MEMORANDUM

 

Date:         May 1, 2004

 

Subject:     Errata for FDA Briefing Document for May 4, 2004 Oncologic Drugs Advisory Committee Meeting on Evolving Safety Issues Associated with Erythropoietin Products

 

Additions (with the exceptions of the replacement table identified below) are in BOLD type and deletions are in strikeout.

 

Page 4 Executive Summary

 

Under a contractual agreement, Ortho Biotech L.P. has rights to development and marketing of Procrit for any indication other than for the treatment of anemia associated with chronic renal failure in patients undergoing dialysis and diagnostics.

 

Page 6 (Section I)

In addition to proliferation and differentiation of erythroid precursors, erythropoietin has also been shown to be an erythrocyte erythroid survival factor, by modulating pro- and anti-apoptotic mechanisms, and a pro-angiogenic factor5.

 

Page 6 (Section I)

There are two types of is only one erythropoietin receptors, but, possibly due to the presence of different accessory proteins in the membrane and tissue-dependent receptor numbers, two different receptor affinity classes are observed.  hHigh affinity receptors, are expressed predominantly on hematopoietic cells, and have with kDs of approximately 95 pM, and while low affinity receptors are expressed primarily on non-hematopoietic cells, with and have binding affinities of approximately 96 pM to 16 nM.  The binding affinity of an erythropoietin ligand for the erythropoietin receptor is not only influenced by the type of receptor alone, but also by tissue-dependent receptor numbers and accessory proteins8.

 

While the role of…..erythropoietin receptors expressed on some of these tissues are functional.

 

 

Page 8 (Section II)

 Arcacoy, et al33 examined 26 mammary tumor biopsies from 10 patients.

 

Page 9 (Section II)

A lack of proliferative response on erythropoietin receptor-positive cells was also observed by Takashita, et al42 when primary AML and melanoma ALL cells were treated with exogenous erythropoietin.

Page 10 (Section III)

References 44, 45, and 45 are incorrect and should read changed from "Ibid" to "Summary for Basis of Approval, Epoetin alfa (EPOGEN), June 1, 1989."

 

Page 18 (Section V)

6). Slope (m) was classified by group, as follows:

m  < 0.1 g/dL/week (< 1 g/dL  per 10 weeks)

m > 0.1 and < 0.2 g/dL/week (1 g/dL per < 10 to 5 weeks)

            m > 0.2 and < 0.25 g/dL/week (1 g/dL per <5 to 4 weeks)

            m > 0.25 and < 0.333 g/dL/week (1 g/dL per <4 to 3 weeks)

            m > 0.333 and < 0.5 g/dL/week (1 g/dL per <3 to 2 weeks)

            m > 0.5 and < 1 g/dL/week (1 g/dL per < 2 to 1 week)

            m > 1 g/dL/week (1 g/dL per <1 week)

 

Page 18 (Section V)

For Aranesp-treated subjects, there were trends suggesting possible associations between reported Hgb values >13 and seizures, hypertension (HTN), and arrhythmias, though the latter appeared to be associated with Hgb values > <11 g/dL, as well.  Importantly, Hgb values of > <13 g/dL did not appear to be associated with increased risks of these events.  Of note, for ARANESP-treated subjects, Hgb values < <10 g/dL appeared to be associated with excess risks of fluid overload, CHF, pulmonary edema, acute MI and TVA, whereas these risks were not apparent at Hgb values ³ >10 g/dL. 

 

Page 23 (Section V)

Note that event rates (bottom panel) tend to be similar for all ROR categories < 0.50 g/dL/week, whereas event rates for ROR > 0.50 g/dL/week tend to be higher.  The individual Hgb categories are summed in the bottom row (“All Slopes”).  The lowest event rates are in the >11 to < 12 g/dL Hgb category.

 

Page 26 (Section VII.)

Post-Marketing Study to Assess for Tumor Stimulatory effects of EPOGEN/Procrit: Study N93-004

 

Page 26 (Section VII)

In July 2001, Amgen and Ortho Biotech LP notified FDA of its intention to prematurely terminate the study after accrual of 225 224  subjects

 

Page 27 (Section VII.)

Twenty-two percent of the subjects in the Procrit arm and 23% of the subjects in the placebo arm expired experienced at least one thrombotic vascular event.

 

Page 27 (Section VII, table, column 2, row 3)

Correction of upper bound of the 95% confidence interval around observed response rate in placebo arm (upper bound should read 76% rather than 67%)

 

Page 28 (Section VII.)

Correction of incidence of myocardial infarction in table (should read 0% rather than 2%)

 

The median duration of survival (based on Kaplan Meier estimates) was 10.5 months among Procrit-treated subjects compared with 20.4 10.4 months among placebo-treated subjects.

 

Page 30 (Section VIII.)

The recommended starting dose of Epogen/Procrit in cancer patients receiving chemotherapy in the package insert is 150 Units/kg t.i.w. However, many community oncologists administer Epogen/Procrit at a dose of 40,000 Units once a week. FDA is currently reviewing the results of a study55, in which 344 patients with cancer receiving chemotherapy were randomized to receive either placebo or Epogen/Procrit 40,000 U/week.


Page 34 (Section IX). 

 

INCIDENCE OF AEs ASSOCIATED WITH EPOETIN ALFA

 

 

ISS

Protocol 980297

 

Aranesp

Placebo

Procrit

Aranesp

Placebo

 

n=86273

n=2217

n=1153

n=155

159

Hypertension+

 

3.7%

3.2%

2%

9 (6%)

6 (4%)

Convulsions**

 

0.6%

0.5%

 0 1%

0

1 (1%)

Thrombotic events$

 

6.2%

4.1%

5 1%

7 (5%)

5(3%)

 

 

Page 35 (Section IX)

There was also a trend toward higher incidences of deep venous thrombosis (3.3% vs. 2.7% placebo controls) thrombophlebitis thrombophlebitis deep, and  thrombosis in Aranesp-treated patients. 

 

Page 35 (Section IX)

 

Incidence of Thrombotic Events By Preferred Term

                  

Preferred term

rHuEPO

Aranesp

Placebo

 

N= 115

N=873

N=221

Embolism, pulmonary

0

11  

0

Thromboembolism

0

1

0

Thrombophlebitis

0

4  

0

Thrombophlebitis , deep

0

2

1

Thrombosis, venous

1

8    9

2

Thrombosis, venous deep

3 5

27 29 

6

Thrombosis

0

5

0

 Total  # Thrombotic AEs

4 (4.7%) 6(5.2%)

58 (7.4%) 61(7.0%)

9 (4.1%)

Total pts with AEs

85

781 

221 

 

 

Page 36 (Section IX)

            Delete current table and replace with the following:

 

Adverse Event

Event Rates as a function of the slope of increase in hemoglobin (g/dL/week) in 873 patients with cancer receiving Aranesp in clinical studies

< 0.1

>0.1-0.2

>0.2-0.25

>0.25-0.333

>0.333 to 0.5

0.5 to >0.67

>0.67

Unknown

# of slopes

1074

686

635

404

1177

640

1758

2033

Hypertension

1.9

2.9

4.7

7.4

2.5

1.6

5.1

1.0

Seizures

0.9

1.5

0.0

0.0

0.0

0.0

1.1

0.0

Vascular*

1.9

7.3

0.0

2.5

2.5

7.8

4.0

5.9

Fluid overload

27.0

27.7

28.3

27.2

31.4

26.6

31.3

45.3

Cardiac arrest

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

Acute MI

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

CVA

0.0

0.0

1.6

0.0

0.0

0.0

0.4

0.0

*thrombosis, ischemia, infarction

 

Page 36 (Section IX)

 

The analysis provided does not suggest an association between more rapid ROR and thrombotic events in patients with cancer receiving Aranesp. suggests that the incidences of hypertension and vascular events are increased in patients with higher ROR compared to those who had less rapid ROR.

 

Page 37 (Section IX)

Corrections to Table titled “Assessment of ROR and Maximum Hemoglobin Levels in Relationship to the Development and Time of Onset of Pulmonary Emboli in Aranesp-Treated Patients”

·       Rows 9-12, column 2 “OW” should read “QW

·       Row 1, columns 7 and 8, units should read g/dL rather than µg/dL

 

Page 38 (Section X)

The trial was not powered for survival, but there was a trend in overall survival favoring the EPREX placebo arm (log rank test p=0.13; Cox regression analysis hazards ratio of 1.3069 (p=0.0542)).

 

Page 39 (Section X)

The study drug was withheld if the hemoglobin rose above 14 g/dl or if rate of rise in hgb exceeded 2 g/dL/month.

 

Page 40 (Section X. 3rd  bullet)

Twice as many patients in EPREX arm experienced death due to disease progression  within four months of randomization as in the placebo arm:  28 (6%) versus 13 (3%). 

 

Page 40 (Section X. 4th  bullet)

There was also an increased incidence of death in the first four months of study due to thrombotic vascular and cardiovascular adverse events: 2.3% in the EPREX arm versus 0.4% in the placebo arm.

 

Page 42 (Section X)

Correction of lower bound of 95% CI for HR in the ITT population; should read 1.37 and not 1.07

 

Page 49 (Section XII)

Title of Section XII should read “Procrit and EPREX Trials Halted by Johnson & Johnson For Excessive Thrombotic and Cardiovascular Adverse Events

 

Page 49 (Section XII)

The objective of this study is to evaluate the impact of maintaining Hgb in the range of 14 to 16 g/dl on disease progression-free survival using EPREX (Epoetin alfa)/Procrit or placebo

 

Page 50 (Section XII)

Of these 106 patients, 3 (6%)  2(4%) placebo and 18 (34%) 16 (30%) epoetin alfa-treated subjects had a thrombotic vascular event reported.  

 

Page 52 (Section XII, table, column 1, row 10)

            Correction of Treatment Subject ID from 15 to 1145

 

Page 55 (Section XII)

Trial suspended effective Sept. 12, 20023. 

 

Pager 58 (Section XII)

  1. A large proportion of patients on the trial had not completed the 12 week QoL assessment (the primary outcome measure), due to high rates of mortality.

 

Page 61

…dosing resumed when Hgb ≤ 13.5 in males and   < 12.5 in females, at a dose reduction of 30,000 IU.

 

Page 62 (Section XIV)

In the EPO-INT-76 trial, in a population of women with metastatic breast cancer, at four months, there was a higher incidence of death attributed to cardiovascular/thrombotic vascular events in the group who received EPREX  (10.4% in the placebo arm versus 2.3% in the EPREX arm).