Epoetin Alfa      |
+------------------------------+-------------------+-------------------+
|                              | (N=149)           | (N=151)           |
+------------------------------+-------------------+-------------------+
|                              | n (%)             | n (%)             |
+------------------------------+-------------------+-------------------+
| Number and percent of deaths | 50 (34)           | 52 (34) []{.mark} |
+------------------------------+-------------------+-------------------+
| Cause of death^a^            |                   |                   |
+------------------------------+-------------------+-------------------+
| Disease progression          | 41 (28)           | 36 (24) []{.mark} |
+------------------------------+-------------------+-------------------+
| Other                        | 8 (5)             | 13 (9) []{.mark}  |
+------------------------------+-------------------+-------------------+
| Missing                      | 1 (1)             | 3 (2)             |
+------------------------------+-------------------+-------------------+
| ^a^ Percent based on the     |                   |                   |
| total number of subjects in  |                   |                   |
| the group.                   |                   |                   |
|                              |                   |                   |
| Reference: EPO-GBR-7         |                   |                   |
| preliminary report^11^       |                   |                   |
+------------------------------+-------------------+-------------------+

  ------------------------- ---------------------------------------------
  **Table 17:** Listing of  
  "Other" as Cause of       
  Death\                    
  (Study EPO-GBR-7: Head    
  and Neck Cancer)          

  Group/Subject Number      Cause of Death (Verbatims on the CRFs)

  **Observation**           

  41                        Carcinoma of Tongue Carcinomatosis

  153                       Aspiration Pneumonia and Cardiac Arrest

  174                       Alcohol Abuse

  224                       Ischaemic Heart Disease

  231                       Pneumonia + Ischaemic Heart Disease

  303                       Lung Cancer (Second Primary)

  315                       Liver Disease (Alcoholic)

  320                       2nd Primary Lung

                            

  **Epoetin Alfa**          

  13                        Abdominal Sepsis

  102                       Ca Oesophagus

  119                       Heart Attack

  125                       Strangulated Hernia

  136                       Small Bowel Obstruction Ischaemic Colitis

  183                       Unknown

  211                       Carcinomatosa and Lymphargitis of Chest

  265                       Adenocarcinoma of Gastro-Oesophageal Junction

  266                       Chest Infection / Grade IV Glioma

  302                       Pneumonia + Septic Shock

  411                       Aspiration Pneumonia

  413                       2nd Primary (Nasopharynx)

  445                       Presumed Cardiac Event

  Reference: EPO-GBR-7      
  preliminary report.^11^   
  ------------------------- ---------------------------------------------

As of this analysis, the Kaplan-Meier estimate of the 1-year survival
rate was 84.1% for the observation group and 79.6% for the epoetin alfa
group, yielding a difference of -4.6% (epoetin alfa vs. observation)
with 95% confidence interval of (-13.6%, 4.4%). Kaplan-Meier estimates
of the survival curves are shown in Figure 7. The difference between the
treatment groups was not statistically significant (p=0.73, log rank
test).

**Figure 7:** Subject Survival\
(Study EPO-GBR-7: All Subjects Randomized: Head and Neck Cancer)

![](media/image7.wmf){width="5.417361111111111in"
height="4.010416666666667in"}

Reference: EPO-GBR-7 preliminary report.^11^

Presently, the results observed in the placebo and epoetin alfa groups
in study EPO-GBR-7 appear to be generally similar, although there is a
4.6% difference in 1-year survival favoring the placebo group. It is
noted that there are similarities in the designs of EPO-GBR-7 and the
Henke et al. study, although the doses of epoetin alfa studied in
EPO-GBR-7 were lower than the doses of epoetin beta studied by Henke et
al.

### Study N93‑004^12^

This double‑blind, placebo‑controlled study was designed to enroll
subjects with newly-diagnosed limited or extensive stage small cell lung
cancer (SCLC) who were to be treated with etoposide and cisplatin. It
was requested as a post-marketing Phase 4 study by the FDA to evaluate
the possible stimulatory effects of epoetin alfa on solid tumor growth.
The primary objective of the study was to demonstrate that epoetin alfa
does not adversely affect tumor responsiveness to chemotherapy. The
minimum detectable difference to demonstrate non-inferiority was set to
15% in the protocol. The planned number of patients to be enrolled was
400. Initiated in 1993, this was the first study performed by the
Sponsor in which response to chemotherapy and survival were established
as primary and secondary endpoints, respectively, and is the largest
study prospectively designed to measure tumor response as a primary
endpoint.

Subjects were randomly assigned to receive 150 IU/kg epoetin alfa
(PROCRIT) s.c. t.i.w. or placebo until approximately 3 weeks after the
final cycle of etoposide and cisplatin chemotherapy. Subjects were to
have a hemoglobin concentration of ≤14.5 g/dL at study entry. Hemoglobin
concentrations were to be maintained within the range of 14 to 16 g/dL
during the study (it should be noted, however, that the actual
hemoglobin levels in participants over the course of the study were
substantially below these levels, i.e., in the marginally anemic range;
see below). If a subject's hemoglobin was \>16 g/dL, the dose was
withheld until the hemoglobin level was \<14 g/dL, and the dose was to
be restarted at 75 IU/kg t.i.w. All enrolled subjects received the same
chemotherapy and had the same evaluations at the end of the third cycle
of chemotherapy.

Two hundred twenty‑four subjects with a mean age of 64 years were
enrolled in the study; 109 were randomly assigned to receive epoetin
alfa and 115 to receive placebo. Demographic and baseline
characteristics were similar among epoetin alfa- and placebo-treated
subjects with the exception that thrombocytosis was more prevalent among
subjects treated with epoetin alfa than those treated with placebo. A
somewhat higher proportion (66%) of subjects assigned to treatment with
epoetin alfa had extensive stage SCLC at diagnosis than those assigned
to placebo (59%). The intent-to-treat population in this study included
all subjects and was the same as the safety population. As noted
previously, this study was stopped early due to slow enrollment,
resulting from changes in standard chemotherapy treatment approaches for
SCLC such that the regimen specified in the protocol fell into disuse
after 224 of a planned 400 subjects were enrolled.

#### Tumor Response to Chemotherapy / Disease Progression

The optimal method for assessing tumor response in each patient was
determined by the investigator. Evaluations of tumor to assess response
to chemotherapy were performed at baseline, after the third cycle of
chemotherapy, and at the study completion or the termination visit.
Assessments included the extent of measurable and evaluable malignant
lesions and the overall response to chemotherapy, and were performed
after the third cycle of chemotherapy and at study completion. The same
imaging or measurement method and indicator lesions were to be used for
each assessment. Response was also compared between subjects with
limited‑ and extensive‑stage disease.

For the intent-to-treat population, the tumor response rates were
similar for subjects in the epoetin alfa and placebo treatment groups
after 3 cycles of chemotherapy (Tables 18 and 19). The observed
difference in tumor response rates for the intent‑to‑treat population
was 6%, favoring epoetin alfa (Table 20). The 95% CI of the difference
(‑6%, 18%) did not contain ‑15% which was the protocol-specified
criterion for non-inferiority. Thus, the primary objective that epoetin
alfa did not reduce tumor responsiveness to chemotherapy by more than
the minimum detectable difference was achieved.

+--------------------------------+-----------------+-------------------+
| **Table 18**: Response to      |                 |                   |
| Chemotherapy After 3 Cycles\   |                 |                   |
| (Study N93‑004:                |                 |                   |
| Intent‑to‑Treat Population;    |                 |                   |
| Small Cell Lung Cancer)        |                 |                   |
+--------------------------------+-----------------+-------------------+
| Response to Chemotherapy       | Placebo\        | Epoetin Alfa\     |
|                                | N=115           | N=109             |
+--------------------------------+-----------------+-------------------+
| **Intent‑to‑treat population** |                 |                   |
| n (%)                          |                 |                   |
+--------------------------------+-----------------+-------------------+
| > Complete response            | 16 (14)         | 18 (17)           |
+--------------------------------+-----------------+-------------------+
| > Partial response             | 61 (53)         | 61 (56)           |
+--------------------------------+-----------------+-------------------+
| > Overall response (CR + PR)   | 77 (67)         | 79 (72)           |
+--------------------------------+-----------------+-------------------+
| > No response (stable disease) | 10 (9)          | 3 (3)             |
+--------------------------------+-----------------+-------------------+
| > Progressive disease          | 9 (8)           | 8 (7)             |
+--------------------------------+-----------------+-------------------+
| > Missing/Unknown              | 19 (17)         | 19 (17)           |
+--------------------------------+-----------------+-------------------+
| Response to chemotherapy       |                 |                   |
| categories:                    |                 |                   |
|                                |                 |                   |
| [Complete                      |                 |                   |
| response]{.underline}:         |                 |                   |
| complete absence of detectable |                 |                   |
| tumor.                         |                 |                   |
|                                |                 |                   |
| [Partial                       |                 |                   |
| response]{.underline}:         |                 |                   |
| reduction in estimated tumor   |                 |                   |
| mass by ≥50%; \<25% increase   |                 |                   |
| in the size of any measurable  |                 |                   |
| malignant lesion; \<25%        |                 |                   |
| increase in the estimated size |                 |                   |
| of any evaluable but           |                 |                   |
| non‑measurable malignant       |                 |                   |
| lesion; no new lesions.        |                 |                   |
|                                |                 |                   |
| [No response (stable           |                 |                   |
| disease):]{.underline}         |                 |                   |
| reduction of tumor mass by     |                 |                   |
| \<50%; \<25% increase in the   |                 |                   |
| size of any measurable         |                 |                   |
| malignant lesion; \<25%        |                 |                   |
| increase in the estimated size |                 |                   |
| of any evaluable but           |                 |                   |
| non‑measurable malignant       |                 |                   |
| lesion; no new lesions.        |                 |                   |
|                                |                 |                   |
| [Progressive                   |                 |                   |
| disease:]{.underline} increase |                 |                   |
| in estimated tumor mass by     |                 |                   |
| ≥25% or appearance of new      |                 |                   |
| lesion.                        |                 |                   |
|                                |                 |                   |
| Reference: N93‑004 CSR^12^     |                 |                   |
+--------------------------------+-----------------+-------------------+

+--------------------------------+----------+----------+--------------+
| **Table 19**: Tumor Response   |          |          |              |
| Rate After 3 Cycles of         |          |          |              |
| Chemotherapy\                  |          |          |              |
| (Study N93‑004:                |          |          |              |
| Intent‑to‑Treat Population;    |          |          |              |
| Small Cell Lung Cancer)        |          |          |              |
+--------------------------------+----------+----------+--------------+
|                                | Placebo  | Epoetin  | Difference   |
|                                |          | Alfa     | (Epoetin     |
|                                |          |          | Alfa Minus   |
|                                |          |          | Placebo)     |
+--------------------------------+----------+----------+--------------+
| **Intent‑to‑Treat population** |          |          |              |
+--------------------------------+----------+----------+--------------+
| > N                            | 115      | 109      |              |
+--------------------------------+----------+----------+--------------+
| > No. with complete or partial | 77       | 79       |              |
| > response                     |          |          |              |
+--------------------------------+----------+----------+--------------+
| > Tumor Response Rate, (95%    | 67 (58,  | 72 (64,  | 6 (-6, 18)   |
| > CI), %                       | 76)      | 81)      |              |
+--------------------------------+----------+----------+--------------+
| Complete response: complete    |          |          |              |
| absence of detectable tumor.   |          |          |              |
|                                |          |          |              |
| Partial response: reduction in |          |          |              |
| estimated tumor mass by ≥50%;  |          |          |              |
| no new lesions.                |          |          |              |
|                                |          |          |              |
| Reference: N93‑004 CSR^12^     |          |          |              |
+--------------------------------+----------+----------+--------------+

The overall response rate after the 3 cycles of chemotherapy also tended
to favor the epoetin alfa treatment group among a subset of subjects
with extensive‑stage SCLC (Table 20). Among the subjects with
extensive‑stage disease, those who received epoetin alfa had a higher
tumor response rate (74%), indicating that these subjects did not have a
poorer outcome compared with subjects who received placebo. The
clinically objective overall response rate among the subset of subjects
with limited‑stage SCLC was similar after the final cycle of
chemotherapy (Table 21).

+-----------------------------+------------+------------+------------+
| **Table 20**: Tumor         |            |            |            |
| Response After 3 Cycles of  |            |            |            |
| Chemotherapy as a Function  |            |            |            |
| of SCLC Stage at Diagnosis\ |            |            |            |
| (Study N93‑004:             |            |            |            |
| Intent‑to‑Treat Population: |            |            |            |
| Small Cell Lung Cancer)     |            |            |            |
+-----------------------------+------------+------------+------------+
|                             | Placebo    | Epoetin    | Difference |
|                             |            | Alfa       | (Epoetin   |
|                             |            |            | Alfa Minus |
|                             |            |            | Placebo)   |
+-----------------------------+------------+------------+------------+
| **Extensive‑stage SCLC**    |            |            |            |
+-----------------------------+------------+------------+------------+
| > N                         | 68         | 72         |            |
+-----------------------------+------------+------------+------------+
| > No. with a CR or PR       | 41         | 53         |            |
+-----------------------------+------------+------------+------------+
| > Tumor Response Rate,      | 60         | 74         | 13 (-2,    |
| > (95% CI), %               |            |            | 29)        |
+-----------------------------+------------+------------+------------+
| **Limited‑stage SCLC**      |            |            |            |
+-----------------------------+------------+------------+------------+
| > N                         | 47         | 37         |            |
+-----------------------------+------------+------------+------------+
| > No. with a CR or PR       | 36         | 26         |            |
+-----------------------------+------------+------------+------------+
| > Tumor Response Rate,      | 77         | 70         | -6 (-25,   |
| > (95% CI), %               |            |            | 13)        |
+-----------------------------+------------+------------+------------+
| Key: SCLC=small cell lung   |            |            |            |
| cancer\                     |            |            |            |
| Complete response: complete |            |            |            |
| absence of detectable       |            |            |            |
| tumor.\                     |            |            |            |
| Partial response: reduction |            |            |            |
| in estimated tumor mass by  |            |            |            |
| ≥50%; no new lesions.       |            |            |            |
|                             |            |            |            |
| Reference: N93‑004 CSR^12^  |            |            |            |
+-----------------------------+------------+------------+------------+

Tumor response after the final cycle of chemotherapy was a secondary
endpoint of the study. After the final cycle, the proportion of subjects
in the intent-to-treat population who had had a CR or PR was comparable
between the two treatment groups (Tables 21 and 22).

+------------------------------+-------------------+------------------+
| **Table 21**: Response to    |                   |                  |
| Chemotherapy After Final     |                   |                  |
| Chemotherapy Cycle\          |                   |                  |
| (Study N93‑004:              |                   |                  |
| Intent‑to‑Treat Population:  |                   |                  |
| Small Cell Lung Cancer)      |                   |                  |
+------------------------------+-------------------+------------------+
| Response to Chemotherapy     | Placebo\          | Epoetin Alfa\    |
|                              | (N=115)           | (N=109)          |
+------------------------------+-------------------+------------------+
| **Frequency distribution, n  |                   |                  |
| (%)**                        |                   |                  |
+------------------------------+-------------------+------------------+
| > Complete response          | 21 (18)           | 20 (18)          |
+------------------------------+-------------------+------------------+
| > Partial response           | 43 (37)           | 45 (41)          |
+------------------------------+-------------------+------------------+
| > Overall response (CR + PR) | 64 (56)           | 65 (60)          |
+------------------------------+-------------------+------------------+
| > No response (stable        | 6 (5)             | 2 (2)            |
| > disease)                   |                   |                  |
+------------------------------+-------------------+------------------+
| > Progressive disease        | 14 (12)           | 16 (15)          |
+------------------------------+-------------------+------------------+
| > Missing/Unknown            | 31 (27)           | 26 (24)          |
+------------------------------+-------------------+------------------+
| Response to chemotherapy     |                   |                  |
| categories:                  |                   |                  |
|                              |                   |                  |
| [Complete                    |                   |                  |
| response]{.underline}:       |                   |                  |
| complete absence of          |                   |                  |
| detectable tumor.            |                   |                  |
|                              |                   |                  |
| [Partial                     |                   |                  |
| response]{.underline}:       |                   |                  |
| reduction in estimated tumor |                   |                  |
| mass by ≥50%; no new         |                   |                  |
| lesions.                     |                   |                  |
|                              |                   |                  |
| [No response (stable         |                   |                  |
| disease)]{.underline} :      |                   |                  |
| reduction of tumor mass by   |                   |                  |
| \<50%; \<25% increase in the |                   |                  |
| size of any measurable       |                   |                  |
| malignant lesion; \<25%      |                   |                  |
| increase in the estimated    |                   |                  |
| size of any evaluable but    |                   |                  |
| non‑measurable malignant     |                   |                  |
| lesion; no new lesions.      |                   |                  |
|                              |                   |                  |
| [Progressive                 |                   |                  |
| disease]{.underline}:        |                   |                  |
| increase in estimated tumor  |                   |                  |
| mass by ≥25% or appearance   |                   |                  |
| of new lesion.               |                   |                  |
|                              |                   |                  |
| Reference: N93‑004 CSR^12^   |                   |                  |
+------------------------------+-------------------+------------------+

+---------------------+-------------+---------------+-----------------+
| **Table 22**:       |             |               |                 |
| Overall Response to |             |               |                 |
| Chemotherapy After  |             |               |                 |
| Final Chemotherapy  |             |               |                 |
| Cycle as a Function |             |               |                 |
| of SCLC Stage at    |             |               |                 |
| Diagnosis\          |             |               |                 |
| (Study N93‑004:     |             |               |                 |
| Intent‑to‑Treat     |             |               |                 |
| Population: Small   |             |               |                 |
| Cell Lung Cancer)   |             |               |                 |
+---------------------+-------------+---------------+-----------------+
|                     | Overall     |               | Difference      |
|                     | Response    |               | (Epoetin        |
|                     | (CR and PR) |               |                 |
+---------------------+-------------+---------------+-----------------+
|                     | Placebo     | Epoetin Alfa  | Alfa Minus      |
|                     |             |               | Placebo)        |
+---------------------+-------------+---------------+-----------------+
| **Total             |             |               |                 |
| population**        |             |               |                 |
+---------------------+-------------+---------------+-----------------+
| > N                 | 115         | 109           |                 |
+---------------------+-------------+---------------+-----------------+
| > No. (%) subjects  | 64 (56)     | 65 (60)       | 4               |
+---------------------+-------------+---------------+-----------------+
| > 95% CI, %         | 47, 65      | 50, 69        | ‑9, 17          |
+---------------------+-------------+---------------+-----------------+
| **Extensive‑stage   |             |               |                 |
| SCLC**              |             |               |                 |
+---------------------+-------------+---------------+-----------------+
| > N                 | 68          | 72            |                 |
+---------------------+-------------+---------------+-----------------+
| > No. (%) subjects  | 35 (51)     | 38 (53)       | 1               |
+---------------------+-------------+---------------+-----------------+
| > 95% CI, %         | 40, 63      | 41, 64        | ‑15, 18         |
+---------------------+-------------+---------------+-----------------+
| **Limited‑stage     |             |               |                 |
| SCLC**              |             |               |                 |
+---------------------+-------------+---------------+-----------------+
| > N                 | 47          | 37            |                 |
+---------------------+-------------+---------------+-----------------+
| > No. (%) subjects  | 29 (62)     | 27 (73)       | 11              |
+---------------------+-------------+---------------+-----------------+
| > 95% CI, %         | 48, 76      | 59, 87        | ‑9, 31          |
+---------------------+-------------+---------------+-----------------+
| Key: CI=confidence  |             |               |                 |
| interval;           |             |               |                 |
| CR=Complete         |             |               |                 |
| response (absence   |             |               |                 |
| of detectable       |             |               |                 |
| tumor); PR=partial  |             |               |                 |
| response (reduction |             |               |                 |
| in estimated tumor  |             |               |                 |
| mass by ≥50%; no    |             |               |                 |
| new lesions);       |             |               |                 |
| SCLC=small cell     |             |               |                 |
| lung cancer.        |             |               |                 |
|                     |             |               |                 |
| Reference: N93‑004  |             |               |                 |
| CSR^12^             |             |               |                 |
+---------------------+-------------+---------------+-----------------+

#### Overall Survival

Two hundred twenty‑four subjects were enrolled in this study. Two
hundred one died at some time during the double‑blind period or in the
3‑year follow‑up period.

The median duration of survival, based on Kaplan‑Meier estimates was
10.5 months for subjects treated with epoetin alfa and 10.4 months for
those who received placebo. The overall mortality rate for subjects in
the epoetin alfa treatment group was 100 of 109 (92%) and the overall
mortality rate for subjects in the placebo group was 101 of 115 (88%).

As shown in Figure 8, the Kaplan-Meier plots of survival were almost
identical for the epoetin alfa and placebo treatment groups through
Month 12 but showed some divergence after this time point. In
considering the longer term parts of the survival curve, it should be
noted that a slightly higher proportion of subjects assigned to placebo
treatment had limited stage SCLC diagnosis (41% for epoetin alfa versus
34% for placebo group).

**Figure 8:** Summary of Survival Over Time

(Study N93-004: Intent-to-Treat Population: Small Cell Lung Cancer)

> ![](media/image8.png){width="5.5465277777777775in"
> height="3.1347222222222224in"}
>
> Placebo, N = 115; Epoetin alfa, N = 109.
>
> Reference: N93‑004 CSR^12^

The results of the study indicated that the response rate in epoetin
alfa-treated subjects was not inferior to that in the control group.
Median survival time and overall survival were similar in the two
treatment groups.

In summary, this study was conducted in predominantly non-anemic cancer
patients and was designed to assess tumor response with survival as a
secondary endpoint. In both arms of Study N93-004, tumor response and
survival through Month 12 appeared similar. Beyond Month 12, there was
divergence in the survival curves favoring the placebo group, though the
data are sparse and complete follow-up information is not available.

The results of Study N93‑004 do not suggest any substantive effect of
epoetin alfa on tumor treatment response or disease progression in SCLC
and the 95% confidence intervals exclude an impairment of response rate
of 6% or higher.

### Other Relevant Information from Clinical Trials

#### Overall Incidence of TVEs in Prior Epoetin Alfa Studies

The Sponsor has also examined data from double-blind, randomized
controlled trials that may aid in the evaluation of the possible role of
TVEs in recent ERA study outcomes.

As noted previously in this document, TVEs have been observed in
association with use of all ERAs, and TVEs may account at least in part
for survival imbalances reported in investigational studies of ERAs.

The list of general TVEs is the Sponsor's broadest approach for
identifying TVEs, and includes all superficial TVEs, all catheter
related TVEs and events that could, but not necessarily would, be caused
by an underlying thrombovascular event, and where no information was
available to prove the contrary. General TVEs are also subclassified as
clinically relevant, a definition that is more focused but still is
broader than the generally accepted clinically important TVEs (e.g.,
DVT, PE, stroke/TIA, and MI).

The incidences of general TVEs based on the 12 completed double-blind,
placebo-controlled, oncology studies (Studies EPO-INT-76, N93-004 and
the 10 clinical studies that focused on correction of anemia in cancer
patients) were 4% to 24% in placebo-treated patients and 3% to 22% for
epoetin alfa-treated patients. Fifty percent of the general TVEs were
assessed as being clinically relevant. The incidences of clinically
relevant TVEs ranged from 0% to 12.3% for placebo-treated patients and
0% to 11% in epoetin alfa-treated patients. See Figure 9 for the odds
ratios of the clinically relevant TVEs.

**Figure 9:** Incidence of Clinically Relevant Thrombotic Vascular
Events Odds Ratios and 95% Confidence Intervals (All 12 Double-Blind,
Placebo-Controlled, Completed Oncology Studies: Safety Population)

![](media/image9.png){width="4.98125in" height="5.503472222222222in"}

Key: TVE=thrombotic vascular event; OR=odds ratio; C.I.=confidence
interval

Note: Odds ratios were calculated using the Cochran-Mantel-Haenszel
method stratified by study for all pooled analyses.

#### Recently Discontinued Studies With Imbalances in Thrombotic Vascular Events and/or Survival

Data are presented for 5 discontinued studies in which imbalances in the
occurrence of TVEs and/or survival were noted: PR00‑03‑006,
PR01‑04‑005/GOG‑0191, EPO‑CAN‑15, PR99‑03‑046/RTOG 99‑03, and
EPO‑CAN‑20. Data collection and analyses are ongoing for these recently
discontinued studies, and the information provided here is preliminary.
It should be noted that the recent study discontinuations started with
an observation of an imbalance in TVEs in one study, PR00‑03‑006 (see
below). This observation, plus the information emerging from EPO-INT-76
and Henke studies, led the Company to request evaluations of clinical
safety findings across its full program of ongoing oncology epoetin alfa
studies. While most of the Company's epoetin alfa oncology studies are
continuing, four additional studies were stopped for TVE and/or survival
imbalances that were identified in this review.

Study PR00-03-006

This was a double-blind, placebo-controlled, multicenter study in
patients with gastric or rectal cancer receiving a fluoropyrimidine
concurrent with radiation. Planned recruitment was 184 patients.
Patients were randomized 1:1 to receive epoetin alfa 40,000 IU s.c. once
weekly or placebo. Patients had hemoglobin levels of ≥10 to \<15 g/dL at
entry, and were treated with PROCRIT epoetin alfa at 40,000 IU/week,
with dose adjustments depending on response. If hemoglobin was ≤13 g/dL
after 4 weeks, the epoetin alfa dose was increased to 60,000 IU/week; if
hemoglobin exceeded 15 g/dL, treatment was interrupted and restarted at
a lower dose when hemoglobin was ≤14 g/dL.

Data were available for 59 patients at the time the study was analyzed.
Eight patients experienced at least one TVE, 6% (2/31) of placebo
patients and 21% (6/28) of epoetin alfa patients. Seven of 8 TVEs were
deep vein thromboses and were assessed by the investigator as serious.
The eighth TVE was chest pain and was assessed as not serious. TVEs
occurred in 11% (6/53) of patients with rectal cancer and 33% (2/6) of
patients with gastric cancer.

Twenty percent (7/35) of patients with a baseline hemoglobin\> 13 g/dL
experienced at least one TVE, compared with 4% (1/24) of patients with a
baseline hemoglobin ≤ 13 g/dL. Patients commonly had a hemoglobin level
\>13 g/dL within the 28 days before the TVE; but such levels were also
common in patients who did not have TVEs. No patient had a hemoglobin
increase of more than 2 g/dL in the 4‑week period before their TVE.

Study PR01‑04‑005/GOG‑0191

This was an open-label, randomized, multicenter, investigator-sponsored
study in patients with cervical cancer receiving concurrent radiation
and cisplatin. The study was intended to determine whether epoetin alfa
treatment to maintain higher hemoglobin levels could prolong
progression-free survival. Planned recruitment was 460 patients.
Patients were randomized 1:1 to receive epoetin alfa 40,000 IU s.c. once
weekly or standard of care. Patients had \<14 g/dL at entry. Epoetin
alfa dose was increased to 60,000 IU/week if hemoglobin could not be
maintained \>12 g/dL. Dosing was interrupted if hemoglobin exceeded 14
g/dL for 2 weeks or more, then restarted at the same dose when
hemoglobin fell to \<13 g/dL.

Data were available for 79 patients at the time the study was analyzed.
Fifteen patients experienced at least one TVE, 5 (9%) of the 55 Cis+Rt
patients and 10 (17%) of the 58 Cis+Rt+Epo patients. TVEs were
classified as venous in 10 patients, arterial in 3 patients and
unclassifiable in 2 patients. There was no apparent association between
level of hemoglobin at baseline or on treatment and the occurrence of a
TVE.

Four Cis+Rt+Epo patients had a hemoglobin increase of more than 2 g/dL
in the 4-week period prior to the TVE. These hemoglobin increases could
be explained by pRBC transfusions for 3 of the 4 patients.

Study EPO-CAN-15

This was a double-blind, randomized, placebo-controlled, multicenter
study in which patients with limited disease SCLC received combined
modality chemoradiation therapy. The study was intended to determine
whether epoetin alfa treatment to maintain higher hemoglobin levels
could prolong progression-free survival. Planned recruitment was 620
patients. Patients were randomized 1:1 to epoetin alfa 40,000 IU s.c.
once weekly or placebo. Initially, the protocol was designed to maintain
hemoglobin levels in the range of 14-16 g/dL. An amendment in October
2002 reduced this targeted hemoglobin range to 13-14 g/dL.

Data were available for 106 patients at the time the study was analyzed.
Overall, there were 22 TVEs reported: 19 TVEs were reported in the
epoetin alfa arm and 3 TVEs were reported in the placebo group. Of the
TVEs in the epoetin alfa group, 2 of the events occurred prior to study
drug treatment and 1 event was determined to not be significant from a
clinical perspective. As such, subsequent analyses only consider the 16
clinically relevant TVEs in this group. In the placebo group, 1 of the
events occurred prior to study drug treatment, and as such, the analyses
for this group only consider 2 clinically significant TVEs.

Interestingly, the majority of TVEs in the epoetin alfa arm (14 of 16)
occurred in patients randomized to the higher target range hemoglobin
protocol (the pre‑amendment protocol). An imbalance in mortality was
also observed in this study, with several deaths associated with TVEs.
Among the 16 patients experiencing TVEs in the epoetin alfa arm, there
were 4 deaths.

Study PR99‑03‑046/RTOG 99‑03

This was an open-label, investigator-sponsored cooperative group study
in which patients with head and neck cancer were randomly assigned 1:1
to PROCRIT 40,000 IU s.c. once weekly plus radiotherapy or radiotherapy
alone. Planned enrollment was 372 patients. The study was intended to
determine whether treatment with epoetin alfa to maintain relatively
high hemoglobin levels (up to 14 g/dL in women, up to 16 g/dL in men)
would enhance the effectiveness of radiation therapy. When the study
safety data (for the initial 148 patients enrolled) were analyzed,
non-significant imbalances were noted in both locoregional disease
control and survival, with the observed imbalances favoring the placebo
group. These findings, together with the findings of the Henke et al.
which had just been published, prompted closure of the study.

Study EPO-CAN-20

This was a double-blind, randomized, placebo-controlled, multicenter
study in which patients with non-small cell lung cancer were treated
with EPREX epoetin alfa, with the goal of evaluating quality of life
effects. Planned enrollment was 300 patients. An analysis of safety
findings among the 66 patients randomized to date (62 with data
available) revealed poor survival in both the epoetin alfa and control
groups. There had been 25 deaths in the epoetin alfa group, and 20
deaths in the control group, and it was noted that median survival was
shorter in the epoetin alfa group (2 months versus 4 months). The study
has been closed, and further analyses are in progress.

### Conclusion

The results of the EPO-INT-76 and Henke et al. studies raised concerns
regarding the possibility of adverse outcomes in cancer patients,
including the possibility of shortened survival or enhanced disease
progression. Other pre‑clinical and clinical study data have provided
little support for an adverse effect on tumor growth or lesion
progression. Alternative explanations for the survival observations of
the EPO-INT-76 and Henke studies must also be considered. In this
regard, while ERAs generally have a limited spectrum of adverse effects,
TVEs are described in labeling for all ERAs, and are potentially more
likely to occur when ERA use is extended beyond the treatment of anemia.
Considering the results of the EPO-INT-76 and Henke studies, together
with other recently suspended studies, ERAs may be associated with
reduced survival when they are used beyond the correction of anemia in
cancer patients, and an increased risk of TVE may contribute
substantially to the survival effect. However, other data provide strong
support for the safety of PROCRIT when used in the labelled indication,
treatment of anemia in cancer patients on chemotherapy.

## BENEFIT AND RISK ASSESSMENT OF ERAs IN PATIENTS WITH CANCER

ERAs provide significant benefits to anemic patients with cancer
receiving chemotherapy. Millions of patients have been treated with
these products, to ameliorate the symptoms of anemia and to reduce
transfusion requirements. This class of medications provides the only
alternative to blood transfusions, which carry their own inherent risks,
and are a limited resource.

Beyond the proven benefits in reduction of transfusion requirements, two
studies, EPO-INT-10^7^ and a study by Vansteenkiste et al.^8^,
demonstrated a non-significant trend to improved survival associated
with ERA treatment of patients with cancer. Of note, these studies were
not designed to detect a positive impact on survival and patients were
treated to correct anemia with the primary end-points being Quality Of
Life and reduction of transfusion requirements.

Recent trials testing potential survival benefits with ERA
investigational uses beyond the correction of anemia have reported
inferior survival and excesses of TVEs associated with these uses.

These reported outcomes have resulted in an evaluation of the
Benefit-Risk assessment of ERAs in patients with cancer. The intent of
this assessment is to better understand the appropriate investigational
uses of these products, and to confirm the ongoing positive Benefit-Risk
profile of marketed products when used for their approved indication.

The known presence of erythropoietin receptors on cell lines other than
erythroid precursor cells, including tumor cells, directed one component
of the assessment to the evaluation of whether ERAs might have tumor
proliferative effects. In order to assess this, all available clinical
data were reviewed, using tumor progression/tumor response as a
surrogate for this effect.

In addition, the observed excess of TVEs with this new investigational
use, and imbalance in fatal TVEs observed in EPO-INT-76, directed
another focus of the evaluation to determine what contribution, if any,
these may have had to the observed survival differences in these
studies.

In order to ensure the safety and well-being of patients, the Sponsor's
initial Risk Mitigation Plan included:

-   A review of our supported, ongoing and planned, oncology studies to
    ensure safety of participants.

-   Arrangements to ensure independent safety monitoring in clinical
    studies.

The data from the Sponsor's analyses of the survival risk, and risks of
tumor progression and TVE's are summarized below with a benefit-risk
assessment.

Survival

Among the many drugs used in the palliative treatment of cancer
patients, epoetin alfa is one of the most extensively studied. Analyses
of survival in the Sponsor's randomized controlled trials of epoetin
alfa in anemic patients on cancer chemotherapy have not revealed
evidence of significant imbalances. This is supported further by the two
completed studies, EPO-INT-10^7^ (included in the combined analysis) and
a study by Vansteenkiste et al.^8^ using darbepoetin alfa, suggesting a
modest positive impact on mortality although they were not powered to
detect this. These findings are also supported by the outcomes of the
still continuing AGO/NOGGO study^10^ in cervical cancer supported by the
Sponsor. These data, although from a large number of studies, do not
exclude the possibility of any adverse effect on survival conferred by
epoetin alfa.

The Sponsor's data suggest that the survival signal from a small number
of studies are associated with investigational uses of ERAs in patients
with cancer, in studies with protocol-defined treatment beyond the
correction of anemia. These findings are not seen in studies of the use
of epoetin alfa for the correction of chemotherapy-induced anemia as
labeled, where there is a large volume of data supporting the safety and
efficacy of ERAs.

Tumor Progression/Tumor Response

The Sponsor's analysis of the available data supports the conclusion
that therapy with ERAs did not affect the response to antineoplastic
therapy or lead to tumor progression via increased tumor cell
proliferation, angiogenesis, or anti-apoptosis.

Most importantly, data from 7 randomized studies in patients with
cancer, including 5 studies involving correction of anemia and 2 studies
of ERA beyond the correction of anemia, do not support that epoetin alfa
lowers tumor response rates or increases tumor progression. In the one
study (N93-004) specifically designed to address this issue, and in
which response to antineoplastic therapy was the primary end point,
epoetin alfa did not impair the response to chemotherapy. Indeed, a
substantial adverse effect could be statistically excluded.

Additional evidence for this conclusion comes from EPO-INT-76. This
study, as described previously, showed a decreased 12-month overall
survival in subjects with metastatic breast cancer who were treated with
new investigational use of epoetin alfa to maintain hemoglobin
concentrations in the range of 12 to 14 g/dL for 1 year. While most of
the deaths in this study were clinically attributed to disease
progression, a blinded analysis of tumor response and disease
progression did not support the hypothesis that these deaths were due to
effects of epoetin alfa on tumor progression or tumor response. Although
baseline and regular, on-study tumor measurements were not performed for
all patients, substantial information regarding both response rates and
disease progression was available for many, and are the basis for the
following key findings:

-   while there were limitations in the data, tumor response to
    chemotherapy appeared to be similar in the 2 treatment groups,
    suggesting that epoetin alfa did not interfere with the efficacy of
    chemotherapy;

-   time to disease progression was also similar in both groups,
    suggesting that effects on tumor response and disease progression
    did not account for much of the observed differences in survival
    associated with epoetin alfa use in the study; and

-   analyses of causes of death in the study, including a blinded chart
    review, suggested that undiagnosed TVEs may have accounted for more
    of the difference between deaths on epoetin alfa and deaths on
    placebo than was originally appreciated.

The questions raised by the study of Henke et al. cannot be addressed
further by the Sponsor at this time, as we have not had access to the
data.

A review of the body of preclinical literature does not suggest an
adverse impact of ERA therapy on tumors or cancer cells. Although there
are reported studies suggesting proliferative or other potentially
adverse effects of ERAs on tumor cells, these effects were observed at
concentrations substantially exceeding those achieved with epoetin alfa
therapy in the in-vivo clinical setting. One should also note that the
preclinical in-vitro models do not accurately replicate the complex
physiological milieu of the human tumors with respect to complex
interactions between hypoxia and receptor-cytokine response regulation.
This review of the relevant preclinical data is summarized in Attachment
5.

Although there is strong evidence preclinically and clinically to the
contrary, the possibility that epoetin alfa can act as a growth factor
for any tumor type, particularly myeloid malignancies, cannot be totally
excluded. This potential effect is acknowledged and adequately described
in the current labeling. The current benefit/risk of ERA use within
labeled indications is unchanged.

Thrombotic Vascular Events

The association of TVEs with ERAs is described in the approved labeling
for products in this class of medications. In other populations (e.g.,
renal), the frequency of TVEs associated with ERA therapy increases with
rising hemoglobin levels.

Our analysis of TVEs from combined data of 12 studies (3,104 patients)
suggests ERA treatment of anemic cancer patients is associated with some
elevation in TVE frequency, consistent with that described in current
product labeling.

As noted above, in Study EPO-INT-76, in which patients were treated
beyond the correction of anemia, recognized and documented TVEs
accounted for a significant share of the excess mortality observed in
the epoetin alfa arm. More importantly, a blinded case review of
mortality data from this trial supports that undiagnosed fatal TVE may
have accounted for some of the deaths in patients who were reported to
have died from disease progression. Finally, no objective evidence of
impaired tumor response or accelerated tumor progression could be found
in this study to account for the survival imbalance. Given the frequent
uncertainty regarding proximate causes of death in cancer patients, it
is important to consider the possibility that unrecognized fatal TVEs
may have accounted, to a substantial degree, for the excess of deaths on
the epoetin alfa arm.

As part of our risk mitigation strategy the Sponsor reviewed the ongoing
trials of ERAs in cancer patients, and discontinued 3 studies for
reportedly high TVE rates in the epoetin alfa group. These studies
involved the use of epoetin alfa beyond the correction of anemia, in
patients receiving chemotherapy and radiation therapy.

In summary, the Benefit-Risk assessment for ERAs, used to correct anemia
in patients with cancer remains favorable when used for the approved
indication. The risk profile of ERAs in clinical trials also remains
favorable when these drugs are used to correct anemia. The association
of TVEs with this class of medications is recognized and is included in
labeling and reference safety information for clinical trials.

## CONCLUSION 

In some investigational studies, ERA treatment of patients beyond the
correction of anemia has resulted in decreased survival or increased
side effects. These specific investigational designs should be avoided
in future development programs.

The available data support the conclusion that, when used for approved
indications and within established guidelines for baseline and target
hemoglobin concentrations, the benefits of ERA therapy continue to be
supported by a well-defined and acceptable risk profile.

.

## REFERENCES

1.  Leyland‑Jones B. Breast cancer trial with erythropoietin terminated
    unexpectedly. Lancet 2003; 4:459‑460.

2.  Henke M, Laszig R, Rube C, Schafer U, et al. Erythropoietin to treat
    head and neck cancer patients with anemia undergoing radiotherapy:
    Randomized, double‑blind, placebo‑controlled trial. Lancet
    2003;362:1255‑1260.

3.  Bohlius J. et al. Does Erythropoietin Improve Overall Survival in
    the Treatment of Patients with Malignant Diseases? Results of a
    Comprehensive Meta-Analysis. Session Type: Oral Session, 2003; Blood
    102(11), abstract 709.

4.  Glaser C, Millesi W, Wanschitz F, et al. r‑HuErythropoietin
    treatment increases efficacy of neoadjuvant radiochemotherapy and
    improves cancer free survival of patients with oral squamous cell
    carcinoma: a 17‑month follow‑up. J Clin Oncol 1999;18:399a.

5.  Strauss HG, Haensgen G, Becker A, et al. Prognostic impact of
    changes in the tumor tissue pO~2~ during early radiotherapy in
    cervical cancers: Improved local control in primarily hypoxic tumors
    with "reoxygenation" and the impact of hemoglobin. Int J Radiat
    Oncol Biol Phys 1999; 45(Suppl):364.

6.  Thomas GM. Raising hemoglobin: An opportunity for increasing
    survival? Oncology 2002;63 (Suppl. 2):19‑28.

7.  Littlewood TJ, Bajetta E, Nortier JW, et al. Effects of epoetin alfa
    on hematologic parameters and quality of life in cancer patients
    receiving nonplatinum chemotherapy: results of a randomized,
    double‑blind, placebo‑controlled trial. J Clin Oncol
    2001;19:2865‑2874.

8.  Vansteenkiste J, Pirker R, Massuti B, et al. Double blind placebo
    controlled randomized phase III trial of darbepoetin alfa in lung
    cancer patients receiving chemotherapy. J Natl Cancer Inst
    2002;94:1211‑1220.

9.  Vercammen E, Xiu L, Hendler J. A double‑blind, randomized,
    placebo‑controlled study to evaluate the impact of maintaining
    hemoglobin using EPREX^®^ (Epoetin Alfa; RWJPRI‑22512) in metastatic
    breast carcinoma patients receiving chemotherapy
    (Protocol PRI/EPO‑INT-76/EPO-CA-489). Document ID No.
    EDMS‑USRA‑8230809:2.0 (16 April 2003).

10. Blohmer J. et al. Impact of Epoetin Alfa on Disease-free Survival in
    High-risk Cervical Cancer Patients Receiving Sequential Adjuvant
    Chemotherapy. Abstract presented at ECCO Sept 2003

11. Open‑label randomized comparative group evaluation of the effect of
    epoetin alfa on local disease‑free survival and quality of life in
    head and neck cancer patients receiving radical radiotherapy
    (Protocol EPO‑GBR‑7)(data on file).

12. Vercammen E, Sullivan D, Matone P. The Effect of r‑HuEPO in Patients
    with Small Cell Lung Cancer (SCLC): A Randomized, Double‑Blind,
    Placebo‑Controlled Trial. (Protocol N93‑004; Phase 4). Document ID
    No. EDMS‑USRA‑8057829:4.0 (26 September 2002).

.

# APPENDIX {#appendix .unnumbered}

[]{#__RefHeading___Toc68427463 .anchor}**Attachment 1:** Package Insert

**PROCRIT^®^**

**(Epoetin alfa)**

**FOR INJECTION**

**DESCRIPTION**

Erythropoietin is a glycoprotein which stimulates red blood cell
production. It is produced in the kidney and stimulates the division and
differentiation of committed erythroid progenitors in the bone marrow.
PROCRIT^^ (Epoetin alfa), a 165 amino acid glycoprotein manufactured by
recombinant DNA technology, has the same biological effects as
endogenous erythropoietin.^1^ It has a molecular weight of 30,400
daltons and is produced by mammalian cells into which the human
erythropoietin gene has been introduced. The product contains the
identical amino acid sequence of isolated natural erythropoietin.

PROCRIT^^ is formulated as a sterile, colorless liquid in an isotonic
sodium chloride/sodium citrate buffered solution or a sodium
chloride/sodium phosphate buffered solution for intravenous (IV) or
subcutaneous (SC) administration.

**Single-dose, Preservative-free Vial:** Each 1 mL of solution contains
2000, 3000, 4000 or 10,000 Units of Epoetin alfa, 2.5 mg Albumin
(Human), 5.8 mg sodium citrate, 5.8 mg sodium chloride, and 0.06 mg
citric acid in Water for Injection, USP (pH 6.9 ± 0.3). This formulation
contains no preservative.

**Single-dose, Preservative-free Vial:** 1 mL (40,000 Units/mL). Each 1
mL of solution contains 40,000 Units of Epoetin alfa, 2.5 mg Albumin
(Human), 1.2 mg sodium phosphate monobasic monohydrate, 1.8 mg sodium
phosphate dibasic anhydrate, 0.7 mg sodium citrate, 5.8 mg sodium
chloride, and 6.8 mcg citric acid in Water for Injection, USP (pH 6.9 ±
0.3). This formulation contains no preservative.

**Multidose, Preserved Vial:** 2 mL (20,000 Units, 10,000 Units/mL).
Each 1 mL of solution contains 10,000 Units of Epoetin alfa, 2.5 mg
Albumin (Human), 1.3 mg sodium citrate, 8.2 mg sodium chloride, 0.11 mg
citric acid, and 1% benzyl alcohol as preservative in Water for
Injection, USP (pH 6.1 ± 0.3).

**Multidose, Preserved Vial:** 1 mL (20,000 Units/mL). Each 1 mL of
solution contains 20,000 Units of Epoetin alfa, 2.5 mg Albumin (Human),
1.3 mg sodium citrate, 8.2 mg sodium chloride, 0.11 mg citric acid, and
1% benzyl alcohol as preservative in Water for Injection, USP (pH 6.1 ±
0.3).

**CLINICAL PHARMACOLOGY**

***Chronic Renal Failure Patients***

Endogenous production of erythropoietin is normally regulated by the
level of tissue oxygenation. Hypoxia and anemia generally increase the
production of erythropoietin, which in turn stimulates
erythropoiesis.^2^ In normal subjects, plasma erythropoietin levels
range from 0.01 to 0.03 Units/mL and increase up to 100- to 1000-fold
during hypoxia or anemia.^2^ In contrast, in patients with chronic renal
failure (CRF), production of erythropoietin is impaired, and this
erythropoietin deficiency is the primary cause of their anemia.^3,4^

Chronic renal failure is the clinical situation in which there is a
progressive and usually irreversible decline in kidney function. Such
patients may manifest the sequelae of renal dysfunction, including
anemia, but do not necessarily require regular dialysis. Patients with
end-stage renal disease (ESRD) are those patients with CRF who require
regular dialysis or kidney transplantation for survival.

PROCRIT^^ has been shown to stimulate erythropoiesis in anemic patients
with CRF, including both patients on dialysis and those who do not
require regular dialysis. ^4-13^ The first evidence of a response to the
three times weekly (TIW) administration of PROCRIT^^ is an increase in
the reticulocyte count within 10 days, followed by increases in the red
cell count, hemoglobin, and hematocrit, usually within 2 to 6
weeks.^4,5^ [Because of the length of time required for erythropoiesis
-- several days for erythroid progenitors to mature and be released into
the circulation -- a clinically significant increase in hematocrit is
usually not observed in less than 2 weeks and may require up to 6 weeks
in some patients.]{.underline} Once the hematocrit reaches the suggested
target range (30% to 36%), that level can be sustained by PROCRIT^^
therapy in the absence of iron deficiency and concurrent illnesses.

The rate of hematocrit increase varies between patients and is dependent
upon the dose of PROCRIT^^, within a therapeutic range of approximately
50 to 300 Units/kg TIW.^4^ A greater biologic response is not observed
at doses exceeding 300 Units/kg TIW.^6^ Other factors affecting the rate
and extent of response include availability of iron stores, the baseline
hematocrit, and the presence of concurrent medical problems.

***Zidovudine-treated HIV-infected Patients***

Responsiveness to PROCRIT^^ in HIV-infected patients is dependent upon
the endogenous serum erythropoietin level prior to treatment. Patients
with endogenous serum erythropoietin levels ≤ 500 mUnits/mL, and who are
receiving a dose of zidovudine ≤ 4200 mg/week, may respond to PROCRIT^^
therapy. Patients with endogenous serum erythropoietin levels \> 500
mUnits/mL do not appear to respond to PROCRIT^^ therapy. In a series of
four clinical trials involving 255 patients, 60% to 80% of HIV-infected
patients treated with zidovudine had endogenous serum erythropoietin
levels ≤ 500 mUnits/mL.

Response to PROCRIT^^ in zidovudine-treated HIV-infected patients is
manifested by reduced transfusion requirements and increased hematocrit.

***Cancer Patients on Chemotherapy***

Anemia in cancer patients may be related to the disease itself or the
effect of concomitantly administered chemotherapeutic agents. PROCRIT^^
has been shown to increase hematocrit and decrease transfusion
requirements after the first month of therapy (months 2 and 3), in
anemic cancer patients undergoing chemotherapy.

A series of clinical trials enrolled 131 anemic cancer patients who were
receiving cyclic cisplatin- or non cisplatin-containing chemotherapy.
Endogenous baseline serum erythropoietin levels varied among patients in
these trials with approximately 75% (n = 83/110) having endogenous serum
erythropoietin levels ≤ 132 mUnits/mL, and approximately 4% (n = 4/110)
of patients having endogenous serum erythropoietin levels \> 500
mUnits/mL. In general, patients with lower baseline serum erythropoietin
levels responded more vigorously to PROCRIT^^ than patients with higher
baseline erythropoietin levels. Although no specific serum
erythropoietin level can be stipulated above which patients would be
unlikely to respond to PROCRIT^^ therapy, treatment of patients with
grossly elevated serum erythropoietin levels (eg, \> 200 mUnits/mL) is
not recommended.

**[Pharmacokinetics]{.underline}**

Intravenously administered PROCRIT^^ is eliminated at a rate consistent
with first order kinetics with a circulating half-life ranging from
approximately 4 to 13 hours in adult and pediatric patients with
CRF.^14-16^ Within the therapeutic dose range, detectable levels of
plasma erythropoietin are maintained for at least 24 hours. After SC
administration of PROCRIT^^ to patients with CRF, peak serum levels are
achieved within 5 to 24 hours after administration and decline slowly
thereafter. There is no apparent difference in half-life between adult
patients not on dialysis whose serum creatinine levels were greater than
3, and adult patients maintained on dialysis.

In normal volunteers, the half-life of IV administered PROCRIT^^ is
approximately 20% shorter than the half-life in CRF patients. The
pharmacokinetics of PROCRIT^^ have not been studied in HIV-infected
patients.

The pharmacokinetic profile of PROCRIT^^ in children and adolescents
appears to be similar to that of adults. Limited data are available in
neonates.^17^

It has been demonstrated in normal volunteers that the 10,000 Units/mL
citrate-buffered Epoetin alfa formulation and the 40,000 Units/mL
phosphate-buffered Epoetin alfa formulation are bioequivalent after SC
administration of single 750 Units/kg doses. The C~max~ and t~1/2~ after
administration of the phosphate buffered Epoetin alfa formulation were
1.8 ± 0.7 Units/mL and 19.0 ± 5.9 hours (mean ± SD), respectively. The
corresponding mean ± SD values for the citrate-buffered Epoetin alfa
formulation were 2 ± 0.9 Units/mL and 16.3 ± 3.0 hours. There was no
notable accumulation in serum after two weekly 750 Units/kg SC doses of
Epoetin alfa.

**INDICATIONS AND USAGE**

***Treatment of Anemia of Chronic Renal Failure Patients***

PROCRIT^^ is indicated for the treatment of anemia associated with CRF,
including patients on dialysis (ESRD) and patients not on dialysis.
PROCRIT^^ is indicated to elevate or maintain the red blood cell level
(as manifested by the hematocrit or hemoglobin determinations) and to
decrease the need for transfusions in these patients.

Non-dialysis patients with symptomatic anemia considered for therapy
should have a hematocrit less than 30%.

PROCRIT^^ is not intended for patients who require immediate correction
of severe anemia. PROCRIT^^ may obviate the need for maintenance
transfusions but is not a substitute for emergency transfusion.

Prior to initiation of therapy, the patient's iron stores should be
evaluated. Transferrin saturation should be at least 20% and ferritin at
least 100 ng/mL. Blood pressure should be adequately controlled prior to
initiation of PROCRIT^^ therapy, and must be closely monitored and
controlled during therapy.

PROCRIT^^ should be administered under the guidance of a qualified
physician (see DOSAGE AND ADMINISTRATION).

***Treatment of Anemia in Zidovudine-treated HIV-infected Patients***

PROCRIT^^ is indicated for the treatment of anemia related to therapy
with zidovudine in HIV-infected patients. PROCRIT^^ is indicated to
elevate or maintain the red blood cell level (as manifested by the
hematocrit or hemoglobin determinations) and to decrease the need for
transfusions in these patients. PROCRIT^^ is not indicated for the
treatment of anemia in HIV-infected patients due to other factors such
as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding,
which should be managed appropriately.

PROCRIT^^, at a dose of 100 Units/kg TIW, is effective in decreasing
the transfusion requirement and increasing the red blood cell level of
anemic, HIV-infected patients treated with zidovudine, when the
endogenous serum erythropoietin level is ≤ 500 mUnits/mL and when
patients are receiving a dose of zidovudine ≤ 4200 mg/week.

***Treatment of Anemia in Cancer Patients on Chemotherapy***

PROCRIT^^ is indicated for the treatment of anemia in patients with
non-myeloid malignancies where anemia is due to the effect of
concomitantly administered chemotherapy. PROCRIT^^ is indicated to
decrease the need for transfusions in patients who will be receiving
concomitant chemotherapy for a minimum of 2 months. PROCRIT^^ is not
indicated for the treatment of anemia in cancer patients due to other
factors such as iron or folate deficiencies, hemolysis, or
gastrointestinal bleeding, which should be managed appropriately.

***Reduction of Allogeneic Blood Transfusion in Surgery Patients***

PROCRIT^^ is indicated for the treatment of anemic patients (hemoglobin
\> 10 to ≤ 13 g/dL) scheduled to undergo elective, noncardiac,
nonvascular surgery to reduce the need for allogeneic blood
transfusions.^18-20^ PROCRIT^^ is indicated for patients at high risk
for perioperative transfusions with significant, anticipated blood loss.
PROCRIT^^ is not indicated for anemic patients who are willing to
donate autologous blood. The safety of the perioperative use of
PROCRIT^^ has been studied only in patients who are receiving
anticoagulant prophylaxis.

**CLINICAL EXPERIENCE: RESPONSE TO PROCRIT**^^

***Chronic Renal Failure Patients***

Response to PROCRIT^^ was consistent across all studies. In the
presence of adequate iron stores (see IRON EVALUATION), the time to
reach the target hematocrit is a function of the baseline hematocrit and
the rate of hematocrit rise.

The rate of increase in hematocrit is dependent upon the dose of
PROCRIT^^ administered and individual patient variation. In clinical
trials at starting doses of 50 to 150 Units/kg TIW, adult patients
responded with an average rate of hematocrit rise of:

+-----------------------+-----------------------+-----------------------+
| **Starting Dose**     | ####### Hematocrit I  |                       |
|                       | ncrease {#hematocrit- |                       |
|                       | increase .unnumbered} |                       |
+-----------------------+-----------------------+-----------------------+
| **(TIW IV)**          | #                     | ####### P             |
|                       | ###### Points/Day {#p | oints/2 Weeks {#point |
|                       | ointsday .unnumbered} | s2-weeks .unnumbered} |
+-----------------------+-----------------------+-----------------------+
| 50 Units/kg           | 0.11                  | 1.5                   |
+-----------------------+-----------------------+-----------------------+
| 100 Units/kg          | 0.18                  | 2.5                   |
+-----------------------+-----------------------+-----------------------+
| 150 Units/kg          | 0.25                  | 3.5                   |
+-----------------------+-----------------------+-----------------------+

Over this dose range, approximately 95% of all patients responded with a
clinically significant increase in hematocrit, and by the end of
approximately 2 months of therapy virtually all patients were
transfusion-independent. Changes in the quality of life of adult
patients treated with PROCRIT^^ were assessed as part of a phase 3
clinical trial.^5,8^ Once the target hematocrit (32% to 38%) was
achieved, statistically significant improvements were demonstrated for
most quality of life parameters measured, including energy and activity
level, functional ability, sleep and eating behavior, health status,
satisfaction with health, sex life, well-being, psychological effect,
life satisfaction, and happiness. Patients also reported improvement in
their disease symptoms. They showed a statistically significant increase
in exercise capacity (VO~2~ max), energy, and strength with a
significant reduction in aching, dizziness, anxiety, shortness of
breath, muscle weakness, and leg cramps.^8,21^

*Adult Patients on Dialysis*: Thirteen clinical studies were conducted,
involving IV administration to a total of 1010 anemic patients on
dialysis for 986 patient-years of PROCRIT^^ therapy. In the three
largest of these clinical trials, the median maintenance dose necessary
to maintain the hematocrit between 30% to 36% was approximately 75
Units/kg TIW. In the US multicenter phase 3 study, approximately 65% of
the patients required doses of 100 Units/kg TIW, or less, to maintain
their hematocrit at approximately 35%. Almost 10% of patients required a
dose of 25 Units/kg, or less, and approximately 10% required a dose of
more than 200 Units/kg TIW to maintain their hematocrit at this level.

A multicenter unit dose study was also conducted in 119 patients
receiving peritoneal dialysis who self-administered PROCRIT^^
subcutaneously for approximately 109 patient-years of experience.
Patients responded to PROCRIT^^ administered SC in a manner similar to
patients receiving IV administration.^22^

*Pediatric Patients on Dialysis:* One hundred twenty-eight children from
2 months to 19 years of age with CRF requiring dialysis were enrolled in
4 clinical studies of PROCRIT^^. The largest study was a
placebo-controlled, randomized trial in 113 children with anemia
(hematocrit ≤ 27%) undergoing peritoneal dialysis or hemodialysis. The
initial dose of PROCRIT^^ was 50 Units/kg IV or SC TIW. The dose of
study drug was titrated to achieve either a hematocrit of 30% to 36% or
an absolute increase in hematocrit of 6 percentage points over baseline.

At the end of the initial 12 weeks, a statistically significant rise in
mean hematocrit (9.4% vs 0.9%) was observed only in the PROCRIT^^ arm.
The proportion of children achieving a hematocrit of 30%, or an increase
in hematocrit of 6 percentage points over baseline, at any time during
the first 12 weeks was higher in the PROCRIT^^ arm (96% vs 58%). Within
12 weeks of initiating PROCRIT^^ therapy, 92.3% of the pediatric
patients were transfusion-independent as compared to 65.4% who received
placebo. Among patients who received 36 weeks of PROCRIT^^,
hemodialysis patients required a higher median maintenance dose (167
Units/kg/week \[n = 28\] vs 76 Units/kg/week \[n = 36\]) and took longer
to achieve a hematocrit of 30% to 36% (median time to response 69 days
vs 32 days) than patients undergoing peritoneal dialysis.

***Patients With CRF Not Requiring Dialysis***

Four clinical trials were conducted in patients with CRF not on dialysis
involving 181 patients treated with PROCRIT^^ for approximately 67
patient-years of experience. These patients responded to PROCRIT^^
therapy in a manner similar to that observed in patients on dialysis.
Patients with CRF not on dialysis demonstrated a dose-dependent and
sustained increase in hematocrit when PROCRIT^^ was administered by
either an IV or SC route, with similar rates of rise of hematocrit when
PROCRIT^^ was administered by either route. Moreover, PROCRIT^^ doses
of 75 to 150 Units/kg [per]{.underline} [week]{.underline} have been
shown to maintain hematocrits of 36% to 38% for up to 6 months.
Correcting the anemia of progressive renal failure will allow patients
to remain active even though their renal function continues to
decrease.^23-24^

***Zidovudine-treated HIV-infected Patients***

PROCRIT^^ has been studied in four placebo-controlled trials enrolling
297 anemic (hematocrit \< 30%) HIV-infected (AIDS) patients receiving
concomitant therapy with zidovudine (all patients were treated with
Epoetin alfa manufactured by Amgen Inc. \[Amgen\]). In the subgroup of
patients (89/125 PROCRIT^^ and 88/130 placebo) with prestudy endogenous
serum erythropoietin levels ≤ 500 mUnits/mL, PROCRIT^^ reduced the mean
cumulative number of units of blood transfused per patient by
approximately 40% as compared to the placebo group.^25^ Among those
patients who required transfusions at baseline, 43% of patients treated
with PROCRIT^^ versus 18% of placebo-treated patients were
transfusion-independent during the second and third months of therapy.
PROCRIT^^ therapy also resulted in significant increases in hematocrit
in comparison to placebo. When examining the results according to the
weekly dose of zidovudine received during month 3 of therapy, there was
a statistically significant (p \< 0.003) reduction in transfusion
requirements in patients treated with PROCRIT^^ (n = 51) compared to
placebo treated patients (n = 54) whose mean weekly zidovudine dose was
≤ 4200 mg/week.^25^

Approximately 17% of the patients with endogenous serum erythropoietin
levels ≤ 500 mUnits/mL receiving PROCRIT^^ in doses from 100 to 200
Units/kg TIW achieved a hematocrit of 38% without administration of
transfusions or significant reduction in zidovudine dose. In the
subgroup of patients whose prestudy endogenous serum erythropoietin
levels were \> 500 mUnits/mL, PROCRIT^^ therapy did not reduce
transfusion requirements or increase hematocrit, compared to the
corresponding responses in placebo-treated patients.

In a 6 month open-label PROCRIT^^ study, patients responded with
decreased transfusion requirements and sustained increases in hematocrit
and hemoglobin with doses of PROCRIT^^ up to 300 Units/kg TIW.^25-27^

Responsiveness to PROCRIT^^ therapy may be blunted by intercurrent
infectious/inflammatory episodes and by an increase in zidovudine
dosage. Consequently, the dose of PROCRIT^^ must be titrated based on
these factors to maintain the desired erythropoietic response.

***Cancer Patients on Chemotherapy***

PROCRIT^^ has been studied in a series of placebo-controlled,
double-blind trials in a total of 131 anemic cancer patients. Within
this group, 72 patients were treated with concomitant non
cisplatin-containing chemotherapy regimens and 59 patients were treated
with concomitant cisplatin-containing chemotherapy regimens. Patients
were randomized to PROCRIT^^ 150 Units/kg or placebo subcutaneously TIW
for 12 weeks.

PROCRIT^^ therapy was associated with a significantly (p \< 0.008)
greater hematocrit response than in the corresponding placebo-treated
patients (see table).^25^

+-----------------------+-----------------------+-----------------------+
| **Hematocrit (%):     |                       |                       |
| Mean Change From      |                       |                       |
| Baseline To Final     |                       |                       |
| Value ^\*^**          |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **Study**             | **PROCRIT**^^        | **Placebo**           |
+-----------------------+-----------------------+-----------------------+
| Chemotherapy          | 7.6                   | 1.3                   |
+-----------------------+-----------------------+-----------------------+
| Cisplatin             | 6.9                   | 0.6                   |
+-----------------------+-----------------------+-----------------------+
| > Significantly       |                       |                       |
| > higher in           |                       |                       |
| > PROCRIT^^ patients |                       |                       |
| > than in placebo     |                       |                       |
| > patients\           |                       |                       |
| > (p \< 0.008)        |                       |                       |
+-----------------------+-----------------------+-----------------------+

In the two types of chemotherapy studies (utilizing a PROCRIT^^ dose of
150 Units/kg TIW), the mean number of units of blood transfused per
patient after the first month of therapy was significantly (p \< 0.02)
lower in patients treated with PROCRIT^^ (0.71 units in months 2, 3)
than in corresponding placebo-treated patients (1.84 units in months 2,
3). Moreover, the proportion of patients transfused during months 2 and
3 of therapy combined was significantly (p \< 0.03) lower in the
patients treated with PROCRIT^^ than in the corresponding
placebo-treated patients (22% vs 43%).^25^

Comparable intensity of chemotherapy in the PROCRIT^^ and placebo
groups in the chemotherapy trials was suggested by a similar area under
the neutrophil time curve in patients treated with PROCRIT^^ and
placebo-treated patients as well as by a similar proportion of patients
in groups treated with PROCRIT^^ and placebo-treated groups whose
absolute neutrophil counts fell below 1000 cells/µL. Available evidence
suggests that patients with lymphoid and solid cancers respond
equivalently to PROCRIT^^ therapy, and that patients with or without
tumor infiltration of the bone marrow respond equivalently to PROCRIT^^
therapy.

***Surgery Patients***

PROCRIT^^ has been studied in a placebo-controlled, double-blind trial
enrolling 316 patients scheduled for major, elective orthopedic hip or
knee surgery who were expected to require ≥ 2 units of blood and who
were not able or willing to participate in an autologous blood donation
program. Based on previous studies which demonstrated that pretreatment
hemoglobin is a predictor of risk of receiving transfusion,^20,28^
patients were stratified into one of three groups based on their
pretreatment hemoglobin \[≤ 10 (n = 2), \> 10 to ≤ 13 (n = 96), and \>
13 to ≤ 15 g/dL (n = 218)\] and then randomly assigned to receive 300
Units/kg PROCRIT^^, 100 Units/kg PROCRIT^^ or placebo by SC injection
for 10 days before surgery, on the day of surgery, and for 4 days after
surgery.^18^ All patients received oral iron and a low-dose
post-operative warfarin regimen.^18^

Treatment with PROCRIT^^ 300 Units/kg significantly (p = 0.024) reduced
the risk of allogeneic transfusion in patients with a pretreatment
hemoglobin of \> 10 to ≤ 13 g/dL; 5/31 (16%) of PROCRIT^^ 300 Units/kg,
6/26 (23%) of PROCRIT^^ 100 Units/kg, and 13/29 (45%) of
placebo-treated patients were transfused.^18^ There was no significant
difference in the number of patients transfused between PROCRIT^^ (9%
300 Units/kg, 6% 100 Units/kg) and placebo (13%) in the \> 13 to ≤ 15
g/dL hemoglobin stratum. There were too few patients in the ≤ 10 g/dL
group to determine if PROCRIT^^ is useful in this hemoglobin strata. In
the \> 10 to ≤ 13 g/dL pretreatment stratum, the mean number of units
transfused per PROCRIT^^-treated patient (0.45 units blood for 300
Units/kg, 0.42 units blood for 100 Units/kg) was less than the mean
transfused per placebo-treated patient (1.14 units) (overall p = 0.028).
In addition, mean hemoglobin, hematocrit, and reticulocyte counts
increased significantly during the presurgery period in patients treated
with PROCRIT^^.^18^

PROCRIT^^ was also studied in an open-label, parallel-group trial
enrolling 145 subjects with a pretreatment hemoglobin level of ≥ 10 to ≤
13 g/dL who were scheduled for major orthopedic hip or knee surgery and
who were not participating in

an autologous program.^19^ Subjects were randomly assigned to receive
one of two SC dosing regimens of PROCRIT^^ (600 Units/kg once weekly
for 3 weeks prior to surgery and on the day of surgery or 300 Units/kg
once daily for 10 days prior to surgery, on the day of surgery and for 4
days after surgery). All subjects received oral iron and appropriate
pharmacologic anticoagulation therapy.

From pretreatment to presurgery, the mean increase in hemoglobin in 600
Units/kg weekly group (1.44 g/dL) was greater than observed in the 300
Units/kg daily group.^19^ The mean increase in absolute reticulocyte
count was smaller in the weekly group (0.11 x 10^6^/mm^3^) compared to
the daily group (0.17 x 10^6^/mm^3^). Mean hemoglobin levels were
similar for the two treatment groups throughout the postsurgical period.

The erythropoietic response observed in both treatment groups resulted
in similar transfusion rates \[11/69 (16%) in the 600 Units/kg weekly
group and 14/71 (20%) in the 300 Units/kg daily group\].^19^ The mean
number of units transfused per subject was approximately 0.3 units in
both treatment groups.

**CONTRAINDICATIONS**

PROCRIT^^ is contraindicated in patients with:

1\. Uncontrolled hypertension.

2\. Known hypersensitivity to mammalian cell-derived products.

3\. Known hypersensitivity to Albumin (Human).

**WARNINGS**

**Pediatric Use**

The multidose preserved formulation contains benzyl alcohol. Benzyl
alcohol has been reported to be associated with an increased incidence
of neurological and other complications in premature infants which are
sometimes fatal.

**Thrombotic Events and Increased Mortality**

A randomized, prospective trial of 1265 hemodialysis patients with
clinically evident cardiac disease (ischemic heart disease or congestive
heart failure) was conducted in which patients were assigned to
PROCRIT^^ treatment targeted to a maintenance hematocrit of either 42 ±
3% or 30 ± 3%.^42^ Increased mortality was observed in 634 patients
randomized to a target hematocrit of 42% \[221 deaths (35% mortality)\]
compared to 631 patients targeted to remain at a hematocrit of 30% \[185
deaths (29% mortality)\]. The reason for increased mortality observed in
these studies is unknown, however, the incidence of non-fatal myocardial
infarctions (3.1% vs 2.3%), vascular access thromboses (39% vs 29%), and
all other thrombotic events (22% vs 18%) were also higher in the group
randomized to achieve a hematocrit of 42%.

Increased mortality was also observed in a randomized placebo-controlled
study of PROCRIT^^ in adult patients who did not have CRF who were
undergoing coronary artery bypass surgery (7 deaths in 126 patients
randomized to PROCRIT^^ versus no deaths among 56 patients receiving
placebo). Four of these deaths occurred during the period of study drug
administration and all four deaths were associated with thrombotic
events. While the extent of the population affected is unknown, in
patients at risk for thrombosis, the anticipated benefits of PROCRIT^^
treatment should be weighed against the potential for increased risks
associated with therapy.

Pure Red Cell Aplasia

Pure red cell aplasia (PRCA), in association with neutralizing
antibodies to native erythropoietin, has been observed in patients
treated with recombinant erythropoietins. PRCA has been reported in a
limited number of patients exposed to PROCRIT^^. This has been reported
predominantly in patients with CRF. Any patient with loss of response to
PROCRIT^^ should be evaluated for the etiology of loss of effect (see
PRECAUTIONS: LACK OR LOSS OF RESPONSE). PROCRIT^^ should be
discontinued in any patient with evidence of PRCA and the patient
evaluated for the presence of binding and neutralizing antibodies to
PROCRIT^^, native erythropoietin, and any other recombinant
erythropoietin administered to the patient. Amgen/Ortho Biotech
Products, L.P. should be contacted to assist in this evaluation. In
patients with PRCA secondary to neutralizing antibodies to
erythropoietin, PROCRIT^^ should not be administered and such patients
should not be switched to another product as anti-erythropoietin
antibodies cross-react with other erythropoietins (see ADVERSE
REACTIONS).

***Chronic Renal Failure Patients***

**Hypertension:** Patients with uncontrolled hypertension should not be
treated with PROCRIT^^; blood pressure should be controlled adequately
before initiation of therapy. Up to 80% of patients with CRF have a
history of hypertension.^29^ Although there does not appear to be any
direct pressor effects of PROCRIT^^, blood pressure may rise during
PROCRIT^^ therapy. During the early phase of treatment when the
hematocrit is increasing, approximately 25% of patients on dialysis may
require initiation of, or increases in, antihypertensive therapy.
Hypertensive encephalopathy and seizures have been observed in patients
with CRF treated with PROCRIT^^.

[Special care should be taken to closely monitor and aggressively
control blood pressure in patients treated with PROCRIT]{.underline}^^.
Patients should be advised as to the importance of compliance with
antihypertensive therapy and dietary restrictions. If blood pressure is
difficult to control by initiation of appropriate measures, the
hematocrit may be reduced by decreasing or withholding the dose of
PROCRIT^^. A clinically significant decrease in hematocrit may not be
observed for several weeks.

[It is recommended that the dose of PROCRIT^^ be decreased if the
hematocrit increase exceeds 4 points in any 2-week period,]{.underline}
because of the possible association of excessive rate of rise of
hematocrit with an exacerbation of hypertension. In CRF patients on
hemodialysis with clinically evident ischemic heart disease or
congestive heart failure, the hematocrit should be managed carefully,
not to exceed 36% (see THROMBOTIC EVENTS).

**Seizures:** Seizures have occurred in patients with CRF participating
in PROCRIT^^ clinical trials.

In adult patients on dialysis, there was a higher incidence of seizures
during the first 90 days of therapy (occurring in approximately 2.5% of
patients) as compared with later timepoints.

Given the potential for an increased risk of seizures during the first
90 days of therapy, blood pressure and the presence of premonitory
neurologic symptoms should be monitored closely. Patients should be
cautioned to avoid potentially hazardous activities such as driving or
operating heavy machinery during this period.

While the relationship between seizures and the rate of rise of
hematocrit is uncertain, [it is recommended that the dose of PROCRIT^^
be decreased if the hematocrit increase exceeds 4 points in any 2-week
period.]{.underline}

**Thrombotic Events:** During hemodialysis, patients treated with
PROCRIT^^ may require increased anticoagulation with heparin to prevent
clotting of the artificial kidney (see ADVERSE REACTIONS for more
information about thrombotic events).

Other thrombotic events (eg, myocardial infarction, cerebrovascular
accident, transient ischemic attack) have occurred in clinical trials at
an annualized rate of less than 0.04 events per patient year of
PROCRIT^^ therapy. These trials were conducted in adult patients with
CRF (whether on dialysis or not) in whom the target hematocrit was 32%
to 40%. However, the risk of thrombotic events, including vascular
access thrombosis, was significantly increased in adult patients with
ischemic heart disease or congestive heart failure receiving PROCRIT^^
therapy with the goal of reaching a normal hematocrit (42%) as compared
to a target hematocrit of 30%. Patients with pre-existing cardiovascular
disease should be monitored closely.

***Zidovudine treated HIV-infected Patients***

In contrast to CRF patients, PROCRIT^^ therapy has not been linked to
exacerbation of hypertension, seizures, and thrombotic events in
HIV-infected patients.

**PRECAUTIONS**

The parenteral administration of any biologic product should be attended
by appropriate precautions in case allergic or other untoward reactions
occur (see CONTRAINDICATIONS). In clinical trials, while transient
rashes were occasionally observed concurrently with PROCRIT^^ therapy,
no serious allergic or anaphylactic reactions were reported (see ADVERSE
REACTIONS for more information regarding allergic reactions).

The safety and efficacy of PROCRIT^^ therapy have not been established
in patients with a known history of a seizure disorder or underlying
hematologic disease (eg, sickle cell anemia, myelodysplastic syndromes,
or hypercoagulable disorders).

In some female patients, menses have resumed following PROCRIT^^
therapy; the possibility of pregnancy should be discussed and the need
for contraception evaluated.

**Hematology**

Exacerbation of porphyria has been observed rarely in patients with CRF
treated with PROCRIT^^. However, PROCRIT^^ has not caused increased
urinary excretion of porphyrin metabolites in normal volunteers, even in
the presence of a rapid erythropoietic response. Nevertheless,
PROCRIT^^ should be used with caution in patients with known porphyria.

In preclinical studies in dogs and rats, but not in monkeys, PROCRIT^^
therapy was associated with subclinical bone marrow fibrosis. Bone
marrow fibrosis is a known complication of CRF in humans and may be
related to secondary hyperparathyroidism or unknown factors. The
incidence of bone marrow fibrosis was not increased in a study of adult
patients on dialysis who were treated with PROCRIT^^ for 12 to 19
months, compared to the incidence of bone marrow fibrosis in a matched
group of patients who had not been treated with PROCRIT^^.

Hematocrit in CRF patients should be measured twice a week;
zidovudine-treated HIV-infected and cancer patients should have
hematocrit measured once a week until hematocrit has been stabilized,
and measured periodically thereafter.

**Lack or Loss of Response**

If the patient fails to respond or to maintain a response to doses
within the recommended dosing range, the following etiologies should be
considered and evaluated:

1\. Iron deficiency: Virtually all patients will eventually require
supplemental iron therapy (see IRON EVALUATION).

2\. Underlying infectious, inflammatory, or malignant processes.

3\. Occult blood loss.

4\. Underlying hematologic diseases (ie, thalassemia, refractory anemia,
or other myelodysplastic disorders).

5\. Vitamin deficiencies: Folic acid or vitamin B12.

6\. Hemolysis.

7\. Aluminum intoxication.

8\. Osteitis fibrosa cystica.

9\. Pure Red Cell Aplasia (PRCA): In the absence of another etiology,
the patient should be evaluated for evidence of PRCA and sera should be
tested for the presence of antibodies to recombinant erythropoietins.

**Iron Evaluation**

During PROCRIT^^ therapy, absolute or functional iron deficiency may
develop. Functional iron deficiency, with normal ferritin levels but low
transferrin saturation, is presumably due to the inability to mobilize
iron stores rapidly enough to support increased erythropoiesis.
Transferrin saturation should be at least 20% and ferritin should be at
least 100 ng/mL.

Prior to and during PROCRIT^^ therapy, the patient's iron status,
including transferrin saturation (serum iron divided by iron binding
capacity) and serum ferritin, should be evaluated. Virtually all
patients will eventually require supplemental iron to increase or
maintain transferrin saturation to levels which will adequately support
erythropoiesis stimulated by PROCRIT^^. All surgery patients being
treated with PROCRIT^^ should receive adequate iron supplementation
throughout the course of therapy in order to support erythropoiesis and
avoid depletion of iron stores.

**[Drug Interactions]{.underline}**

No evidence of interaction of PROCRIT^^ with other drugs was observed
in the course of clinical trials.

**[Carcinogenesis, Mutagenesis, and Impairment of
Fertility]{.underline}**

Carcinogenic potential of PROCRIT^^ has not been evaluated. PROCRIT^^
does not induce bacterial gene mutation (Ames Test), chromosomal
aberrations in mammalian cells, micronuclei in mice, or gene mutation at
the HGPRT locus. In female rats treated IV with PROCRIT^^, there was a
trend for slightly increased fetal wastage at doses of 100 and 500
Units/kg.

**[Pregnancy Category C]{.underline}**

PROCRIT^^ has been shown to have adverse effects in rats when given in
doses 5 times the human dose. There are no adequate and well-controlled
studies in pregnant women. PROCRIT^^ should be used during pregnancy
only if potential benefit justifies the potential risk to the fetus.

In studies in female rats, there were decreases in body weight gain,
delays in appearance of abdominal hair, delayed eyelid opening, delayed
ossification, and decreases in the number of caudal vertebrae in the F1
fetuses of the 500 Units/kg group. In female rats treated IV, there was
a trend for slightly increased fetal wastage at doses of 100 and 500
Units/kg. PROCRIT^^ has not shown any adverse effect at doses as high
as 500 Units/kg in pregnant rabbits (from day 6 to 18 of gestation).

**[Nursing Mothers]{.underline}**

Postnatal observations of the live offspring (F1 generation) of female
rats treated with PROCRIT^^ during gestation and lactation revealed no
effect of PROCRIT^^ at doses of up to 500 Units/kg. There were,
however, decreases in body weight gain, delays in appearance of
abdominal hair, eyelid opening, and decreases in the number of caudal
vertebrae in the F1 fetuses of the 500 Units/kg group. There were no
PROCRIT^^-related effects on the F2 generation fetuses.

It is not known whether PROCRIT^^ is excreted in human milk. Because
many drugs are excreted in human milk, caution should be exercised when
PROCRIT^^ is administered to a nursing woman.

Pediatric Use

See WARNINGS: PEDIATRIC USE.

*Pediatric Patients on Dialysis:* PROCRIT^^ is indicated in infants (1
month to 2 years), children (2 years to 12 years), and adolescents (12
years to 16 years) for the treatment of anemia associated with CRF
requiring dialysis. Safety and effectiveness in pediatric patients less
than 1 month old have not been established (see CLINICAL EXPERIENCE:
CHRONIC RENAL FAILURE, PEDIATRIC PATIENTS ON DIALYSIS). The safety data
from these studies show that there is no increased risk to pediatric CRF
patients on dialysis when compared to the safety profile of PROCRIT^^
in adult CRF patients (see ADVERSE REACTIONS and WARNINGS). Published
literature^30-33^ provides supportive evidence of the safety and
effectiveness of PROCRIT^^ in pediatric CRF patients on dialysis.

*Pediatric Patients Not Requiring Dialysis:* Published literature^33,34^
has reported the use of PROCRIT^^ in 133 pediatric patients with anemia
associated with CRF not requiring dialysis, ages 3 months to 20 years,
treated with 50 to 250 Units/kg SC or IV, QW to TIW. Dose-dependent
increases in hemoglobin and hematocrit were observed with reductions in
transfusion requirements.

*Pediatric HIV-infected Patients:* Published literature^35,36^ has
reported the use of PROCRIT^^ in 20 zidovudine-treated anemic
HIV-infected pediatric patients ages 8 months to 17 years, treated with
50 to 400 Units/kg SC or IV, 2 to 3 times per week. Increases in
hemoglobin levels and in reticulocyte counts, and decreases in or
elimination of blood transfusions were observed.

*Pediatric Cancer Patients on Chemotherapy:* Published literature^37,38^
has reported the use of PROCRIT^^ in approximately 64 anemic pediatric
cancer patients ages 6 months to 18 years, treated with 25 to 300
Units/kg SC or IV, 3 to 7 times per week. Increases in hemoglobin and
decreases in transfusion requirements were noted.

**Chronic Renal Failure Patients**

***Patients with CRF Not Requiring Dialysis***

Blood pressure and hematocrit should be monitored no less frequently
than for patients maintained on dialysis. Renal function and fluid and
electrolyte balance should be closely monitored, as an improved sense of
well-being may obscure the need to initiate dialysis in some patients.

**Hematology**

Sufficient time should be allowed to determine a patient's
responsiveness to a dosage of PROCRIT^^ before adjusting the dose.
Because of the time required for erythropoiesis and the red cell
half-life, an interval of 2 to 6 weeks may occur between the time of a
dose adjustment (initiation, increase, decrease, or discontinuation) and
a significant change in hematocrit.

In order to avoid reaching the suggested target hematocrit too rapidly,
or exceeding the suggested target range (hematocrit of 30% to 36%), the
guidelines for dose and frequency of dose adjustments (see DOSAGE AND
ADMINISTRATION) should be followed.

For patients who respond to PROCRIT^^ with a rapid increase in
hematocrit (eg, more than 4 points in any 2-week period), the dose of
PROCRIT^^ should be reduced because of the possible association of
excessive rate of rise of hematocrit with an exacerbation of
hypertension.

The elevated bleeding time characteristic of CRF decreases toward normal
after correction of anemia in adult patients treated with PROCRIT^^.
Reduction of bleeding time also occurs after correction of anemia by
transfusion.

Laboratory Monitoring

The hematocrit should be determined twice a week until it has stabilized
in the suggested target range and the maintenance dose has been
established. After any dose adjustment, the hematocrit should also be
determined twice weekly for at least 2 to 6 weeks until it has been
determined that the hematocrit has stabilized in response to the dose
change. The hematocrit should then be monitored at regular intervals.

A complete blood count with differential and platelet count should be
performed regularly. During clinical trials, modest increases were seen
in platelets and white blood cell counts. While these changes were
statistically significant, they were not clinically significant and the
values remained within normal ranges.

In patients with CRF, serum chemistry values (including blood urea
nitrogen \[BUN\], uric acid, creatinine, phosphorus, and potassium)
should be monitored regularly. During clinical trials in adult patients
on dialysis, modest increases were seen in BUN, creatinine, phosphorus,
and potassium. In some adult patients with CRF not on dialysis treated
with PROCRIT^^, modest increases in serum uric acid and phosphorus were
observed. While changes were statistically significant, the values
remained within the ranges normally seen in patients with CRF.

**Diet**

As the hematocrit increases and patients experience an improved sense of
well-being and quality of life, the importance of compliance with
dietary and dialysis prescriptions should be reinforced. In particular,
hyperkalemia is not uncommon in patients with CRF. In US studies in
patients on dialysis, hyperkalemia has occurred at an annualized rate of
approximately 0.11 episodes per patient-year of PROCRIT^^ therapy,
often in association with poor compliance to medication, diet, and/or
dialysis.

**Dialysis Management**

Therapy with PROCRIT^^ results in an increase in hematocrit and a
decrease in plasma volume which could affect dialysis efficiency. In
studies to date, the resulting increase in hematocrit did not appear to
adversely affect dialyzer function^9,10^ or the efficiency of high flux
hemodialysis.^11^ During hemodialysis, patients treated with PROCRIT^^
may require increased anticoagulation with heparin to prevent clotting
of the artificial kidney.

Patients who are marginally dialyzed may require adjustments in their
dialysis prescription. As with all patients on dialysis, the serum
chemistry values (including BUN, creatinine, phosphorus, and potassium)
in patients treated with PROCRIT^^ should be monitored regularly to
assure the adequacy of the dialysis prescription.

**[Information for Patients]{.underline}**

In those situations in which the physician determines that a home
dialysis patient can safely and effectively self-administer PROCRIT^^,
the patient should be instructed as to the proper dosage and
administration. Home dialysis patients should be referred to the full
"Information For Home Dialysis Patients" insert; it is not a disclosure
of all possible effects. Patients should be informed of the signs and
symptoms of allergic drug reaction and advised of appropriate actions.
If home use is prescribed for a home dialysis patient, the patient
should be thoroughly instructed in the importance of proper disposal and
cautioned against the reuse of needles, syringes, or drug product. A
puncture-resistant container for the disposal of used syringes and
needles should be available to the patient. The full container should be
disposed of according to the directions provided by the physician.

**Renal Function**

In adult patients with CRF not on dialysis, renal function and fluid and
electrolyte balance should be closely monitored, as an improved sense of
well-being may obscure the need to initiate dialysis in some patients.
In patients with CRF not on dialysis, placebo-controlled studies of
progression of renal dysfunction over periods of greater than 1 year
have not been completed. In shorter term trials in adult patients with
CRF not on dialysis, changes in creatinine and creatinine clearance were
not significantly different in patients treated with PROCRIT^^ compared
with placebo-treated patients. Analysis of the slope of 1/serum
creatinine versus time plots in these patients indicates no significant
change in the slope after the initiation of PROCRIT^^ therapy.

***Zidovudine-treated HIV-infected Patients***

**Hypertension**

Exacerbation of hypertension has not been observed in zidovudine-treated
HIV-infected patients treated with PROCRIT^^. However, PROCRIT^^
should be withheld in these patients if pre-existing hypertension is
uncontrolled, and should not be started until blood pressure is
controlled. In double-blind studies, a single seizure has been
experienced by a patient treated with PROCRIT^^ .^25^

***Cancer Patients on Chemotherapy***

**Hypertension**

Hypertension, associated with a significant increase in hematocrit, has
been noted rarely in patients treated with PROCRIT^^. Nevertheless,
blood pressure in patients treated with PROCRIT^^ should be monitored
carefully, particularly in patients with an underlying history of
hypertension or cardiovascular disease.

**Seizures**

In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients
treated with PROCRIT^^ and 2.9% (n = 2/68) of placebo-treated patients
had seizures. Seizures in 1.6% (n = 1/63) of patients treated with
PROCRIT^^ occurred in the context of a significant increase in blood
pressure and hematocrit from baseline values. However, both patients
treated with PROCRIT^^ also had underlying CNS pathology which may have
been related to seizure activity.

**Thrombotic Events**

In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients
treated with PROCRIT^^ and 11.8% (n = 8/68) of placebo-treated patients
had thrombotic events (eg, pulmonary embolism, cerebrovascular
accident).

**Growth Factor Potential**

PROCRIT^^ is a growth factor that primarily stimulates red cell
production. However, the possibility that PROCRIT^^ can act as a growth
factor for any tumor type, particularly myeloid malignancies, cannot be
excluded.

***Surgery Patients***

**Thrombotic/Vascular Events**

In perioperative clinical trials with orthopedic patients, the overall
incidence of thrombotic/vascular events was similar in Epoetin alfa and
placebo-treated patients who had a pretreatment hemoglobin of \> 10 to ≤
13 g/dL. In patients with a hemoglobin of \> 13 g/dL treated with 300
Units/kg of Epoetin alfa, the possibility that PROCRIT^^ treatment may
be associated with an increased risk of postoperative
thrombotic/vascular events cannot be excluded. ^18-20,28^

In one study in which Epoetin alfa was administered in the perioperative
period to patients undergoing coronary artery bypass graft surgery,
there were 7 deaths in the group treated with Epoetin alfa (n = 126) and
no deaths in the placebo-treated group (n = 56). Among the 7 deaths in
the patients treated with Epoetin alfa, 4 were at the time of therapy
(between study day 2 and 8). The 4 deaths at the time of therapy (3%)
were associated with thrombotic/vascular events. A causative role of
Epoetin alfa cannot be excluded (see WARNINGS).

**Hypertension**

Blood pressure may rise in the perioperative period in patients being
treated with PROCRIT^^. Therefore, blood pressure should be monitored
carefully.

**ADVERSE REACTIONS**

**[Immunogenicity]{.underline}**

As with all therapeutic proteins, there is the potential for
immunogenicity. The observed incidence of antibody positivity in an
assay may be influenced by several factors including assay methodology,
sample handling, timing of sample collection, concomitant medications,
and underlying disease. For these reasons, comparison of the incidence
of antibodies to PROCRIT^^ with the incidence of antibodies to other
products may be misleading.

A few cases of PRCA associated with antibodies with neutralizing
activity have been reported in patients receiving PROCRIT^^ (see
WARNINGS: PURE RED CELL APLASIA). These cases were observed in patients
treated by either SC or IV routes of administration and occurred
predominantly in CRF patients.

***Chronic Renal Failure Patients***

PROCRIT^^ is generally well-tolerated. The adverse events reported are
frequent sequelae of CRF and are not necessarily attributable to
PROCRIT^^ therapy. In double-blind, placebo-controlled studies
involving over 300 patients with CRF, the events reported in greater
than 5% of patients treated with PROCRIT^^ during the blinded phase
were:

  ----------------------- ----------------- ----------------------- -------------------- ----------------------
                          **Percent Of                                                   
                          Patients                                                       
                          Reporting Event**                                              

  **Event**               **Patients                                **Placebo-treated\   
                          Treated With\                             Patients\            
                          PROCRIT**^^**\                           (n = 135)**          
                          (n = 200)**                                                    

  Hypertension            24%                                       19%                  

  Headache                16%                                       12%                  

  Arthralgias             11%                                       6%                   

  Nausea                  11%                                       9%                   

  Edema                   9%                                        10%                  

  Fatigue                 9%                                        14%                  

  Diarrhea                9%                                        6%                   

  Vomiting                8%                                        5%                   

  Chest Pain              7%                                        9%                   

  Skin Reaction           7%                                        12%                  
  (Administration Site)                                                                  

  Asthenia                7%                                        12%                  

  Dizziness               7%                                        13%                  

  Clotted Access          7%                                        2%                   

  Significant adverse                                                                    
  events of concern in                                                                   
  patients with CRF                                                                      
  treated in                                                                             
  double-blind,                                                                          
  placebo-controlled                                                                     
  trials occurred in the                                                                 
  following percent of                                                                   
  patients during the                                                                    
  blinded phase of the                                                                   
  studies:                                                                               

  Seizure                                   1.1%                                         1.1%

  CVA/TIA                                   0.4%                                         0.6%

  MI                                        0.4%                                         1.1%

  Death                                     0                                            1.7%
  ----------------------- ----------------- ----------------------- -------------------- ----------------------

In the US PROCRIT^^ studies in adult patients on dialysis (over 567
patients), the incidence (number of events per patient-year) of the most
frequently reported adverse events were: hypertension (0.75), headache
(0.40), tachycardia (0.31), nausea/vomiting (0.26), clotted vascular
access (0.25), shortness of breath (0.14), hyperkalemia (0.11), and
diarrhea (0.11). Other reported events occurred at a rate of less than
0.10 events per patient per year.

Events reported to have occurred within several hours of administration
of PROCRIT^^ were rare, mild, and transient, and included injection
site stinging in dialysis patients and flu-like symptoms such as
arthralgias and myalgias.

In all studies analyzed to date, PROCRIT^^ administration was generally
well-tolerated, irrespective of the route of administration.

*Pediatric CRF Patients:* In pediatric patients with CRF on dialysis,
the pattern of most adverse events was similar to that found in adults.
Additional adverse events reported during the double-blind phase in \>
10% of pediatric patients in either treatment group were: abdominal
pain, dialysis access complications including access infections and
peritonitis in those receiving peritoneal dialysis, fever, upper
respiratory infection, cough, pharyngitis, and constipation. The rates
are similar between the treatment groups for each event.

**Hypertension:** Increases in blood pressure have been reported in
clinical trials, often during the first 90 days of therapy. On occasion,
hypertensive encephalopathy and seizures have been observed in patients
with CRF treated with PROCRIT^^. When data from all patients in the US
phase 3 multicenter trial were analyzed, there was an apparent trend of
more reports of hypertensive adverse events in patients on dialysis with
a faster rate of rise of hematocrit (greater than 4 hematocrit points in
any 2-week period). However, in a double-blind, placebo-controlled
trial, hypertensive adverse events were not reported at an increased
rate in the group treated with PROCRIT^^ (150 Units/kg TIW) relative to
the placebo group.

**Seizures:** There have been 47 seizures in 1010 patients on dialysis
treated with PROCRIT^^ in clinical trials, with an exposure of 986
patient-years for a rate of approximately 0.048 events per patient-year.
However, there appeared to be a higher rate of seizures during the first
90 days of therapy (occurring in approximately 2.5% of patients) when
compared to subsequent 90-day periods. The baseline incidence of
seizures in the untreated dialysis population is difficult to determine;
it appears to be in the range of 5% to 10% per patient-year.^39-41^

**Thrombotic Events:** In clinical trials where the maintenance
hematocrit was 35 ± 3% on PROCRIT^^, clotting of the vascular access
(A-V shunt) has occurred at an annualized rate of about 0.25 events per
patient-year, and other thrombotic events (eg, myocardial infarction,
cerebral vascular accident, transient ischemic attack, and pulmonary
embolism) occurred at a rate of 0.04 events per patient-year. In a
separate study of 1111 untreated dialysis patients, clotting of the
vascular access occurred at a rate of 0.50 events per patient-year.
However, in CRF patients on hemodialysis who also had clinically evident
ischemic heart disease or congestive heart failure, the risk of A-V
shunt thrombosis was higher (39% vs 29%, p \< 0.001), and myocardial
infarction, vascular ischemic events, and venous thrombosis were
increased, in patients targeted to a hematocrit of 42 ± 3% compared to
those maintained at 30 ± 3% (see WARNINGS).

In patients treated with commercial PROCRIT^^, there have been rare
reports of serious or unusual thrombo-embolic events including migratory
thrombophlebitis, microvascular thrombosis, pulmonary embolus, and
thrombosis of the retinal artery, and temporal and renal veins. A causal
relationship has not been established.

**Allergic Reactions:** There have been no reports of serious allergic
reactions or anaphylaxis associated with PROCRIT^^ administration
during clinical trials. Skin rashes and urticaria have been observed
rarely and when reported have generally been mild and transient in
nature.

There have been rare reports of potentially serious allergic reactions
including urticaria with associated respiratory symptoms or circumoral
edema, or urticaria alone. Most reactions occurred in situations where a
causal relationship could not be established. Symptoms recurred with
rechallenge in a few instances, suggesting that allergic reactivity may
occasionally be associated with PROCRIT^^ therapy.

If an anaphylactoid reaction occurs, PROCRIT^^ should be immediately
discontinued and appropriate therapy initiated.

***Zidovudine-treated HIV-infected Patients***

Adverse events reported in clinical trials with PROCRIT^^ in
zidovudine-treated HIV-infected patients were consistent with the
progression of HIV infection. In double-blind, placebo-controlled
studies of 3 months duration involving approximately 300
zidovudine-treated HIV-infected patients, adverse events with an
incidence of ≥ 10% in either patients treated with PROCRIT^^ or
placebo-treated patients were:

+-------------------------+-----------------------+--------------------+
|                         | ####### Pe            |                    |
|                         | rcent of Patients Rep |                    |
|                         | orting Event {#percen |                    |
|                         | t-of-patients-reporti |                    |
|                         | ng-event .unnumbered} |                    |
+-------------------------+-----------------------+--------------------+
| **Event**               | **Patients Treated    | **Placebo-treated  |
|                         | With PROCRIT**^^**\  | Patients\          |
|                         | (n = 144)**           | (n = 153)**        |
+-------------------------+-----------------------+--------------------+
| Pyrexia                 | 38%                   | 29%                |
+-------------------------+-----------------------+--------------------+
| Fatigue                 | 25%                   | 31%                |
+-------------------------+-----------------------+--------------------+
| Headache                | 19%                   | 14%                |
+-------------------------+-----------------------+--------------------+
| Cough                   | 18%                   | 14%                |
+-------------------------+-----------------------+--------------------+
| Diarrhea                | 16%                   | 18%                |
+-------------------------+-----------------------+--------------------+
| Rash                    | 16%                   | 8%                 |
+-------------------------+-----------------------+--------------------+
| Congestion,\            | 15%                   | 10%                |
| Respiratory             |                       |                    |
+-------------------------+-----------------------+--------------------+
| Nausea                  | 15%                   | 12%                |
+-------------------------+-----------------------+--------------------+
| Shortness of Breath     | 14%                   | 13%                |
+-------------------------+-----------------------+--------------------+
| Asthenia                | 11%                   | 14%                |
+-------------------------+-----------------------+--------------------+
| Skin Reaction\          | 10%                   | 7%                 |
| Medication Site         |                       |                    |
+-------------------------+-----------------------+--------------------+
| Dizziness               | 9%                    | 10%                |
+-------------------------+-----------------------+--------------------+

There were no statistically significant differences between treatment
groups in the incidence of the above events.

In the 297 patients studied, PROCRIT^^ was not associated with
significant increases in opportunistic infections or mortality.^25^ In
71 patients from this group treated with PROCRIT^^ at 150 Units/kg TIW,
serum p24 antigen levels did not appear to increase.^27^ Preliminary
data showed no enhancement of HIV replication in infected cell lines in
vitro.^25^

Peripheral white blood cell and platelet counts are unchanged following
PROCRIT^^ therapy.

**Allergic Reactions:** Two zidovudine-treated HIV-infected patients had
urticarial reactions within 48 hours of their first exposure to study
medication. One patient was treated with PROCRIT^^ and one was treated
with placebo (PROCRIT^^ vehicle alone). Both patients had positive
immediate skin tests against their study medication with a negative
saline control. The basis for this apparent pre-existing
hypersensitivity to components of the PROCRIT^^ formulation is unknown,
but may be related to HIV-induced immunosuppression or prior exposure to
blood products.

**Seizures:** In double-blind and open-label trials of PROCRIT^^ in
zidovudine-treated HIV-infected patients, 10 patients have experienced
seizures.^25^ In general, these seizures appear to be related to
underlying pathology such as meningitis or cerebral neoplasms, not
PROCRIT^^ therapy.

***Cancer Patients on Chemotherapy***

Adverse experiences reported in clinical trials with PROCRIT^^ in
cancer patients were consistent with the underlying disease state. In
double-blind, placebo-controlled studies of up to 3 months duration
involving 131 cancer patients, adverse events with an incidence \> 10%
in either patients treated with PROCRIT^^ or placebo-treated patients
were as indicated below:

+-----------------------+----------------------+----------------------+
| #######  {            | ####### Percent      |                      |
| #section .unnumbered} | of Patients Reportin |                      |
|                       | g Event {#percent-of |                      |
|                       | -patients-reporting- |                      |
|                       | event-1 .unnumbered} |                      |
+-----------------------+----------------------+----------------------+
| **\                   | **Patients Treated   | **Placebo-treated**  |
| \                     | With PROCRIT**^^**\ |                      |
| Event**               | (n = 63)**           | **Patients\          |
|                       |                      | (n = 68)**           |
+-----------------------+----------------------+----------------------+
| Pyrexia               | 29%                  | 19%                  |
+-----------------------+----------------------+----------------------+
| Diarrhea              | 21% ^a^              | 7%                   |
+-----------------------+----------------------+----------------------+
| Nausea                | 17% ^b^              | 32%                  |
+-----------------------+----------------------+----------------------+
| Vomiting              | 17%                  | 15%                  |
+-----------------------+----------------------+----------------------+
| Edema                 | 17% ^c^              | 1%                   |
+-----------------------+----------------------+----------------------+
| Asthenia              | 13%                  | 16%                  |
+-----------------------+----------------------+----------------------+
| Fatigue               | 13%                  | 15%                  |
+-----------------------+----------------------+----------------------+
| Shortness of Breath   | 13%                  | 9%                   |
+-----------------------+----------------------+----------------------+
| Paresthesia           | 11%                  | 6%                   |
+-----------------------+----------------------+----------------------+
| Upper Respiratory\    | 11%                  | 4%                   |
| Infection             |                      |                      |
+-----------------------+----------------------+----------------------+
| Dizziness             | 5%                   | 12%                  |
+-----------------------+----------------------+----------------------+
| Trunk Pain            | 3% ^d^               | 16%                  |
+-----------------------+----------------------+----------------------+
| ^a^ p = 0.041 ^b^ p = |                      |                      |
| 0.069 ^c^ p = 0.0016  |                      |                      |
| ^d^p = 0.017          |                      |                      |
+-----------------------+----------------------+----------------------+

Although some statistically significant differences between patients
treated with PROCRIT^^ and placebo-treated patients were noted, the
overall safety profile of PROCRIT^^ appeared to be consistent with the
disease process of advanced cancer. During double-blind and subsequent
open-label therapy in which patients (n = 72 for total exposure to
PROCRIT^^) were treated for up to 32 weeks with doses as high as 927
Units/kg, the adverse experience profile of PROCRIT^^ was consistent
with the progression of advanced cancer.

Based on comparable survival data and on the percentage of patients
treated with PROCRIT^^ and placebo-treated patients who discontinued
therapy due to death, disease progression, or adverse experiences (22%
and 13%, respectively; p = 0.25), the clinical outcome in patients
treated with PROCRIT^^ and placebo-treated patients appeared to be
similar. Available data from animal tumor models and measurement of
proliferation of solid tumor cells from clinical biopsy specimens in
response to PROCRIT^^ suggest that PROCRIT^^ does not potentiate tumor
growth. Nevertheless, as a growth factor, the possibility that
PROCRIT^^ may potentiate growth of some tumors, particularly myeloid
tumors, cannot be excluded. A randomized controlled phase 4 study is
currently ongoing to further evaluate this issue.

The mean peripheral white blood cell count was unchanged following
PROCRIT^^ therapy compared to the corresponding value in the
placebo-treated group.

***Surgery Patients***

Adverse events with an incidence of ≥ 10% are shown in the following
table:

+------------------+---------+---------+--------+---------+---------+
|                  | **      |         |        |         |         |
|                  | Percent |         |        |         |         |
|                  | of      |         |        |         |         |
|                  | P       |         |        |         |         |
|                  | atients |         |        |         |         |
|                  | Re      |         |        |         |         |
|                  | porting |         |        |         |         |
|                  | Event** |         |        |         |         |
+------------------+---------+---------+--------+---------+---------+
| **\              | **Pa    | **P     | **Pla  | **P     | **P     |
| \                | tients\ | atients | cebo-t | atients | atients |
| \                | T       | T       | reated | T       | T       |
| \                | reated\ | reated\ | Pat    | reated\ | reated\ |
| Event**          | With    | With    | ients\ | With\   | With\   |
|                  | P       | P       | \      | P       | P       |
|                  | ROCRIT* | ROCRIT* | \      | ROCRIT* | ROCRIT* |
|                  | *^^**\ | *^^**\ | (n =   | *^^**\ | *^^**\ |
|                  | 300     | 100     | 103)   | 600     | 300     |
|                  | U/kg\   | U/kg\   | ^a^**  | U/kg\   | U/kg\   |
|                  | (n =    | (n =    |        | (n =    | (n =    |
|                  | 112)    | 101)    |        | 73)     | 7       |
|                  | ^a^**   | ^a^**   |        | ^b^**   | 2)^b^** |
+------------------+---------+---------+--------+---------+---------+
| Pyrexia          | 51%     | 50%     | 60%    | 47%     | 42%     |
+------------------+---------+---------+--------+---------+---------+
| Nausea           | 48%     | 43%     | 45%    | 45%     | 58%     |
+------------------+---------+---------+--------+---------+---------+
| Constipation     | 43%     | 42%     | 43%    | 51%     | 53%     |
+------------------+---------+---------+--------+---------+---------+
| Skin Reaction,\  | 25%     | 19%     | 22%    | 26%     | 29%     |
| Medication Site  |         |         |        |         |         |
+------------------+---------+---------+--------+---------+---------+
| Vomiting         | 22%     | 12%     | 14%    | 21%     | 29%     |
+------------------+---------+---------+--------+---------+---------+
| Skin Pain        | 18%     | 18%     | 17%    | 5%      | 4%      |
+------------------+---------+---------+--------+---------+---------+
| Pruritus         | 16%     | 16%     | 14%    | 14%     | 22%     |
+------------------+---------+---------+--------+---------+---------+
| Insomnia         | 13%     | 16%     | 13%    | 21%     | 18%     |
+------------------+---------+---------+--------+---------+---------+
| Headache         | 13%     | 11%     | 9%     | 10%     | 19%     |
+------------------+---------+---------+--------+---------+---------+
| Dizziness        | 12%     | 9%      | 12%    | 11%     | 21%     |
+------------------+---------+---------+--------+---------+---------+
| Urinary Tract\   | 12%     | 3%      | 11%    | 11%     | 8%      |
| Infection        |         |         |        |         |         |
+------------------+---------+---------+--------+---------+---------+
| Hypertension     | 10%     | 11%     | 10%    | 5%      | 10%     |
+------------------+---------+---------+--------+---------+---------+
| Diarrhea         | 10%     | 7%      | 12%    | 10%     | 6%      |
+------------------+---------+---------+--------+---------+---------+
| Deep Venous\     | 10%     | 3%      | 5%     | 0%^c^   | 0%^c^   |
| Thrombosis       |         |         |        |         |         |
+------------------+---------+---------+--------+---------+---------+
| Dyspepsia        | 9%      | 11%     | 6%     | 7%      | 8%      |
+------------------+---------+---------+--------+---------+---------+
| Anxiety          | 7%      | 2%      | 11%    | 11%     | 4%      |
+------------------+---------+---------+--------+---------+---------+
| Edema            | 6%      | 11%     | 8%21a  | 11%     | 7%      |
+------------------+---------+---------+--------+---------+---------+
| ^a^ Study        |         |         |        |         |         |
| including        |         |         |        |         |         |
| patients         |         |         |        |         |         |
| undergoing       |         |         |        |         |         |
| orthopedic       |         |         |        |         |         |
| surgery treated  |         |         |        |         |         |
| with PROCRIT^^  |         |         |        |         |         |
| or placebo for   |         |         |        |         |         |
| 15 days          |         |         |        |         |         |
|                  |         |         |        |         |         |
| ^b^ Study        |         |         |        |         |         |
| including        |         |         |        |         |         |
| patients         |         |         |        |         |         |
| undergoing       |         |         |        |         |         |
| orthopedic       |         |         |        |         |         |
| surgery treated  |         |         |        |         |         |
| with PROCRIT^^  |         |         |        |         |         |
| 600 Units/kg     |         |         |        |         |         |
| weekly x 4 or    |         |         |        |         |         |
| 300 Units/kg     |         |         |        |         |         |
| daily x 15       |         |         |        |         |         |
|                  |         |         |        |         |         |
| ^c^ Determined   |         |         |        |         |         |
| by clinical      |         |         |        |         |         |
| symptoms         |         |         |        |         |         |
+------------------+---------+---------+--------+---------+---------+

**Thrombotic/Vascular Events:** In three double-blind,
placebo-controlled orthopedic surgery studies, the rate of deep venous
thrombosis (DVT) was similar among Epoetin alfa and placebo-treated
patients in the recommended population of patients with a pretreatment
hemoglobin of \> 10 to ≤ 13 g/dL.^18,20,28^ However, in 2 of 3
orthopedic surgery studies the overall rate (all pretreatment hemoglobin
groups combined) of DVTs detected by postoperative ultrasonography
and/or surveillance venography was higher in the group treated with
Epoetin alfa than in the placebo-treated group (11% vs 6%). This finding
was attributable to the difference in DVT rates observed in the subgroup
of patients with pretreatment hemoglobin \> 13 g/dL. However, the
incidence of DVTs was within the range of that reported in the
literature for orthopedic surgery patients.

In the orthopedic surgery study of patients with pretreatment hemoglobin
of \> 10 to ≤ 13 g/dL which compared two dosing regimens (600 Units/kg
weekly x 4 and 300 Units/kg daily x 15), 4 subjects in the 600 Units/kg
weekly PROCRIT^^ group (5%) and no subjects in the 300 Units/kg daily
group had a thrombotic vascular event during the study period. ^19^

In a study examining the use of Epoetin alfa in 182 patients scheduled
for coronary artery bypass graft surgery, 23% of patients treated with
Epoetin alfa and 29% treated with placebo experienced
thrombotic/vascular events. There were 4 deaths among the Epoetin
alfa-treated patients that were associated with a thrombotic/vascular
event. A causative role of Epoetin alfa cannot be excluded (see
WARNINGS).

**OVERDOSAGE**

The maximum amount of PROCRIT^^ that can be safely administered in
single or multiple doses has not been determined. Doses of up to 1500
Units/kg TIW for 3 to 4 weeks have been administered to adults without
any direct toxic effects of PROCRIT^^ itself.^6^ Therapy with
PROCRIT^^ can result in polycythemia if the hematocrit is not carefully
monitored and the dose appropriately adjusted. If the suggested target
range is exceeded, PROCRIT^^ may be temporarily withheld until the
hematocrit returns to the suggested target range; PROCRIT^^ therapy may
then be resumed using a lower dose (see DOSAGE AND ADMINISTRATION). If
polycythemia is of concern, phlebotomy may be indicated to decrease the
hematocrit.

**DOSAGE AND ADMINISTRATION**

***Chronic Renal Failure Patients***

The recommended range for the starting dose of PROCRIT^^ is 50 to 100
Units/kg TIW for adult patients. The recommended starting dose for
pediatric CRF patients on dialysis is 50 Units/kg TIW. The dose of
PROCRIT^^ should be reduced as the hematocrit approaches 36% or
increases by more than 4 points in any 2-week period. The dosage of
PROCRIT^^ must be individualized to maintain the hematocrit within the
suggested target range. At the physician's discretion, the suggested
target hematocrit range may be expanded to achieve maximal patient
benefit.

PROCRIT^^ may be given either as an IV or SC injection. In patients on
hemodialysis, PROCRIT^^ usually has been administered as an IV bolus
TIW. While the administration of PROCRIT^^ is independent of the
dialysis procedure, PROCRIT^^ may be administered into the venous line
at the end of the dialysis procedure to obviate the need for additional
venous access. In adult patients with CRF not on dialysis, PROCRIT^^
may be given either as an IV or SC injection.

Patients who have been judged competent by their physicians to
self-administer PROCRIT^^ without medical or other supervision may give
themselves either an IV or SC injection. The table below provides
general therapeutic guidelines for patients with CRF:

+-----------------------------+----------------------------------------+
| **Starting Dose:**          |                                        |
+-----------------------------+----------------------------------------+
| Adults                      | 50 to 100 Units/kg TIW; IV or SC       |
+-----------------------------+----------------------------------------+
| Pediatric Patients          | 50 Units/kg TIW; IV or SC              |
+-----------------------------+----------------------------------------+
|                             |                                        |
+-----------------------------+----------------------------------------+
| **Reduce Dose When:**       | 1\. Hct. approaches 36% or,\           |
|                             | 2. Hct. increases \> 4 points in any   |
|                             | 2-week period                          |
+-----------------------------+----------------------------------------+
|                             |                                        |
+-----------------------------+----------------------------------------+
| **Increase Dose If:**       | Hct. does not increase by 5 to 6 point |
|                             | after 8 weeks of therapy, and hct. is  |
|                             | below suggested target range           |
+-----------------------------+----------------------------------------+
|                             |                                        |
+-----------------------------+----------------------------------------+
| **Maintenance Dose:**       | Individually titrate                   |
+-----------------------------+----------------------------------------+
|                             |                                        |
+-----------------------------+----------------------------------------+
| **Suggested Target**        | 30% to 36%                             |
|                             |                                        |
| **Hct. Range:**             |                                        |
+-----------------------------+----------------------------------------+

During therapy, hematological parameters should be monitored regularly
(see LABORATORY MONITORING).

**Pretherapy Iron Evaluation:** Prior to and during PROCRIT^^ therapy,
the patient's iron stores, including transferrin saturation (serum iron
divided by iron binding capacity) and serum ferritin, should be
evaluated. Transferrin saturation should be at least 20%, and ferritin
should be at least 100 ng/mL. Virtually all patients will eventually
require supplemental iron to increase or maintain transferrin saturation
to levels that will adequately support erythropoiesis stimulated by
PROCRIT^^.

**Dose Adjustment:** Following PROCRIT^^ therapy, a period of time is
required for erythroid progenitors to mature and be released into
circulation resulting in an eventual increase in hematocrit.
Additionally, red blood cell survival time affects hematocrit and may
vary due to uremia. As a result, the time required to elicit a
clinically significant change in hematocrit (increase or decrease)
following any dose adjustment may be 2 to 6 weeks.

Dose adjustment should not be made more frequently than once a month,
unless clinically indicated. After any dose adjustment, the hematocrit
should be determined twice weekly for at least 2 to 6 weeks (see
LABORATORY MONITORING).

• If the hematocrit is increasing and approaching 36%, the dose should
be reduced to maintain the suggested target hematocrit range. If the
reduced dose does not stop the rise in hematocrit, and it exceeds 36%,
doses should be temporarily withheld until the hematocrit begins to
decrease, at which point therapy should be reinitiated at a lower dose.

• At any time, if the hematocrit increases by more than 4 points in a
2-week period, the dose should be immediately decreased. After the dose
reduction, the hematocrit should be monitored twice weekly for 2 to 6
weeks, and further dose adjustments should be made as outlined in
MAINTENANCE DOSE.

• If a hematocrit increase of 5 to 6 points is not achieved after an
8-week period and iron stores are adequate (see LACK OR LOSS OF
RESPONSE), the dose of PROCRIT^^ may be incrementally increased.
Further increases may be made at 4 to 6 week intervals until the desired
response is attained.

**Maintenance Dose:** The maintenance dose must be individualized for
each patient on dialysis. In the US phase 3 multicenter trial in
patients on hemodialysis, the median maintenance dose was 75 Units/kg
TIW, with a range from 12.5 to 525 Units/kg TIW. Almost 10% of the
patients required a dose of 25 Units/kg, or less, and approximately 10%
of the patients required more than 200 Units/kg TIW to maintain their
hematocrit in the suggested target range. In pediatric hemodialysis and
peritoneal dialysis patients, the median maintenance dose was 167
Units/kg/week (49 to 447 Units/kg per week) and 76 Units/kg per week (24
to 323 Units/kg/week) administered in divided doses (TIW or BIW),
respectively to achieve the target range of 30% to 36%.

If the hematocrit remains below, or falls below, the suggested target
range, iron stores should be re-evaluated. If the transferrin saturation
is less than 20%, supplemental iron should be administered. If the
transferrin saturation is greater than 20%, the dose of PROCRIT^^ may
be increased. Such dose increases should not be made more frequently
than once a month, unless clinically indicated, as the response time of
the hematocrit to a dose increase can be 2 to 6 weeks. Hematocrit should
be measured twice weekly for 2 to 6 weeks following dose increases. In
adult patients with CRF not on dialysis, the maintenance dose must also
be individualized. PROCRIT^^ doses of 75 to 150 Units/kg/week have been
shown to maintain hematocrits of 36% to 38% for up to 6 months.

**Lack or Loss of Response:** Over 95% of patients with CRF responded
with clinically significant increases in hematocrit, and virtually all
patients were transfusion-independent within approximately 2 months of
initiation of PROCRIT^^ therapy.

If a patient fails to respond or maintain a response, other etiologies
should be considered and evaluated as clinically indicated (See
PRECAUTIONS: LACK OR LOSS OF RESPONSE).

***Zidovudine-treated HIV-infected Patients***

Prior to beginning PROCRIT^^, it is recommended that the endogenous
serum erythropoietin level be determined (prior to transfusion).
Available evidence suggests that patients receiving zidovudine with
endogenous serum erythropoietin levels \> 500 mUnits/mL are unlikely to
respond to therapy with PROCRIT^^.

**Starting Dose**: For adult patients with serum erythropoietin levels ≤
500 mUnits/mL who are receiving a dose of zidovudine ≤ 4200 mg/week, the
recommended starting dose of PROCRIT^^ is 100 Units/kg as an IV or SC
injection TIW for 8 weeks. For pediatric patients, see PRECAUTIONS:
PEDIATRIC USE.

**Increase Dose**: During the dose adjustment phase of therapy, the
hematocrit should be monitored weekly. If the response is not
satisfactory in terms of reducing transfusion requirements or increasing
hematocrit after 8 weeks of therapy, the dose of PROCRIT^^ can be
increased by 50 to 100 Units/kg TIW. Response should be evaluated every
4 to 8 weeks thereafter and the dose adjusted accordingly by 50 to 100
Units/kg increments TIW. If patients have not responded satisfactorily
to a PROCRIT^^ dose of 300 Units/kg TIW, it is unlikely that they will
respond to higher doses of PROCRIT^^.

**Maintenance Dose:** After attainment of the desired response (ie,
reduced transfusion requirements or increased hematocrit), the dose of
PROCRIT^^ should be titrated to maintain the response based on factors
such as variations in zidovudine dose and the presence of intercurrent
infectious or inflammatory episodes. If the hematocrit exceeds 40%, the
dose should be discontinued until the hematocrit drops to 36%. The dose
should be reduced by 25% when treatment is resumed and then titrated to
maintain the desired hematocrit.

***Cancer Patients on Chemotherapy***

Baseline endogenous serum erythropoietin levels varied among patients in
these trials with approximately 75% (n = 83/110) having endogenous serum
erythropoietin levels \< 132 mUnits/mL, and approximately 4% (n = 4/110)
of patients having endogenous serum erythropoietin levels \> 500
mUnits/mL. In general, patients with lower baseline serum erythropoietin
levels responded more vigorously to PROCRIT^^ than patients with higher
erythropoietin levels. Although no specific serum erythropoietin level
can be stipulated above which patients would be unlikely to respond to
PROCRIT^^ therapy, treatment of patients with grossly elevated serum
erythropoietin levels (eg, \> 200 mUnits/mL) is not recommended. The
hematocrit should be monitored on a weekly basis in patients receiving
PROCRIT^^ therapy until hematocrit becomes stable.

**Starting Dose:** The recommended starting dose of PROCRIT^^ for
adults is 150 Units/kg SC TIW. For pediatric patients, see PRECAUTIONS:
PEDIATRIC USE.

**Dose Adjustment:** If the response is not satisfactory in terms of
reducing transfusion requirements or increasing hematocrit after 8 weeks
of therapy, the dose of PROCRIT^^ can be increased up to 300 Units/kg
TIW. If patients have not responded satisfactorily to a PROCRIT^^ dose
of 300 Units/kg TIW, it is unlikely that they will respond to higher
doses of PROCRIT^^. If the hematocrit exceeds 40%, the dose of
PROCRIT^^ should be withheld until the hematocrit falls to 36%. The
dose of PROCRIT^^ should be reduced by 25% when treatment is resumed
and titrated to maintain the desired hematocrit. If the initial dose of
PROCRIT^^ includes a very rapid hematocrit response (eg, an increase of
more than 4 percentage points in any 2-week period), the dose of
PROCRIT^^ should be reduced.

***Surgery Patients***

Prior to initiating treatment with PROCRIT^^ a hemoglobin should be
obtained to establish that it is \> 10 to ≤ 13 g/dL.^18^ The recommended
dose of PROCRIT^^ is 300 Units/kg/day subcutaneously for 10 days before
surgery, on the day of surgery, and for 4 days after surgery.

An alternate dose schedule is 600 Units/kg PROCRIT^^ subcutaneously in
once weekly doses (21, 14 and 7 days before surgery) plus a fourth dose
on day of surgery.^19^

All patients should receive adequate iron supplementation. Iron
supplementation should be initiated no later than the beginning of
treatment with PROCRIT^^ and should continue throughout the course of
therapy.

**PREPARATION AND ADMINISTRATION OF PROCRIT**^^

1\. Do not shake. It is not necessary to shake PROCRIT^^. Prolonged
vigorous shaking may denature any glycoprotein, rendering it
biologically inactive.

2\. Parenteral drug products should be inspected visually for
particulate matter and discoloration prior to administration. Do not use
any vials exhibiting particulate matter or discoloration.

3\. Using aseptic techniques, attach a sterile needle to a sterile
syringe. Remove the flip top from the vial containing PROCRIT^^, and
wipe the septum with a disinfectant. Insert the needle into the vial,
and withdraw into the syringe an appropriate volume of solution.

4\. **Single-dose:** 1 mL vial contains no preservative. Use one dose
per vial; do not re-enter vial. Discard unused portions.

> **Multidose:** 1 mL and 2 mL vials contain preservative. Store at 2°
> to 8°C after initial entry and between doses. Discard 21 days after
> initial entry.

5\. Do not dilute or administer in conjunction with other drug
solutions. However, at the time of SC administration, preservative-free
PROCRIT^^ from single-use vials may be admixed in a syringe with
bacteriostatic 0.9% sodium chloride injection, USP, with benzyl alcohol
0.9% (bacteriostatic saline) at a 1:1 ratio using aseptic technique. The
benzyl alcohol in the bacteriostatic saline acts as a local anesthetic
which may ameliorate SC injection site discomfort. Admixing is not
necessary when using the multidose vials of PROCRIT^^ containing benzyl
alcohol.

**HOW SUPPLIED**

PROCRIT^^, containing Epoetin alfa, is available in vials containing
color coded labels and caps.

1 mL **Single-Dose, Preservative-free** Solution

Each dosage form is supplied in the following packages:

Cartons containing six (6) **single-dose** vials:

> 2000 Units/mL (NDC 59676-302-01) (Purple)
>
> 3000 Units/mL (NDC 59676-303-01) (Magenta)
>
> 4000 Units/mL (NDC 59676-304-01) (Green)
>
> 10,000 Units/mL (NDC 59676-310-01) (Red)

Cartons containing four (4**) single-dose** vials:

> 40,000 Units/mL (NDC 59676-340-01) (Orange)

Trays containing twenty-five (25) **single-dose** vials:

> 2000 Units/mL (NDC 59676-302-02) (Purple)
>
> 3000 Units/mL (NDC 59676-303-02) (Magenta)
>
> 4000 Units/mL (NDC 59676-304-02) (Green)
>
> 10,000 Units/mL (NDC 59676-310-02) (Red)

2 mL **Multidose, Preserved** Solution

Cartons containing six (6) **multidose** vials:

> 10,000 Units/mL (NDC 59676-312-01) (Blue)

1 mL **Multidose, Preserved** Solution

Cartons containing six (6) **multidose** vials:

> 20,000 Units/mL (NDC 59676-320-01) (Lime)

**STORAGE**

**Store at 2° to 8° C (36° to 46° F). Do not freeze or shake.**

**REFERENCES:**

1\. Egrie JC, Strickland TW, Lane J, et al. Characterization and
Biological Effects of Recombinant Human Erythropoietin. *Immunobiol*.
1986;72:213-224.

2\. Graber SE, Krantz SB. Erythropoietin and the Control of Red Cell
Production. *Ann Rev Med*. 1978;29:51-66.

3\. Eschbach JW, Adamson JW. Anemia of End-Stage Renal Disease (ESRD).
*Kidney Intl*. 1985;28:1-5.

4\. Eschbach JW, Egrie JC, Downing MR, et al. Correction of the Anemia
of End-Stage Renal Disease with Recombinant Human Erythropoietin.
*NEJM.* 1987;316:73-78.

5\. Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant Human
Erythropoietin in Anemic Patients with End-Stage Renal Disease. *Ann
Intern* *Med*. 1989;111:992-1000.

6\. Eschbach JW, Egrie JC, Downing MR, et al. The Use of Recombinant
Human Erythropoietin (r-HuEPO): Effect in End-Stage Renal Disease
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7\. Egrie JC, Eschbach JW, McGuire T, Adamson JW. Pharmacokinetics of
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(HD) Patients. *Kidney Intl*. 1988;33:262.

8\. Evans RW, Rader B, Manninen DL, et al. The Quality of Life of
Hemodialysis Recipients Treated with Recombinant Human Erythropoietin.
*JAMA.* 1990;263:825-830.

9\. Paganini E, Garcia J, Ellis P, et al. Clinical Sequelae of
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10\. Delano BG, Lundin AP, Golansky R, et al*.* Dialyzer Urea and
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11\. Stivelman J, Van Wyck D, and Ogden D. Use of Recombinant
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12\. Lim VS, DeGowin RL, Zavala D, et al. Recombinant Human
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13\. Stone WJ, Graber SE, Krantz SB, et al. Treatment of the Anemia of
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14\. Braun A, Ding R, Seidel C, Fies T, Kurtz A, Scharer K.
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15\. Geva P, Sherwood JB. Pharmacokinetics of recombinant human
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16\. Jabs K, Grant JR, Harmon W, et al. Pharmacokinetics of Epoetin alfa
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17\. Kling PJ, Widness JA, Guillery EN, Veng-Pedersen P, Peters C,
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19\. Goldberg MA and McCutchen JW. A Safety and Efficacy Comparison
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20\. Faris PM and Ritter MA. The Effects of Recombinant Human
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21\. Lundin AP, Akerman MJH, Chesler RM, et al. Exercise in Hemodialysis
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22\. Amgen Inc., data on file.

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27\. Fischl M, Galpin JE, Levine JD, et al. Recombinant Human
Erythropoietin for Patients with AIDS Treated with Zidovudine. *NEJM.*
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28\. Laupacis A. Effectiveness of Perioperative Recombinant Human
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1993;341:1228-1232.

29\. Kerr DN. Chronic Renal Failure. In: Beeson PB, McDermott W,
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30\. Campos A, Garin EH. Therapy of renal anemia in children and
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31\. Montini G, Zacchello G, Baraldi E*,* et al. Benefits and risks of
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32\. Offner G, Hoyer PF, Latta K, Winkler L, Brodehl J, Scigalla P. One
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1990;4:498-500.

33\. Muller-Wiefel DE, Scigalla P. Specific problems of renal anemia in
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34\. Scharer K, Klare B, Dressel P, Gretz N. Treatment of renal anemia
by subcutaneous erythropoietin in children with preterminal chronic
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35\. Mueller BU, Jacobsen RN, Jarosinski P, et al. Erythropoietin for
zidovudine-associated anemia in children with HIV infection. *Pediatr
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36\. Zuccotti GV, Plebani A, Biasucci G, et al. Granulocyte-colony
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37\. Beck MN, Beck D. Recombinant erythropoietin in acute
chemotherapy-induced anemia of children with cancer. *Med Pediatr
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38\. Bennetts G, Bertolone S, Bray G*,* Dinndorf P, Feusner J, Cairo M.
Erythropoietin reduces volumes of red cell transfusions required in some
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39\. Raskin NH, Fishman RA. Neurologic Disorders in Renal Failure (First
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40\. Raskin NH and Fishman RA. Neurologic Disorders in Renal Failure
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41\. Messing RO, Simon RP. Seizures as a Manifestation of Systemic
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42\. Besarab A, Bolton WK, Browne JK*,* et al. The effects of normal as
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Manufactured by:

Amgen Inc.

One Amgen Center Drive

Thousand Oaks, California 91320-1799

Distributed by:

**Ortho Biotech Products, L.P.**

Raritan, New Jersey 08869-0670

Revised September 2003

© OBPLP 2000 638-10-979-2

Printed in U. S. A.

[]{#__RefHeading___Toc68427464 .anchor}**Attachment 2:** Lancet Letter
to the Editor on EPO-INT-76

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**Attachment 2:** Lancet Letter to the Editor on EPO-INT-76 (Continued)

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[]{#__RefHeading___Toc68427465 .anchor}**Attachment 3:** Henke Lancet
Article

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**Attachment 3:** Henke Lancet Article (Continued)

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**Attachment 3:** Henke Lancet Article (Continued)

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**Attachment 3:** Henke Lancet Article (Continued)

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**Attachment 3:** Henke Lancet Article (Continued)

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**Attachment 3:** Henke Lancet Article (Continued)

![](media/image16.png){width="6.030555555555556in"
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**Attachment 3:** Henke Lancet Article (Continued)

![](media/image17.png){width="6.284722222222222in"
height="8.526388888888889in"}

<table style="width:100%;">
<colgroup>
<col style="width: 17%" />
<col style="width: 0%" />
<col style="width: 32%" />
<col style="width: 0%" />
<col style="width: 27%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 4%" />
<col style="width: 0%" />
<col style="width: 4%" />
<col style="width: 0%" />
<col style="width: 6%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="14"><span id="__RefHeading___Toc68427466"
class="anchor"></span><strong>Attachment 4:</strong> Overview and Design
of PROCRIT and EPREX Clinical Studies in Oncology</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="8">No. of Subjects<sup>a</sup></td>
</tr>
<tr class="odd">
<td colspan="2">Protocol</td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="7">DB Phase</td>
<td>OL Phase</td>
</tr>
<tr class="even">
<td colspan="2">(Country)</td>
<td colspan="2">Study Type</td>
<td colspan="2">Dose Regimen</td>
<td colspan="2">EPO</td>
<td colspan="3">PBO</td>
<td colspan="2"><strong>Total</strong></td>
<td>EPO</td>
</tr>
<tr class="odd">
<td colspan="9"><strong>Completed studies</strong></td>
<td colspan="5"></td>
</tr>
<tr class="even">
<td>Non-Chemotherapy<sup>b</sup> (H87‑032, 87-014, 87-015)<br />
(U.S.)</td>
<td colspan="2"><strong>Type:</strong> Parallel-group, multicenter
studies in subjects with chronic anemia secondary to advanced mixed
cancers who are not receiving chemotherapy. DB phase followed by OL
extension.</td>
<td colspan="2">100 IU/kg PROCRIT or PBO s.c., t.i.w. for up to 8 weeks
or until a hematocrit of 38%-40% was achieved.</td>
<td colspan="2">65</td>
<td colspan="3">59</td>
<td colspan="2"><strong>124</strong></td>
<td colspan="2">93</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"><p><strong>Primary End point:</strong> Transfusion
requirements, Hct, correction of anemia unrelated to transfusion,
response to therapy unrelated to transfusion</p>
<p><strong>Entry/Target Hb:</strong> ≤10.5 g/dL<sup>c</sup>/Hct of
38%-40%</p></td>
<td colspan="2"><strong>Change:</strong> If, after 4 weeks the Hct had
decreased by 15% or more from baseline, or if the subject’s Hct reached
38%-40%, the subject was allowed to move to the OL phase of the study
during which time all subjects received epoetin alfa at a dose titrated
to maintain the Hct between 38%-40%.</td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td>Noncisplatin chemotherapy<sup>b</sup><br />
(I88-037, 87-016, 87-017)<br />
(U.S.)</td>
<td colspan="2"><strong>Type:</strong> Multicenter studies in subjects
with mixed cancers receiving aggressive noncisplatin-containing
chemotherapy. DB phase followed by OL phase.</td>
<td colspan="2">150 IU/kg PROCRIT or PBO, s.c., t.i.w. for 12 weeks in
DB phase, epoetin alfa dose titrated to maintain Hct between 38%-40% in
OL phase</td>
<td colspan="2">81</td>
<td colspan="3">76</td>
<td colspan="2"><strong>157</strong></td>
<td colspan="2">117</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="2"><strong>Primary End point:</strong> Increase in Hct;
decreased transfusion rate</td>
<td colspan="2"><strong>Change:</strong> If Hct reached 38%-40%, the
dose was titrated to maintain Hct within this target range.</td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td></td>
<td colspan="2"><strong>Entry/Target Hb:</strong> ≤10.5 g/dL/ Hct of
38%-40%</td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td>Cisplatin chemotherapy<sup>b</sup><br />
(I88-036, 87-018, 87-019)<br />
(U.S.)</td>
<td colspan="2"><strong>Type:</strong> Multicenter studies in subjects
with mixed cancers receiving aggressive cisplatin-containing
chemotherapy. DB phase followed by OL phase.</td>
<td colspan="2">150 IU/kg PROCRIT or PBO, s.c., t.i.w. for 12 weeks in
DB phase, epoetin alfa dose titrated to maintain Hct between 38%-40% in
OL phase</td>
<td colspan="2">67</td>
<td colspan="3">65</td>
<td colspan="2"><strong>132</strong></td>
<td colspan="2">78</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="2"><strong>Primary End point:</strong> Increase in Hct;
decreased transfusion rate</td>
<td colspan="2"><strong>Change:</strong> If Hct reached 38%-40%, the
dose was titrated to maintain Hct within this target range.</td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="2"><strong>Entry/Target Hb:</strong> ≤10.5 g/dL/ Hct of
38%-40%</td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="even">
<td colspan="14"><p><sup>a</sup> Actual number of subjects enrolled.</p>
<p><sup>b</sup> Prior to study completion, a decision was made to pool
data within each study type(according to type of cancer treatment).
Thus, data in each category were pooled and reported as a single entity
as follows: no chemotherapy treatment (Protocols H87‑032, 87-014,
87-015), treatment with noncisplatin chemotherapy (Protocols I88-037,
87-016, 87-017), and treatment with cisplatin chemotherapy (Protocols
I88-036, 87-018, 87-019).</p>
<p><sup>c</sup> Under Protocol 87-014.</p>
<p>Key: DB=double-blind; EPO=epoetin alfa; Hct=hematocrit; No.=number;
OL=open-label; PBO=placebo; s.c.=subcutaneous; t.i.w.=3 times weekly;
U.S.=United States of America (continued)</p></td>
</tr>
</tbody>
</table>

<table style="width:100%;">
<colgroup>
<col style="width: 16%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 33%" />
<col style="width: 1%" />
<col style="width: 0%" />
<col style="width: 23%" />
<col style="width: 1%" />
<col style="width: 3%" />
<col style="width: 0%" />
<col style="width: 1%" />
<col style="width: 3%" />
<col style="width: 0%" />
<col style="width: 1%" />
<col style="width: 4%" />
<col style="width: 0%" />
<col style="width: 6%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="18"><strong>Attachment 4:</strong> Overview and Design of
PROCRIT and EPREX in Clinical Studies in Oncology (Continued)</td>
</tr>
<tr class="even">
<td colspan="4"></td>
<td></td>
<td colspan="4"></td>
<td colspan="9">No. of Subjects<sup>a</sup></td>
</tr>
<tr class="odd">
<td colspan="4">Protocol</td>
<td></td>
<td colspan="4"></td>
<td colspan="8">DB Phase</td>
<td>OL Phase</td>
</tr>
<tr class="even">
<td colspan="4">(Country)</td>
<td>Study Type</td>
<td colspan="4">Dose Regimen</td>
<td colspan="3">EPO</td>
<td colspan="3">PBO</td>
<td colspan="2"><strong>Total</strong></td>
<td>EPO</td>
</tr>
<tr class="odd">
<td colspan="3"><strong>Completed Studies (continued)</strong></td>
<td colspan="2"></td>
<td colspan="4"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="even">
<td colspan="4">J89-040<br />
(Canada and U.S.)</td>
<td><strong>Type:</strong> PBO-controlled, multicenter study in CLL
subjects. DB phase followed by OL extension.</td>
<td colspan="4">150 IU/kg PROCRIT, EPREX or PBO, s.c., t.i.w. for
12 weeks in DBphase; epoetin alfa dose titrated to maintain Hct between
38%-40% in OL phase</td>
<td colspan="3">142</td>
<td colspan="3">79</td>
<td colspan="2"><strong>221</strong></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="4"></td>
<td><strong>Primary End point:</strong> Change in Hct from baseline to
endpoint</td>
<td colspan="4"><strong>Change:</strong> NA for DB phase</td>
<td colspan="3"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="even">
<td colspan="4"></td>
<td><strong>Entry/Target Hb:</strong> NA<sup>b</sup>/Hct 38%-40% in OL
phase (after 12 weeks DB treatment or reached Hct 38%-40% in DB
phase)</td>
<td colspan="4"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="4">CC2574-P-174<br />
(Europe)</td>
<td><strong>Type:</strong> PBO-controlled, multicenter study in CLL
subjects. DB phase followed by OL extension.</td>
<td colspan="4">150 IU/kg EPREX or PBO, s.c., t.i.w. for 12 weeks in DB
phase; epoetin alfa dose titrated to maintain Hct between 38%-40% in OL
phase</td>
<td colspan="3">33</td>
<td colspan="3">12</td>
<td colspan="2"><strong>45</strong></td>
<td></td>
</tr>
<tr class="even">
<td colspan="4"></td>
<td><strong>Primary End point:</strong> Change in Hct from baseline to
endpoint</td>
<td colspan="4"><strong>Change:</strong> NA for DB phase</td>
<td colspan="3"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="4"></td>
<td><strong>Entry/Target Hb:</strong> NA<sup>b</sup>/Hct 38%-40% in OL
phase and, if reached Hb &gt;11.5 g/dL at end of OL phase, Hct 35%-45%
in maintenance phase</td>
<td colspan="4"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="even">
<td colspan="4">CC 2574-P-416/EPO-INT-1 (Europe and Israel)</td>
<td><strong>Type:</strong> DB, PBO-controlled, multicenter study in
subjects with ovarian cancer receiving cyclic platinum-based
chemotherapy.</td>
<td colspan="4">150 IU/kg, 300 IU/kg EPREX or PBO, s.c., t.i.w. for 1
month past chemotherapy.</td>
<td colspan="3">165<sup>c</sup></td>
<td colspan="3">81</td>
<td colspan="2"><strong>246</strong></td>
<td>NA</td>
</tr>
<tr class="odd">
<td colspan="4"></td>
<td><p><strong>Primary End point:</strong> Transfusion requirements</p>
<p><strong>Entry/Target Hb:</strong> 1) &lt;11.0 g/dL;</p>
<p>2) declined ≥1.5 g/dL since the beginning of chemotherapy when the
baseline Hb level prior to chemo was &lt;14 g/dL; or<br />
3) declined ≥2 g/dL since the beginning of chemotherapy when baseline Hb
prior to chemotherapy was ≥14 g/dL./12.5‑14 g/dL and rate of rise &lt;2
g/dL per month</p></td>
<td colspan="4"><strong>Change:</strong> For subjects randomized to
150 IU/kg group, if reticulocyte count after 4 weeks of study drug had
increased ≥40,000/μL above baseline, study drug was continued at that
dose until 1 month after completion of the last cycle of chemo in the
present course. If the reticulocyte count after 4 weeks of
administration had increased &lt;40,000/μL above baseline, the dose of
study drug was increased to 300 IU/kg t.i.w. until 1 month after
completion of the last cycle of chemotherapy in the present course. If
Hb increased ≥1 g/dL above baseline after 4 weeks of therapy, the dose
of study drug was maintained at 150 IU/kg t.i.w. regardless of
reticulocyte count. If Hb for any subject in any group exceeded 14 g/dL,
therapy was withheld until Hb decreased below 12.5 g/dL, and then
restarted in a dose 25% lower that the dose previously administered. If
Hb level rose by ≥2 g/dL/month, therapy was reduced by approximately 25%
to maintain the rate of increase of Hb to &lt;2 g/dL/month.</td>
<td colspan="3"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="even">
<td colspan="18"><p><sup>a</sup> Actual number of subjects enrolled.</p>
<p><sup>b</sup> Defined as having a prestudy hematocrit &lt;32%.</p>
<p><sup>c</sup> 80 subjects in 300 IU/kg group and 85 subjects in
150 IU/kg group.</p>
<p>Key: DB=double-blind; CLL=chronic lymphocytic leukemia; EPO=epoetin
alfa; Hb=hemoglobin; Hct=hematocrit; NA=not applicable; No.=number;
OL=open-label; PBO=placebo; s.c.=subcutaneous; t.i.w.=3 times weekly;
U.S.=United States of America (continued)</p></td>
</tr>
<tr class="odd">
<td colspan="18"><strong>Attachment 4:</strong> Overview and Design of
PROCRIT and EPREX Clinical Studies in Oncology (Continued)</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="4"></td>
<td colspan="2"></td>
<td colspan="10">No. of Subjects<sup>a</sup></td>
</tr>
<tr class="odd">
<td colspan="2">Protocol</td>
<td colspan="4"></td>
<td colspan="2"></td>
<td colspan="8">DB Phase</td>
<td colspan="2">OL Phase</td>
</tr>
<tr class="even">
<td colspan="2">(Country)</td>
<td colspan="4">Study Type</td>
<td colspan="2">Dose Regimen</td>
<td colspan="2">EPO</td>
<td colspan="3">PBO</td>
<td colspan="3"><strong>Total</strong></td>
<td colspan="2">EPO</td>
</tr>
<tr class="odd">
<td colspan="18"><strong>Completed studies (continued)</strong></td>
</tr>
<tr class="even">
<td>CC 2574‑P‑467/<br />
EPO‑INT‑2<br />
(Europe and Israel)</td>
<td colspan="6"><strong>Type:</strong> PBO-controlled, multicenter study
in subjects with multiple myeloma. DB phase followed by OL
extension.</td>
<td>150-300 IU/kg EPREX, ERYPO or PBO, s.c., t.i.w. for 12 weeks in
double-blind phase; 150 IU/kg epoetin alfa, s.c., t.i.w. for 12 weeks in
OL phase</td>
<td colspan="3">69</td>
<td colspan="3">76</td>
<td colspan="2"><strong>145</strong></td>
<td colspan="2">87</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="6"><p><strong>Primary End point:</strong> Transfusion
requirements</p>
<p><strong>Entry/Target Hb:</strong> &lt;11.0 g/dL/12-14 g/dL and rate
of rise &lt;2 g/dL per month</p></td>
<td><strong>Change:</strong> If after 4 wks of therapy Hb increased by
&lt;1 g/dL above baseline, the initial dose (150 IU/kg) was doubled to
300 IU/kg. If Hb exceeded 14 g/dL at any time during the study, therapy
was withheld until Hb decreased below 12 g/dL then was restarted at a
dose 25% below that which was previously administered.</td>
<td colspan="3"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td>CC 2574‑P‑034/<br />
EPO‑INT‑3<br />
(Europe)</td>
<td colspan="6"><strong>Type:</strong> DB, PBO-controlled, randomized,
multicenter study in subjects with mixed cancers receiving
chemotherapy.</td>
<td>150-300 IU/kg EPREX ERYPO or PBO, s.c., t.i.w. for 12 weeks in DB
phase; 150‑300 IU/kg epoetin alfa, s.c., t.i.w. for 12 weeks in OL
phase</td>
<td colspan="3">136</td>
<td colspan="3">65</td>
<td colspan="2"><strong>201<br />
</strong></td>
<td colspan="2">153</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="6"><p><strong>Primary End point:</strong> Transfusion
requirements</p>
<p><strong>Entry/Target Hb:</strong> &lt;12 g/dL or Hb decline ≥1.5 g/dL
during current chemotherapy cycle/12-14 g/dL and rate of rise &lt;2 g/dL
per month</p></td>
<td><strong>Change:</strong> If after 4 wks of therapy Hb increased by
&lt;1 g/dL above baseline, the initial dose (150 IU/kg t.i.w.) was
doubled to 300 IU/kg t.i.w. If Hb exceeded 14 g/dL for women or 16 g/dL
for men at any time during the study, therapy was withheld until Hb
decreased below 12 g/dL for women or 14 g/dL for men, then was restarted
at a dose 25% below that which was previously administered.</td>
<td colspan="3"></td>
<td colspan="3"></td>
<td colspan="2"></td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td colspan="18"><p><sup>a</sup> Actual number of subjects enrolled.</p>
<p>Key: DB=double-blind; EPO=epoetin alfa; Hb=hemoglobin;
Hct=hematocrit; No.=number; OL=open-label; PBO=placebo;
s.c.=subcutaneous; t.i.w.=3 times weekly; U.S.=United States of America
(continued)</p></td>
</tr>
</tbody>
</table>

<table style="width:100%;">
<colgroup>
<col style="width: 15%" />
<col style="width: 0%" />
<col style="width: 36%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 23%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 4%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="18"><strong>Attachment 4:</strong> Overview and Design of
PROCRIT and EPREX Clinical Studies in Oncology (Continued)</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="12">No. of Subjects<sup>a</sup></td>
</tr>
<tr class="odd">
<td>Protocol</td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="9">DB Phase</td>
<td colspan="3">OL Phase</td>
</tr>
<tr class="even">
<td>(Country)</td>
<td colspan="2">Study Type</td>
<td colspan="3">Dose Regimen</td>
<td colspan="3">EPO</td>
<td colspan="3">PBO</td>
<td colspan="3"><strong>Total</strong></td>
<td colspan="3">EPO</td>
</tr>
<tr class="odd">
<td colspan="18"><strong>Completed Studies (continued)</strong></td>
</tr>
<tr class="even">
<td colspan="2">EPO‑C111‑457/<br />
EPO‑INT‑10<br />
(Europe and South Africa)</td>
<td colspan="3"><strong>Type:</strong> DB, multicenter study in subjects
with non-myeloid malignancies receiving non-platinum chemotherapy.</td>
<td colspan="3">150-300 IU/kg EPREX ERYPO or PBO, s.c., t.i.w. for up to
6 cycles or 24 weeks</td>
<td colspan="3">251</td>
<td colspan="3">124</td>
<td colspan="3"><strong>375</strong></td>
<td>NA</td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="3"><p><strong>Primary End point:</strong> Transfusion
requirements</p>
<p><strong>Entry/Target Hb:</strong> ≤10.5 g/dL or Hb decline ≥1.5 g/dL
during current chemotherapy cycle/12-15 g/dL and rate of rise &lt;2 g/dL
per month</p></td>
<td colspan="3"><strong>Change:</strong> If after 4 wks of therapy
reticulocyte count increased &lt;40,000/μL above baseline and Hb
increased by &lt;1 g/dL above baseline, the initial dose (150 IU/kg) was
doubled to 300 IU/kg. If Hb exceeded 15 g/dL at any time during the
study, therapy was withheld until Hb decreased below 12 g/dL then was
restarted at a dose 25% below that which was previously administered. If
Hb rose ≥2 g/dL per month or cycle the dose was reduced by 25%.</td>
<td colspan="3"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">N93-004<br />
(U.S.)</td>
<td colspan="3"><strong>Type:</strong> DB, multicenter study in subjects
with small cell lung cancer./14-16 g/dL</td>
<td colspan="3">150 IU/kg s.c., t.i.w. PROCRIT or PBO until 3 weeks
after completing their initial course of treatment</td>
<td colspan="3">109</td>
<td colspan="3">115</td>
<td colspan="3"><strong>224</strong></td>
<td>NA</td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="3"><p><strong>Primary End point:</strong> Tumor
response</p>
<p><strong>Entry/Target Hb:</strong> ≤14.5 g/dL</p></td>
<td colspan="3">If Hb exceeded 16 g/dL, study drug was held until the Hb
fell below 14 g/dL and then was restarted at a dose of 75 IU/kg, s.c.
t.i.w.</td>
<td colspan="3"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">EPO-INT-76<sup>b</sup><br />
(Europe, Canada, South Africa, and Australia.)<br />
(B. Leyland-Jones, M.D.)<sup>c</sup></td>
<td colspan="3"><strong>Type:</strong> DB, PBO-controlled, randomized,
multicenter study in women receiving first-line chemotherapy for
metastatic breast carcinoma.</td>
<td colspan="3">40,000 IU s.c., q.w. EPREX or PBO for 12 months</td>
<td colspan="3">448</td>
<td colspan="3">456</td>
<td colspan="3"><strong>904</strong></td>
<td>NA</td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="3"><p><strong>Primary End point:</strong> 12-month survival
rate</p>
<p><strong>Entry/Target Hb:</strong> No upper or lower limit on Hb for
inclusion/12‑14 g/dL and rate of rise &lt;2 g/dL per month</p></td>
<td colspan="3"><strong>Change:</strong> If, at any time after receiving
4 weekly doses, Hb was &lt;10.5 g/dL, and in the previous 4 wks Hb had
increased by &lt;1 g/dL or reticulocyte count had increased by
&lt;40,000 cells/μL, study drug was to be increased to 60,000 IU q.w.
The maximum dose of study drug was not to exceed 60,000 IU q.w. If, at
any time, Hb increased to &gt;14 g/dL, study drug was to be withheld
until Hb decreased to 12 g/dL or lower; study drug was then to be
resumed at 75% of the last dose administered.</td>
<td colspan="3"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td></td>
</tr>
<tr class="even">
<td colspan="18"><p><sup>a</sup> Actual number of subjects enrolled.</p>
<p><sup>b</sup> Study drug was discontinued in April 2002. The study is
ongoing for following up per protocol.</p>
<p><sup>c</sup> Coordinating investigator.</p>
<p>Key: DB=double-blind; EPO=epoetin alfa; Hb=hemoglobin; NA=not
applicable; No.=number; OL=open-label; PBO=placebo; q.w.=once weekly;
s.c.=subcutaneous; t.i.w.=3 times weekly; U.S.=United States of
America</p></td>
</tr>
<tr class="odd">
<td colspan="18"><strong>Attachment 4:</strong> Overview and Design of
PROCRIT and EPREX Clinical Studies in Oncology (Continued)</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="12">No. of Subjects<sup>a</sup></td>
</tr>
<tr class="odd">
<td>Protocol</td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="9">DB Phase</td>
<td colspan="3">OL Phase</td>
</tr>
<tr class="even">
<td>(Country)</td>
<td colspan="2">Study Type</td>
<td colspan="3">Dose Regimen</td>
<td colspan="3">EPO</td>
<td colspan="3">PBO</td>
<td colspan="3"><strong>Total</strong></td>
<td colspan="3">EPO</td>
</tr>
<tr class="odd">
<td colspan="2">PR98-27-008<br />
(U.S. and Canada)</td>
<td colspan="2"><strong>Type:</strong> DB, PBO-controlled, randomized,
multicenter study in anemic subjects with advanced mixed cancers
receiving myelosuppressive, cytotoxic chemotherapy.</td>
<td colspan="3">40,000 IU s.c., q.w. PROCRIT or PBO for 16 weeks</td>
<td colspan="3">174</td>
<td colspan="3">170</td>
<td colspan="3"><strong>344</strong></td>
<td colspan="2">NA</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td colspan="2"><p><strong>Primary End point:</strong> Transfusion
requirements<sup>b</sup></p>
<p><strong>Entry/Target Hb:</strong> ≤11.5 g/dL for men and ≤10.5 g/dL
for women/13‑15 g/dL</p></td>
<td colspan="3"><strong>Change:</strong> The dose was to be increased to
60,000 IU q.w. if Hb had not increased by &gt;1 g/dL after 4 weeks of
therapy or if the subject had received a transfusion during the first 4
weeks of therapy. The dose was to be withheld if Hb was &gt;15 g/dL and
re-initiated with a 25% dose reduction if Hb became &lt;13 g/dL.</td>
<td colspan="3"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="18"><strong>Discontinued studies</strong></td>
</tr>
<tr class="even">
<td colspan="2">PR00-03-006<br />
(U.S.)<br />
(S. Vadhan Raj, M.D.)<sup>c</sup></td>
<td colspan="3"><strong>Type:</strong> DB, randomized, PBO‑controlled,
multicenter study in subjects with gastric or rectal cancer receiving
fluoropyrimidine (5-FU or Xeloda<sup></sup>)-based therapy concurrent
with radiation; randomization 1:1 epoetin alfa vs. PBO.</td>
<td colspan="3">40,000 IU s.c., q.w. PROCRIT or PBO</td>
<td colspan="3">29</td>
<td colspan="3">31</td>
<td colspan="3"><strong>60</strong></td>
<td>NA</td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="3"><p><strong>Primary End point:</strong> Transfusion
requirements</p>
<p><strong>Entry/Target Hb:</strong> ≥10 g/dL to
&lt;15 g/dL/&gt;14-&lt;15 g/dL</p></td>
<td colspan="3"><strong>Change:</strong> If Hb decreased by ≥1 g/dL or
was ≤13 g/dL after 4 weeks of treatment, the dose of study drug was to
be increased to 60,000 IU q.w., starting from Week 4 of chemoradiation.
The dose of study drug was to be withheld if Hb increased to ≥15 g/dL
and was to be resumed once the Hb decreased to ≤14.0 g/dL at a dose of
20,000 IU q.w. less than the current dose.</td>
<td colspan="3"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td></td>
</tr>
<tr class="even">
<td colspan="18"><p><sup>a</sup> For completed studies=actual number of
subjects enrolled; for discontinued studies=actual number of subjects
enrolled when study was discontinued.</p>
<p><sup>b</sup> Primary endpoint per agreement with the U.S. Food and
Drug Administration (FDA). The protocol specified primary endpoint was
quality of life.</p>
<p><sup>c</sup> Coordinating investigator.</p>
<p>Key: DB=double-blind; EPO=epoetin alfa; Hb=hemoglobin; NA=not
applicable; No.=number; OL=open-label; PBO=placebo; q.w.=once weekly;
s.c.=subcutaneous; U.S.=United States of America (continued)</p></td>
</tr>
</tbody>
</table>

<table style="width:100%;">
<colgroup>
<col style="width: 15%" />
<col style="width: 0%" />
<col style="width: 36%" />
<col style="width: 0%" />
<col style="width: 23%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 0%" />
<col style="width: 4%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 0%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="13"><strong>Attachment 4:</strong> Overview and Design of
PROCRIT and EPREX Clinical Studies in Oncology (Continued)</td>
</tr>
<tr class="even">
<td></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="8">No. of Subjects<sup>a</sup></td>
</tr>
<tr class="odd">
<td>Protocol</td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="6">DB Phase</td>
<td colspan="2">OL Phase</td>
</tr>
<tr class="even">
<td>(Country)</td>
<td colspan="2">Study Type</td>
<td colspan="2">Dose Regimen</td>
<td colspan="2">EPO</td>
<td colspan="2">PBO</td>
<td colspan="2"><strong>Total</strong></td>
<td colspan="2">EPO</td>
</tr>
<tr class="odd">
<td colspan="4"><strong>Discontinued studies (continued)</strong></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="even">
<td colspan="2">PR01-04-005<br />
(Denmark, Norway, Sweden, U.S.)<br />
(G. Thomas, M.D.)<sup>b</sup></td>
<td colspan="2"><strong>Type:</strong> OL, randomized, multicenter,
investigator‑sponsored study in subjects with cervical cancer receiving
concurrent radiation and cisplatin, randomization 1:1 epoetin alfa vs.
SOC.</td>
<td colspan="2">40,000 IU s.c., q.w. PROCRIT or SOC</td>
<td colspan="2">NA</td>
<td colspan="2">NA</td>
<td colspan="2"><strong>NA</strong></td>
<td>58<br />
(55 SOC)</td>
</tr>
<tr class="odd">
<td colspan="2"></td>
<td colspan="2"><p><strong>Primary End point:</strong> Progression-free
survival</p>
<p><strong>Entry/Target Hb:</strong> &lt;14 g/dL/13-14 g/dL</p></td>
<td colspan="2"><strong>Change:</strong> If at any time the Hb rose to
&gt;14 g/dL on 2 consecutive wks, epoetin alfa was to be withheld until
Hb dropped to 13 g/dL or below; then was to be reinitiated at the same
dose. If Hb &gt;12 g/dL could not be reached before commencing therapy
or fell abruptly to ≤12 g/dL during therapy and remained ≤12 g/dL for a
period of 1 week despite epoetin alfa, a transfusion was to be given as
soon as possible to raise the Hb &gt;12 g/dL and the dosage of epoetin
alfa was to be escalated to 60,000 IU q.w.</td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="even">
<td colspan="13"><p><sup>a</sup> Actual number of subjects enrolled when
study was discontinued.</p>
<p><sup>b</sup> Coordinating investigator.</p>
<p>Key: EPO=epoetin alfa; Hb=hemoglobin; NA=not applicable; No.=number;
OL=open-label; PBO=placebo; q.w.=once weekly; s.c.=subcutaneous;
SOC=standard of care; U.S.=United States of America (continued)</p></td>
</tr>
</tbody>
</table>

<table style="width:100%;">
<colgroup>
<col style="width: 17%" />
<col style="width: 0%" />
<col style="width: 34%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 23%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 4%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 0%" />
<col style="width: 0%" />
<col style="width: 6%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="17"><strong>Attachment 4:</strong> Overview of PROCRIT and
EPREX Oncology Clinical Studies (Continued)</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td></td>
<td colspan="3"></td>
<td colspan="11">No. of Subjects<sup>a</sup></td>
</tr>
<tr class="odd">
<td colspan="2">Protocol</td>
<td></td>
<td colspan="3"></td>
<td colspan="8">DB Phase</td>
<td colspan="3">OL Phase</td>
</tr>
<tr class="even">
<td colspan="2">(Country)</td>
<td>Study Type</td>
<td colspan="3">Dose Regimen</td>
<td colspan="5">EPO</td>
<td>PBO</td>
<td colspan="2"><strong>Total</strong></td>
<td colspan="3">EPO</td>
</tr>
<tr class="odd">
<td colspan="17"><strong>Discontinued studies (continued)</strong></td>
</tr>
<tr class="even">
<td>EPO-CAN-15<br />
(Canada UK, Spain, Belgium, Italy)<br />
(G. Goss, M.D.)<sup>b</sup></td>
<td colspan="3"><strong>Type:</strong> DB, randomized, PBO-controlled,
multicenter study in subjects with limited disease small‑cell lung
cancer receiving combined modality chemoradiation therapy, randomized
1:1 epoetin alfa vs. PBO.</td>
<td colspan="3">40,000 IU s.c., q.w. EPREX or PBO</td>
<td colspan="2">53</td>
<td colspan="4">53</td>
<td colspan="2"><strong>106</strong></td>
<td colspan="2">NA</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="4"><p><strong>Primary End point:</strong> Progression-free
survival</p>
<p><strong>Entry/Target Hb:</strong> All Hb entered; study drug deferred
until Hb≤14 g/dL (final protocol) or Hb≤13 g/dL (Amendment 1)/14-16 g/dL
(12-14 g/dL post amendment)</p></td>
<td colspan="3"><p><strong>Change:</strong> <u>Final protocol (Nov
2000):</u> If, at any time after receiving epoetin alfa 40,000 IU q.w.
for a minimum of 3 consecutive weeks, Hb was ≤14 g/dL and there had not
been a demonstrated increase in Hb ≥1.5 g/dL in those 3 weeks, the dose
of study drug was to be increased to 60,000 IU q.w. If at any time
during study drug administration Hb was &gt;16 g/dL, study drug was to
be withheld until Hb decreased to ≤14 g/dL. At that time, study drug
administration was to be resumed at a defined lower dose (i.e., down to
30,000 IU if the subject was receiving 40,000 IU, or down to 40,000 IU
if the subject was receiving 60,000 IU). If, after 3 wks following a
dose decrease, Hb was not &gt;14 g/dL, the dose was to be increased to
the previous dose.</p>
<p><u>Amendment 1: (Oct 2002):</u> If, at any time after receiving
epoetin alfa 40,000 IU q.w. for a minimum of 3 consecutive weeks, Hb was
≤13 g/dL and there had not been a demonstrated increase in Hb ≥1.5 g/dL
in those 3 weeks, the dose of study drug was to be increased to 60,000
IU q.w. If at any time during study drug administration Hb was
&gt;14 g/dL, study drug was to be withheld until Hb decreased to ≤13
g/dL. At that time, study drug administration was to be resumed at a
defined lower dose (i.e., down to 30,000 IU if the subject was receiving
40,000 IU, or down to 40,000 IU if the subject was receiving 60,000 IU).
If, after 3 weeks following a dose decrease, Hb was not &gt;13 g/dL, the
dose was to be increased to the previous dose.</p></td>
<td colspan="2"></td>
<td colspan="3"></td>
<td colspan="3"></td>
<td></td>
</tr>
<tr class="even">
<td colspan="17"><p><sup>a</sup> Actual number of subjects enrolled when
study was discontinued.</p>
<p><sup>b</sup> Principal investigator.</p>
<p>Key: DB=double-blind; EPO=epoetin alfa; Hb=hemoglobin; NA=not
applicable; No.=number; OL=open-label; PBO=placebo; q.w.=once weekly;
s.c.=subcutaneous; SOC=standard of care; UK=United Kingdom.
(continued)</p></td>
</tr>
</tbody>
</table>

<table style="width:100%;">
<colgroup>
<col style="width: 17%" />
<col style="width: 0%" />
<col style="width: 34%" />
<col style="width: 0%" />
<col style="width: 23%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 0%" />
<col style="width: 6%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="13"><strong>Attachment 4:</strong> Overview and Design of
PROCRIT and EPREX Clinical Studies in Oncology (Continued)</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td colspan="8">No. of Subjects<sup>a</sup></td>
</tr>
<tr class="odd">
<td colspan="2">Protocol</td>
<td></td>
<td colspan="2"></td>
<td colspan="6">DB Phase</td>
<td colspan="2">OL Phase</td>
</tr>
<tr class="even">
<td colspan="2">(Country)</td>
<td>Study Type</td>
<td colspan="2">Dose Regimen</td>
<td colspan="2">EPO</td>
<td colspan="2">PBO</td>
<td colspan="2"><strong>Total</strong></td>
<td colspan="2">EPO</td>
</tr>
<tr class="odd">
<td>PR99-03-046/RTOG 9903<br />
(U.S.)<br />
(Radiation Therapy Oncology Group)<sup>b</sup></td>
<td colspan="3"><strong>Type:</strong> OL, epoetin alfa vs. control;
randomly assigned 1:1 conducted by the RTOG to evaluate the effect of
epoetin alfa on local-regional control in anemic cancer subjects treated
with radiotherapy for carcinoma of the head and neck</td>
<td colspan="2">40,000 IU s.c., q.w. PROCRIT plus radiotherapy or
radiotherapy alone.</td>
<td colspan="2">NA</td>
<td colspan="2">NA</td>
<td colspan="2"><strong>NA</strong></td>
<td><p>117<sup>c</sup></p>
<p>(61<sup>d</sup> in the control group)</p></td>
</tr>
<tr class="even">
<td></td>
<td colspan="3"><p><strong>Primary End point:</strong> Improvement in
local regional control rate</p>
<p><strong>Entry/Target Hb:</strong> ≥9 to ≤13.5 g/dL for men; ≥9 to
≤12.5 g/dL for women/&gt;13.5-&lt;16 g/dL for men and &gt;12-&lt;14 g/dL
for women</p></td>
<td colspan="2"><strong>Change:</strong> Subjects in the epoetin alfa
group were to receive a starting dose of 40,000 IU s.c., q.w. weekly
basis for 8 to 9 weeks or until completion of radiotherapy. Treatment
with epoetin alfa was to begin 7 to 10 days prior to the start of
radiotherapy. It was anticipated that subjects would have just received
their second dose of epoetin alfa upon starting radiation therapy. If at
any time the Hb concentration rose ≥16 g/dL for men or ≥14 g/dL for
women, EPO was to be withheld until the concentration dropped to ≤13.5
g/dL for men or ≤12 g/dL for women; epoetin alfa treatment was then to
be reinitiated at 30,000 IU q.w. If the Hb concentration failed to
increase by ≥1 g/dL above baseline after the fourth epoetin alfa
injection, the dose of epoetin alfa was to be increased to 60,000 IU
q.w. Subjects randomized to Arm 1 were to receive radiotherapy
only.</td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="13"><p><sup>a</sup> Actual number of subjects enrolled when
study was discontinued.</p>
<p><sup>b</sup> A cooperative research group.</p>
<p><sup>c</sup> A total of 148 subjects were enrolled into the study. Of
these, 1 subject was ineligible and 30 subjects had no reported
follow-up data at the time of this report.</p>
<p><sup>d</sup> Treated with radiation alone or chemoradiation.</p>
<p>Key: EPO=epoetin alfa; Hb=hemoglobin; NA=not applicable; No.=number;
OL=open-label; PBO=placebo; q.w.=once weekly; s.c.=subcutaneous;
SOC=standard of care; U.S.=United States of America.
(continued)</p></td>
</tr>
</tbody>
</table>

<table style="width:100%;">
<colgroup>
<col style="width: 17%" />
<col style="width: 0%" />
<col style="width: 34%" />
<col style="width: 0%" />
<col style="width: 23%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 0%" />
<col style="width: 4%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 0%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="13"><strong>Attachment 4:</strong> Overview of PROCRIT and
EPREX Oncology Clinical Studies (Continued)</td>
</tr>
<tr class="even">
<td colspan="2"></td>
<td></td>
<td colspan="2"></td>
<td colspan="8">No. of Subjects<sup>a</sup></td>
</tr>
<tr class="odd">
<td colspan="2">Protocol</td>
<td></td>
<td colspan="2"></td>
<td colspan="6">DB Phase</td>
<td colspan="2">OL Phase</td>
</tr>
<tr class="even">
<td colspan="2">(Country)</td>
<td>Study Type</td>
<td colspan="2">Dose Regimen</td>
<td colspan="2">EPO</td>
<td colspan="2">PBO</td>
<td colspan="2"><strong>Total</strong></td>
<td colspan="2">EPO</td>
</tr>
<tr class="odd">
<td><p>EPO-CAN-20</p>
<p>(Canada)</p>
<p>(J. Wright, M.D.)<sup>b</sup></p>
<p>(Ontario Clinical Oncology Group)<sup>X</sup></p></td>
<td colspan="3"><strong>Type:</strong> DB, PBO-controlled; randomly
assigned 1:1 epoetin alfa vs. PBO to evaluate the effect of treatment
with epoetin alfa on anemia‑related QoL and anemia in subjects with
advance non-small cell lung cancer.</td>
<td colspan="2">40,000 IU s.c. q.w. EPREX or PBO</td>
<td colspan="2">29</td>
<td colspan="2">29</td>
<td colspan="2"><strong>58</strong><sup>c</sup></td>
<td>NA</td>
</tr>
<tr class="even">
<td></td>
<td colspan="3"><p><strong>Primary End point:</strong> QoL (change from
baseline in FACT-An score)</p>
<p><strong>Entry/Target Hb:</strong> ≤12 g/dL/12-14 g/dL</p></td>
<td colspan="2"><strong>Change:</strong> Subjects were to receive EPO or
placebo s.c. at a starting dose of 40,000 IU q.w. If, after 4 weeks of
therapy, the Hb concentration had not increased by ≥1 g/dL the dose was
to be increased to 60,000 IU for at least the next 4‑week interval. If
the Hb concentration increased by 2 g/dL over any 4-week interval, the
dose was to be reduced by approximately 25%. If at any time, the Hb
concentration exceeded 14 g/dL, the dose was to be withheld until the Hb
concentration decreased below 12 g/dL. The dose was then to be resumed
at approximately 75% of the previous dose.</td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="odd">
<td colspan="13"><strong>Ongoing Study</strong></td>
</tr>
<tr class="even">
<td>GBR-7<sup>d<br />
</sup>(UK)</td>
<td colspan="3"><strong>Type:</strong> OL, multicenter study in subjects
with head and neck cancer for which radical radiotherapy with curative
intent was imminent. Subjects randomly assigned (1:1) to receive either
standard radiotherapy plus epoetin alfa or standard radiotherapy
alone.</td>
<td colspan="2">4,000 IU s.c. t.i.w. or 10,000 IU s.c., t.i.w.
EPREX</td>
<td colspan="2">NA</td>
<td colspan="2">NA</td>
<td colspan="2"><strong>NA</strong></td>
<td>152<br />
(148 in observation group)</td>
</tr>
<tr class="odd">
<td></td>
<td colspan="3"><p><strong>Primary End point:</strong> Local tumor
response at Week 12 after completion of radiotherapy</p>
<p><strong>Entry/Target Hb:</strong> ≤15 g/dL/12.5-15 g/dL</p></td>
<td colspan="2"><strong>Change:</strong> If at any time a subject’s
hemoglobin exceeded 15 g/dL, the epoetin alfa dose was to be halted
until the hemoglobin fell to below 14.5 g/dL, and then restarted at 50%
of the previous dosage so as to maintain the hemoglobin level around
14.5 g/dL. Subjects whose hemoglobin did not reach 12.5 g/dL after 4
weeks were to have their dose doubled.</td>
<td colspan="2"></td>
<td colspan="2"></td>
<td colspan="2"></td>
<td></td>
</tr>
<tr class="even">
<td colspan="13"><p><sup>a</sup> Actual number of subjects enrolled when
study was discontinued.</p>
<p><sup>b</sup> Principal Investigator.</p>
<p><sup>c</sup> At the time the study was discontinued, 70 subjects were
enrolled. The Data Safety Monitoring Board interim analysis only
included baseline and safety analyses data available for 66 of these
subjects. Of the 66, baseline data were only available for 58 subjects
at the time of this report.</p>
<p><sup>d</sup> The study was discontinued in April 2002 due to slow
enrollment. Per protocol, the study treatment phase has been completed
and the 5-year follow-up phase is still ongoing.</p>
<p>Key: DB=double blind; EPO=epoetin alfa; NA=not applicable;
No.=number; OL=open label; PBO=placebo; q.w.=once weekly;
s.c.=subcutaneously; UK=United Kingdom; vs.=versus.</p></td>
</tr>
</tbody>
</table>

[]{#__RefHeading___Toc68427467 .anchor}**Attachment 5**: Preclinical
Data on Epoetins and Tumor Proliferation

The Sponsor has re-evaluated available non-clinical data related to the
role of erythropoietins and EpoR in tumor proliferation, based on the
information in the published literature and the Sponsor\'s research.

Expression of Erythropoietin Receptors on Cells

Erythropoietin is the key regulator for red blood cell production. It
exerts its action by binding to its cognate receptor on cells of
erythroid origin. Recent studies have shown that Erythropoietin and EpoR
expression have been detected in a variety of hematopoietic and
nonhematopoietic cells, including neurons, intestinal cells, liver,
pancreas, prostate, colon and endothelium and malignant cell lines such
as human breast cancer cells. The biological significance of the EpoR on
these cell types is unknown.

Acs et al., (Cancer 95:969-981, 2002)^1^ have reported the
immunohistochemical expression of erythropoietin and EpoR in breast
carcinoma, and suggested that EpoR may play a role in breast
carcinogenesis. However, no correlation between EpoR immunostaining and
tumor size was evident in the study. Similarly, no correlation between
erythropoietin immunostaining and tumor size, tumor grade, presence of
necrosis, lymphovascular invasion, lymph node status, hormone receptor
status, or HER2/neu overexpression was seen. The methodology used in
this study could not identify the cellular localization of the expressed
protein and was unable to differentiate between EpoR on the cell surface
and EpoR in the cytosol (EpoR sequestered in the cytosol is never
activated as it cannot bind to extacellular erythropoietin). Data
indicated that the erythropoietin/EpoR pathway in breast carcinoma is
not apparently associated with other biological features that are known
to correlate with more aggressive tumor growth.

Erythropoietin Receptor Agonists and Proliferation of Tumor Cells

Several investigators have reported that erythropoietin does not
stimulate tumor cell proliferation^2-5^. These results are in agreement
with the results of the Sponsor's own studies in which 6 tumor cells
lines (SK-BR-3, HT-29, MCF-7, PC-3, SK-OV-3 and MDA-MB-453) were treated
with erythropoietin to assess erythropoetin-dependent proliferation. No
effect was seen at any concentration including the highest concentration
of 5 U/mL. This is in sharp contrast to that seen with the hematopoietic
cell line UT-7 where maximal proliferative response was observed at
0.120 U/mL.

Westenfelder and Baranowski^6^ have also reported that Erythropoietin
stimulates cell proliferation of human renal carcinoma cells. However,
the conclusion that erythropoietin stimulated tumor cell proliferation
was based on a minimal proliferative response (125% of control) at
supra‑pharmacological concentrations of r‑HuEPO, \>10 Units/mL (\>5 fold
that seen in clinical application).

A more recent study by Westphal et al.^3^, (2002) investigated
erythropoietin and G-CSF receptor expression in human tumor cells.
Receptor expression was confirmed by reverse transcriptase‑polymerase
chain reaction (RT‑PCR), western blot and immunocytochemistry. Receptor
expression was observed in several tumor cell lines of non‑hematopoietic
origin. On the other hand, no erythropoietin receptor expression by
RT‑PCR analysis was observed in the acute myelogenic leukemia cell line
(KG‑1a), the urinary bladder carcinoma (RT112), Burkitts lymphoma (Raji)
and both primary and immortalized keratinocytes. To test for the
functionality of the erythropoietin receptor on EpoR‑bearing cell lines,
two different parameters were measured; namely, cellular proliferation
and tyrosine phosphorylation. Both analyses revealed that erythropoietin
had no effect on the growth of EpoR‑bearing tumor cell lines. The
authors concluded that EpoR is not essential for cellular growth of
these tumor cells in cell culture.

Erythropoietin and Anti‑Apoptosis

Another active area of investigation is whether erythropoietin confers
an anti‑apoptotic effect on tumor cells and thereby interferes with the
effectiveness of chemotherapeutic agents. Studies have shown that
erythropoietin increases the expression of the anti‑apoptotic genes,
bcl~xl~ and bcl2 in hematopoietic and neuronal cells. In the recent
study by Bahtra et al.,^7^ upregulation of bcl~xl~ and bcl2 was
demonstrated at high erythropoietin concentration, \>30 Units/mL.
Expression of these genes was also observed in the absence of
erythropoietin. The erythropoietin concentration necessary to affect
gene expression is 1000‑fold higher than erythropoietin levels in the
normal physiological range and 10 to 100 fold higher than that seen
after administration of high doses of erythropoietin in the clinical
setting.

Erythropoietin and Angiogenesis

The role of ERAs and angiogenesis is an area that warrants further
attention given that the Epo-R is expressed on endothelial cells^8^. In
vitro studies have demonstrated that human umbilical vein endothelial
cells (HUVECs) exhibit a modest proliferative response when cultured in
the presence of ERAs. Additionally, ERAs exerted pro-angiogenic effects
including increased expression of endothelin-1 (ET-1) and matrix
metalloproteinase-2 at EPO concentrations of 50 U/mL and 2 U/mL,
respectively^9^. ERAs also demonstrated angiogenic potential in a rat
aortic ring assay; however, the minimal dose necessary to induce
angiogenesis was 50 Units/mL, a supra‑pharmacologic dose.

Summary of Findings from Preclinical Data

Although erythropoietin receptors are expressed on a number of malignant
cell lines, none of the pre-clinical data are convincing that
erythropoietin stimulates tumor cell proliferation, local progression,
or the metastatic potential of cancer. No clear association has been
established between ERAs or erythropoietin and increased EpoR expression
on cancer cells. The hypothesis that ERAs stimulate tumor cell
proliferation through an anti‑apoptotic effect or the stimulation of
angiogenesis and endothelial cell proliferation requires further
studies.

References

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