# Presentation: 682721

## ESAs in Oncology andManagement of Risks

- Vinni Juneja, MD
- Division of Biologic Oncology Products

- Oncologic Drugs Advisory Committee
- March 13, 2008

**Notes:**

Welcome to the FDA’s presentation today

I’m VJ, a medical officer in the division of biologic oncology products.

I’d like to remind you that today’s discussion will focus on the ESA oncology indication today and not other indications for ESAs.  

## Review Team

- Chaohong Fan
- Patricia Keegan
- Mark Rothmann
- Yuan Li Shen
- Kyung Lee
- Monica Hughes

## Outline

- Background
- Regulatory History
- Benefits vs Risks
- Adverse Findings in Oncology Trials
- Updates since 2007 ODAC
- Adverse Findings in 2 Additional Trials
- New FDA Analyses
- FDA Actions
- Risk Evaluation and Mitigation Strategies (REMS)

**Notes:**
For our presentation we will start with a background on ESAs.

(CLICK) This background will consist of regulatory history
(CLICK) Benefits versus Risks of ESAs
(CLICK) And oncology trials that have showed decreased survival and/or increased tumor promotion

(CLICK) Since the May 2007 Oncologic Drug Advisory Committee meeting on ESAs, we have several updates to present.  For the rest of the presentation, we will be referring to the Oncologic Drug Advisory Committee as ODAC.
(CLICK)   Two additional trials which have showed decreased survival and/or increased tumor promotion will be presented.
(CLICK) New analyses on hemoglobin levels will be presented.  Current data submitted to and analyzed by FDA, by tumor histology, will also be presented.
(CLICK) We will also outline FDA actions since the May 2007 ODAC.

(CLICK) We will end with a variety of Risk Evaluation and Mitigation Strategies (REMS) to manage the risks of ESAs given current available evidence.

(CLICK) So let’s start with a brief snapshot of the regulatory history of ESAs

## ESAs for Chemotherapy-Induced Anemia (CIA)

| Brand-name | Proper name | Sequence homology to human erythropoietin | Year approved for chemo anemia |
| --- | --- | --- | --- |
| Available in US |  |  |  |
| Procrit® | Epoetin alfa | 100% | 1993 |
| Aranesp® | Darbepoetin alfa |   97% | 2002 |
| Available outside US |  |  |  |
| Eprex® | Epoetin alfa | 100% | 1994 |
| NeoRecormon® | Epoetin beta | 100% | 1995 |
| Aranesp® | Darbepoetin alfa |   97% | 2002 |

- Epoetin alfa and beta have same amino acid sequence but differ in glycosylation

**Notes:**
This slide provides an overview of ESAs for the indication of chemotherapy induced anemia that are available within the US and outside of the US. 

The first ESA to be approved in the US was Procrit, or epoetin alpha, and was approved in 1993.  

Darbopoetin, or Aranesp, was approved in the US in 2002.  

The ESAs Eprex and NeoRecormon are approved for use outside of the US,  and are relevant because numerous studies have been conducting using these agents. 

## Epoetin Chemo induced Anemia (CIA)

**1989**

**2007**

- Epoetin AZT

**1991**

**1993**

**1995**

**1997**

**1999**

**2001**

**2003**

**2005**

**Epoetin** Chemo induced Anemia (CIA)

- Epoetin Pre-surgical

- Darbepoetin CRF

**Darbepoetin** Chemo
- induced
- Anemia
- (CIA)

- ODAC 2004

- ODAC 2007

- Epoetin CRF

**Notes:**
The slide offers a timeline for approval dates epoetin and darbepoetin, as well as dates of previous ODACs.  

The first approval of epoetin in the US was in 1988 for the indication of anemia related to chronic renal failure.  

Epoetin was then approved in 1993 in the oncology indication for use in patients with anemia due to the effect of concomitantly administered chemotherapy.  

Darbepoetin was approved in 2002 in the oncology indication.  

Previous ODAC’s in 2004 and 2007 have been convened by FDA in response to oncology trials demonstrating evidence of decreased survival and/or increased tumor promotion.  

## Outline

- Background
- Regulatory History
***Benefits vs Risks***
- Adverse Findings in Oncology Trials
- Updates since 2007 ODAC
- Adverse Findings in 2 Additional Trials
- New FDA Analyses
- FDA Actions
- Risk Evaluation and Mitigation Strategies (REMS)

**Notes:**
Now we will examine the benefits versus the risks of ESAs in oncology.

## Benefits of ESAs

- _Basis for Approval_: Clinical benefits of ESAs demonstrated in anemic pts receiving chemo → avoid RBC transfusions & concomitant risks
- At best 30% of pts (1 in 3) → benefit through avoidance of transfusion
- All patients incur risks

**Notes:**
Clinical benefits of ESAs, as described in the label, were demonstrated in anemic pts receiving chemo who were able to avoid RBC transfusions and their concomitant risks

At best 30% of the pts (1 in 3) derive the benefit through avoidance of transfusion, while all patients incur the risks of ESAs

## Benefits of ESAs

|  | Week 5-12 |  |
| --- | --- | --- |
|  | Procrit N=51 | Placebo N=58 |
| % transfused | 22% | 43% |

- Procrit 1993 Approval

|  | Week 5-End of Rx |  |
| --- | --- | --- |
|  | Aranesp N=148 | Placebo N=149 |
| % transfused | 21% | 51% |

- Aranesp 2002 Approval

**Notes:**
These are the actual benefits of ESAs  with respect to reducing the proportion of patients  on chemotherapy who are transfused.

Looking at the top table, the 1993 approval of Procrit was based on pooled data from 6 studies with 109 evaluable patients.  These studies demonstrated that 22% of patients were transfused in the Procrit arm, while 43% of patients were transfused in the placebo arm.

Referring to the bottom table, the 2002 approval of Aranesp was based on a study with 297 evaluable patients and demonstrated that 21% of patients were transfused in the Aranesp arm, while 51% of patients were transfused in the placebo arm.

Pts in the Procrit approval received platinum and non platinum chemo, while Pts in the Aranesp approval received platinum chemo.

ESAs do not eliminate the need for xfusion, but impart approximately a 50% reduction in the percentage of anemic pts receiving blood xfusion

Comments-note that Procrit enrolled 131 pts total, and Aranesp enrolled 314 pts total

## Unproven perceptions of ESA “benefits”

- Improved QOL, fatigue, and other symptoms associated with anemia _**NOT**_ established in randomized, double-blind, placebo-controlled trials.
- Improved survival or improved tumor control _**NOT**_ established

**Notes:**
Now these are effects of ESAs that have not been established with sufficient evidence

Improved QOL, fatigue, and other symptoms associated with anemia in cancer patients have NOT been established, according to FDA standards, in randomized, double-blind, placebo-controlled trials.

Improved survival or improved tumor control in cancer patients have NOT been established with the use of ESAs

The majority of trials that we will be mentioning today have been designed to detect evidence of improved survival/tumor outcome.  None of these trials have shown improved survival/tumor outcome

## Risks of RBC transfusion

- Transfusion Related Acute Lung Injury (TRALI)
- Clerical error
- Transfusion Associated Graft vs Host disease
- Infectious (HIV, HBV, HCV, HTLV, West Nile, Bacteria)
- No trial has collected data on RBC transfusion risks to assess impact of ESAs on reduction of transfusion risks in pts w/cancer

**Notes:**
RBC transfusions are the alternative to using ESAs.  

This slide outlines the most significant risks of RBC transfusion.  
The incidence of these risks are estimated to occur in 1 per 1000 units of RBC transfused to 1 per 1 million units of RBC transfused.

Unfortunately, no trial has collected data on adverse events related to RBC transfusion to assess the impact of ESAs on the reduction of transfusion risks in pts w/cancer.

## Risks of ESAs

- Increased thrombovascular events (TVEs)
- Increased Morbidity, Potential Increased Mortality
- Decreased Survival
- Increased Tumor Promotion
- Decreased Locoregional Control
- Decreased Progression-Free Survival

**Notes:**
In contrast to the risks of RBC transfusion, these are the risks of ESAs in cancer patients.

1st, the risk of increased thrombovascular events in both cancer and non-cancer patients.  Numerous oncology trials have shown increased risk of thrombovascular events in patients receiving ESAs.  We can regard this as a known risk of ESAs.
This will cause increased morbidity, and a potentially increased mortality.  This risk needs to be weighed against the benefit of reducing the proportion of patients transfused.

2nd, the risk of decreased survival

3rd, the risk of increased tumor promotion

## Risks of ESAs

- 6 studies→ statistically significant evidence of         ↑ tumor promotion and/or ↓ survival
- BEST (Breast)*
- ENHANCE (Head/Neck)
- DAHANCA (Head/Neck)
- 161 (Lymphoid Ca)*
- CAN-20 (NSCLC)
- 103 (Anemia of Cancer) (Many tumor types)
- 2 studies→ trends of ↑ tumor promotion and/or        ↓ survival
- PREPARE (neoadjuvant breast)*
- GOG 191 (cervical cancer)†

- * = pts receiving chemo

- †=pts receiving chemoRT

**Notes:**
6 studies show statistically significant evidence of ↑ tumor promotion and/or ↓ survival.  
The studies are listed here.  
There’s 1 in breast cancer, 2 in head and neck cancer, 1 study in lymphoid malignancies, 1 study in NSCLC, and 1 study in a variety of tumor types.

(CLICK) 2 additional studies show trends of ↑ tumor promotion and/or ↓ survival, and survival results from these studies have been presented to FDA since the previous ODAC in May 2007. 
(CLICK) the first is the PREPARE study in patients receiving neoadjuvant chemotherapy for breast cancer.
(CLICK) the second is the GOG 191 study in patients receiving concomitant chemoradiotherapy for cervical cancer.

(CLICK) The first 6 studies have previously been discussed in both 2004 and 2007 ODACs. 
(CLICK) The last 2 studies, the PREPARE and GOG-191, will be further discussed here.

## Outline

- Background
- Regulatory History
- Benefits vs Risks
***Adverse Findings in Oncology Trials ***
- Updates since 2007 ODAC
- Adverse Findings in 2 Additional Trials
- New FDA Analyses
- FDA Actions
- Risk Evaluation and Mitigation Strategies (REMS)

**Notes:**
I will now briefly present a timeline of relevant oncology studies, and studies with decreased survival and/or increased tumor promotion, relative to the 2004 and 2007 ODAC.

## ODAC 2004

**N93-004 ****(SCLC)**

**ENHANCE ****(Head/Neck)**

**EPO-ANE-3010 ****(Breast)**

**Darbepoetin**
**2001-0145 ****(SCLC)**
**PREPARE ****(Breast)**
**ARA-03 ****(Breast)**
**DAHANCA ****(H/N)**
**GELA ****(NHL)**

**Epoetin**
**GBR-7 ****(H/N)**
**RTOG 9903 ****(H/N)**
**GER-22 ****(NSCLC)**
**CAN-20 ****(NSCLC)**
**CAN-17 ****(Breast)**
**AGO ****(Cervical)**

- Other Amgen Studies

**Anemia of Cancer ****(103)**
**Lymphoid Ca ****(161)**

**GOG-191 ****(Cervical)**

- ODAC 2007

**Notes:**
This slide provides a road map for where we have been prior to ODAC 2004, important trials presented at ODAC 2004, and events that have occurred subsequent to ODAC 2004 leading to ODAC 2007.  
I am now going to empty out this map and build it back up.  (CLICK for disappearance)

At the time of the approval of epoetin in the indication for chemotherapy induced anemia in 1993, there was a theoretical concern for tumor promotion.  
The pooled studies that resulted in the 1993 approval for epoetin were not designed to assess for tumor promotion.
After the 1993 approval, the postmarketing commitment study N93-004 (CLICK) in SCLC was agreed upon between the Amgen and FDA to assess the tumor promotion potential of Epoetin. 
(CLICK) The BEST and ENHANCE studies were also conducted prior to ODAC 2004, and both showed decreased survival in patients receiving ESAs, which led FDA to convene ODAC in 2004.
(CLICK) Prior to ODAC 2004, the GOG-191 trial in cervical cancer was prematurely terminated due to an increase in thrombovascular events.  The survival results of this trial were not known until December 2007.  3 other trials not shown on the slide in breast Ca, SCLC, and gastric/rectal cancer were also prematurely terminated prior to ODAC 2004 due to an increased rate of thrombovascular events.
(CLICK) The studies in yellow that have appeared in the right hand side of the slide were trials that were discussed at ODAC 2004. 
These studies were already ongoing as of May 2004 and according to Amgen and J&J, were designed to answer questions regarding the potential for ESAs to cause tumor promotion. 
We remind that committee that the majority of these studies were not conducted under an IND and were not reviewed by FDA prior to their initiation.
After review of the study protocols, FDA determined that the majority of these studies were not designed adequately to test for and exclude increased risk.
(CLICK) The study in yellow that has appeared, EPO ANE 3010, was proposed at ODAC 2004 by J&J.  
It is a large breast-cancer trial that has had significant difficulty with pt accrual.
(CLICK) In the bottom part of the screen are other studies of interest since ODAC 2004. 
These were not studies that were designed to look for safety signals, but were studies designed to explore additional indications for ESAs. 
(CLICK) Now, to review the timeline of the studies with safety signals, worsened survival and/or increased tumor promotion from the BEST and ENHANCE trials led FDA to convene ODAC 2004.
(CLICK) Now we have 4 studies highlighted in yellow, the 103, 161, CAN-20, and DAHANCA.  Adverse findings observed in these 4 studies led FDA to convene ODAC 2007.
(CLICK)  And since ODAC 2007, we now have 2 additional studies, PREPARE and GOG-191, with trends to worsened survival and/or increased tumor promotion, which are leading us to convene ODAC today.

## ODAC 2004

**ENHANCE ****(Head/Neck)**

**Darbepoetin**
**PREPARE ****(Breast)**
**DAHANCA ****(H/N)**

**Epoetin**
**CAN-20 ****(NSCLC)**

- Other Amgen Studies

**Anemia of Cancer ****(103)**
**Lymphoid Ca ****(161)**

**GOG-191** **(Cervical)**

- ODAC 2007

** ****Studies with ****↓ S****urvival and/or ↑ Tumor Promotion**

**Notes:**
This slide offers a summary of studies that have shown safety signals of decreased survival and/or increased tumor promotion.

## Study		  N	1° Endpoint	ESA Adverse					Outcome

**Chemo**
- BEST (breast)		939	12 mo OS	↓ 12 mo OS
- 161 (Lymphoid)		344	∆ Hgb	↓ OS
- PREPARE (breast)	733	RFS, OS	↓ RFS*, ↓ OS*
- GOG 191 (cervical)	114	PFS	↓ OS*
**RT**
- ENHANCE (H/N)	351	LR PFS	↓ LR PFS, ↓ OS
- DAHANCA (H/N)	522	LRC	↓ LRC, ↓ OS*
**No Chemo or RT**
- CAN-20 (NSCLC)	70	QOL	↓ OS
- 103 (Heterogenous)	989	Transfusion	↓ OS

- *=trend

**Notes:**
This table summarizes more specifically each of the studies with safety signals shown in the previous slide, and a similar table appears in the revised label issued last Friday.
These studies are divided into 3 categories, studies in which patients received chemotherapy, studies in which patient received radiation therapy, and studies in which patients received neither chemotherapy nor radiation therapy.  Each of the studies randomized patients to ESA versus a control arm that included transfusion support.
We will start with studies in patients who received chemotherapy, which is the labeled indication for ESAs.
(CLICK)  The BEST study enrolled patients with metastatic breast cancer, and demonstrated worse 12 month survival in patients receiving ESAs.
(CLICK)  The 161 study in patients with a variety of lymphoid malignancies, and demonstrated worse overall survival.
(CLICK)  The PREPARE study in neoadjuvant breast cancer patients demonstrates trends to worse relapse free and overall survival.
(CLICK) The GOG-191 study in cervical cancer receiving concurrent chemoradiotherapy shows trends to worse overall survival.
Now moving on to studies that used radiotherapy only, which is an off-label ESA use,
(CLICK) The ENHANCE study in head and neck cancer showed worse locoregional progression free survival and worse overall survival.
(CLICK) The DAHANCA study in head and neck cancer showed worse locoregional control and a trend to worse overall survival.
And lastly, two studies enrolled patients who received neither chemotherapy nor radiation therapy, which is an off-label ESA use.
(CLICK) The CAN-20 study in non-small cell lung cancer showed worse overall survival.
(CLICK) The 103 study enrolled patients with a variety of non-myeloid malignancies, and demonstrated worse overall survival.

 I would like to note that all of these trials targeted hemoglobins greater than or equal to 12 g/dL.  We will discuss this further later on in the presentation.

(CLICK) We will be discussing the two recent studies, PREPARE and GOG 191, highlighted in yellow, which have survival data that has become available since ODAC 2007.

## Outline

- Background
- Regulatory History
- Benefits vs Risks
- Adverse Findings in Oncology Trials
- Updates since 2007 ODAC
***Adverse Findings in 2 Additional Trials***
- New FDA Analyses
- FDA Actions
- Risk Evaluation and Mitigation Strategies (REMS)

**Notes:**
I will now briefly present a timeline of the PREPARE and GOG-191 studies and then we will explore details on both of them.

## Hazard Ratios

- 1.0

- 0.9

- 0.8

- 0.7

- 1.1

- 1.2

- 1.3

- Favors Control

- Favors ESA

**Notes:**
Before we talk about these 2 new studies, I would like to clarify the hazard ratios that will be presented in the rest of this discussion.  
The trials presented in this discussion generally randomized patients to an ESA versus control arm.   
With respect to discussing the outcome of a clinical trial, such as a survival result, a hazard ratio of less than 1 is in favor of the ESA arm, while a hazard ratio of greater than 1 is in favor of the control arm.

## ODAC 2007

**May**

**Feb**

**Jun**

**Jul**

**Aug**

**Sep**

**Oct**

**Nov**

**Dec**

**Jan**

**PREPARE/ GOG-191** Results
-  CSR/Data Submitted  Labeling Updates initiated

- 2007-2008

**Notes:**
Marked on this figure are the months since May 2007 ODAC.  

(CLICK) In late November and December of 2007, FDA was notified of the results of the PREPARE and GOG-191 studies.  
Clinical study reports and data have been submitted to FDA on both of these studies.  
Labeling updates incorporating the results of these two studies have been initiated in December 2007.  
Now we will examine both the studies in more detail.

## ODAC 2004

**Darbepoetin**
**PREPARE ****(Breast)**

**Epoetin**

- Other Amgen Studies

- ODAC 2007

**PREPARE Neoadjuvant Breast**

**Notes:**
We will start with the PREPARE study in patients receiving neoadjuvant chemotherapy for breast cancer

## PREPARE Neoadjuvant Breast

- Post Marketing Commitment study as of March 2006
- March 2006 FDA letter→Sponsor
- “To obtain and submit a final study report, including the primary data and analyses, of the ... PREPARE [study] ... the **final** study report will be submitted to FDA by 11/30/07.”

**Notes:**
As agreed upon between FDA and Amgen, the PREPARE study was a post marketing commitment study as of March 2006.
In a letter in March 2006 from the FDA to Amgen, a post marketing commitment agreement was noted:
(CLICK) To obtain and submit a final study report, including the primary data and analyses, of the ... PREPARE study ... the final study report will be submitted to FDA by November 30, 2007.
However, Amgen has informed us that the results submitted are interim, and that a final study report will be submitted in 4th Quarter of 2008

## PREPARE Neoadjuvant Breast

- Trial identified at ODAC 2004
- Accrual June 2002-March 2005

- E=epirubicin, C=cyclophosphamide, T=paclitaxel, M=MTX, F=5FU

- Breast Cancer ≥2 cm
- N=733

- EC→T       q 21

- Dose Dense + Intense
- E→T→CMF

- Aranesp

- Aranesp

- Transfusion Support

- Transfusion Support

- SURGERY

- 1° Objectives
- RFS, OS [Q21 vs Q14]

- 2° Objectives
- RFS, OS   [control vs ESA]
-  pCR, LN status, in breast recurrence, remission rate, QOL, # transfusions

- Target Hgb       12.5-13

**Notes:**
This is an outline of the PREPARE study.
733 patients with primary breast cancers greater than or equal to 2 cm were enrolled.
Patients were first randomized to either a every 21 day chemotherapy regimen consisting of epirubicin, cyclophosphamide, and paclitaxel, or a dose dense and dose intense regimen that included epirubicin, paclitaxel, cyclophosphamide, methotrexate, and 5-FU.
In each of those arms, patients were then randomized to ESA versus transfusion support.
After the completion of neoadjuvant chemotherapy, patients received surgery.
The co-primary objectives of this trial were to compare relapse free and overall survival of the two chemotherapy arms.
Among numerous secondary objectives, there was a comparison of relapse free and overall survival of the ESA versus transfusion support arms.
The target hemoglobin in the trial was 12.5 – 13.
This trial was identified at ODAC 2004 by Amgen as an ongoing trial that was capable of addressing safety concerns of ESAs.
The trial accrued patients from June 2002 to March 2005.

Comments:
Note that post op, if ER or PR+-> Tamoxifen or GnRHA if premenopausal

## PREPARE Neoadjuvant Breast

- Results (N=733)
- Median f/u 3 yrs

- HR = ESA : Control

**Notes:**
These are the results of the PREPARE trial, based on an analysis of 733 patients with a median follow up of 3 years.  
The results are based on a full analysis data set that excluded ineligible patients, but analyzed patients according their randomized treatment group.
FDA was notified of this data in late November 2007.
The survival rate for patients receiving ESAs was lower than patients receiving transfusion support, with a hazard ratio of 1.42, and a 95% confidence interval of 0.93 to 2.18.
The relapse free survival rate for patients receiving ESAs was lower than patients with transfusion support, with a hazard ratio of 1.33, and a 95% confidence interval of the 0.99 to 1.79.

## PREPARE: RFS

- Control

- ESA

**Notes:**
This is a Kaplan-Meier Plot of the Relapse Free Survival, with the red representing the control arm, and the blue representing the ESA arm.

## PREPARE: OS

- Control

- ESA

**Notes:**
This is a Kaplan-Meier Plot of the Overall Survival, with the red representing the control arm, and the blue representing the ESA arm.

## ODAC 2004

**Darbepoetin**

**Epoetin**

- Other Amgen Studies

**GOG-191 (Cervical)**

- ODAC 2007

**GOG-191 Cervical**

**Notes:**
Now we will discuss the GOG-191 trial in cervical cancer.

## GOG-191 Cervical

- Cervical CA (Stage IIB-IVA)
- N=114

- Platinum+RT
- Epoetin Alfa

- Platinum+RT
- Transfusion Support

- 1° Endpoint: PFS

- Accrual August 2001-September 2003
- Terminated early due to ↑ TVE (19% vs 9%) in ESA arm (Target accrual=460)
- Survival results not available in 2004

- Target Hgb:   12-14

- 2° Endpoint: OS, LC

- LC: Local Control

**Notes:**
The GOG-191 trial enrolled 114 patients with Stage 2B to 4A cervical cancer.  
Patients in both arms received concurrent cisplatin and radiation therapy.  
Patients were randomized to receive either ESA or transfusion support.  
The primary endpoint of this trial was progression free survival.  
The secondary endpoints of this trial were overall survival and local control.  
The target hemoglobin in this trial was 12 – 14
The accrual to this trial occurred between August 2001 and September 2003.
FDA was aware in 2004 that the  trial was terminated early due to an increase in thrombovascular events in the ESA arm, and the incidence of thrombovascular events have been summarized in the FDA briefing document from ODAC 2004.
The trial had been designed to accrue 460 patients, but was prematurely terminated at 114 patients.
Survival results were not available in 2004.  
FDA was notified about survival data in December 2007.

## GOG-191 Cervical

- Results (N=114)

- HR = ESA : Control

**Notes:**
These are the results of the trial, based on accrual of 114 patients.
The progression free survival rate for patients receiving ESAs was lower than patients receiving transfusion support, with a hazard ratio of 1.06, and a 95% confidence interval of 0.58 to 1.90
The survival rate for patients receiving ESAs was lower than patients with transfusion support, with a hazard ratio of 1.28, and a 95% confidence interval of the 0.68 to 2.42
The local and distant recurrence rates were higher in the ESA arm compared to control.

## Summary of Post ODAC 2007 Trials:          ↓ Survival and/or ↑ Tumor Promotion

- PREPARE (neoadjuvant Breast Ca; N=733)
- Trend to ↓ survival w/ESA                         (HR 1.42 [95% CI 0.93, 2.18])
- Trend to ↓ RFS w/ESA                          (HR 1.33 [95% CI 0.99, 1.79])
- GOG 191 (Cervical Ca; N=114)
- Trend to ↓ survival w/ESA                      (HR 1.28 [95% CI 0.68, 2.42])

**Notes:**
So let’s pause to summarize the results of the PREPARE and GOG-191 studies.

(CLICK) the PREPARE study in breast cancer patients receiving neoadjuvant chemotherapy showed trends to decreased overall survival and relapse free survival in patients on the ESA arm

(CLICK) the GOG-191 study in cervical cancer patients receiving chemoradiotherapy showed a trend to decreased overall survival in patients on the ESA arm

## Outline

- Background
- Regulatory History
- Benefits vs Risks
- Adverse Findings in Oncology Trials
- Updates since 2007 ODAC
- Adverse Findings in 2 Additional Trials
***New FDA Analyses***
- FDA Actions
- Risk Evaluation and Mitigation Strategies (REMS)

**Notes:**
Now we will discuss new analyses performed by FDA.

## New FDA Analyses

***Achieved vs Targeted hemoglobin***
- Current evidence by tumor histology

**Notes:**
The first topic will be achieved versus targeted hemoglobins.
The second topic will be classifying studies, by tumor histology, with primary data that has been submitted to and analyzed by FDA.
We’re going to start with achieved versus targeted hemoglobin.

## Achieved vs Target Hgb

- Achieved Hgb ≠ Target Hgb

**Notes:**
A point to remember in the next slide is that the hemoglobin actually achieved in a clinical trial may not be the same as the ideal target hemoglobin.

## Study		 Hgb Target	Achieved Hgb 					Median (Q1, Q3)

**Chemo**
- BEST (breast)		12-14		12.9 (12.2, 13.3)
- 161 (Lymphoid)		13-15 ♂, 13-14 **♀**	11.0 (9.8, 12.1)
- PREPARE (breast)	12.5-13	13.1 (12.5, 13.7)
- GOG 191 (cervical)	12-14		12.7 (12.1, 13.3)
**RT**
- ENHANCE (H/N)	≥15 ♂, ≥14 **♀** 	14.0 (13.0, 14.9)
- DAHANCA (H/N)	14-15.5	Not Available
**No Chemo or RT**
- CAN-20 (NSCLC)	12-14		Insufficient Data
- 103 (Heterogeneous)	12-13		10.6 (9.4, 11.8)

**Notes:**
These are the 8 studies that we have seen in previous slides.  
If you look at the middle column, the hemoglobin target, all of the studies targeted hemoglobins greater than or equal to 12.
To better understand what target hemoglobin means, let’s take the target hemoglobin in the 103 trial, which was 12-13.    (CLICK)
If a patient’s hemoglobin was less than 12, ESAs were given.  
If a patient’s hemoglobin was between 12 and 13, ESAs were dose reduced.
If a patient’s hemoglobin was greater than 13, ESAs were withheld. 
The ideal maintenance range for a patient’s hemoglobin was between 12-13.   
So a hemoglobin target really means an ideal maintenance range for a patient’s hemoglobin.  
However, in a clinical trial, individual patients’ hemoglobins may not actually fall within this hemoglobin target or ideal maintenance range.  
This is the concept of the achieved hemoglobin, which is in the 3rd column.  
The achieved hemoglobins are a compilation of the median hemoglobins of individual patients in the trial, and the numbers in parentheses represent the 1st and 3rd quartiles of hemoglobin.
Data on the achieved hemoglobin has been submitted to FDA on 7 out of 8 of these trials.
(CLICK) I would like to focus on the 2 trials now highlighted in yellow, the 161 and 103 trials.  As you can see, the median achieved hemoglobins in these trials was less than 12.  we will now illustrate concrete examples from 2 of these trials.

- Study 103 “Anemia of Cancer”-Achieved vs Target Hgb

- Target Hgb

- Achieved Hgb, Aranesp

**Notes:**
This is study 103, commonly referred to as the anemia of cancer study.  The study enrolled patients receiving neither chemotherapy nor myelosuppressive RT, which is an off label ESA use.
The shaded area delineates the target hemoglobin in this trial, which was 12-13.  
The blue ovals indicate the median achieved hemoglobins by patients receiving ESAs over the weeks of the study, and the vertical bars through the ovals are the 1st and 3rd quartiles of hemoglobins achieved.  
What is illustrated here is that the median achieved hemoglobins in this trial were less than the ideal target hemoglobin.  
The median achieved hemoglobins in this trial are under 12

- Target Hgb **♂**

- Target Hgb **♀**

- Achieved Hgb, Aranesp

- Study 161 “Lymphoid Ca”-Achieved vs Target Hgb

**Notes:**
This is study 161, commonly referred to as the lymphoid malignancy study.  In contrast to the 103 study, this trial enrolled patients receiving chemotherapy.
The shaded area delineates the target hemoglobin of this trial, which was 13-15.  
Again, the median achieved hemoglobins in this trial were less than the ideal target hemoglobin, and are under 12

## Achieved vs Target Hgb

- Both 161 & 103 trials
- median achieved Hgb <12 g/dL
- statistically significant ↓ OS
- Is the upper range for target Hgb of 12 g/dL safe?

**Boxed Warning**
- The risks of ↓ OS and tumor progression have not been excluded when ESAs are dosed to target Hgb < 12 g/dL.
- To minimize these risks, as well as the risk of serious CV events/TVEs, use the lowest dose needed to avoid RBC transfusions.

**Notes:**
So both the 161 and 103 trials have median achieved hemoglobin of less than 12, and both trials had a statistically significant worsening of overall survival in patients receiving ESAs.
(CLICK) Which leads to the question: Is the upper range for the target Hgb of 12 safe?
(CLICK) The uncertain nature of the risks of ESAs at hemoglobin levels less than 12 have led us to include the following statement in the boxed warning.  The following text are sections from the boxed warning as approved in November 2007.
The risks of decreased survival and tumor progression have not been excluded when ESAs are dosed to target Hgb < 12 g/dL.  
To minimize these risks, as well as the risk of serious cardiovascular events and thrombovascular events, use the lowest dose needed to avoid RBC transfusions.

## New FDA Analyses

- Achieved vs Targeted hemoglobin
***Current evidence by tumor histology***

**Notes:**
Now let’s look at studies, by tumor histology, with primary data that has been submitted to and analyzed by FDA.  

## Survival results in SCLC trials

**Tumor****	****Study****	****  N****	****Survival HR (95% CI)**
- SCLC	N93-004	224	    1.17 (0.89, 1.55)
- 	2001-0145	596	    0.94 (0.78, 1.12)
- 	980297*	 92	    0.68 (0.41, 1.11)

- *=SCLC subset

- HR = ESA : Control

**Notes:**
Data from 2 SCLC Studies have been submitted to and analyzed by FDA, and subset analysis has been performed on one study, 980297 that included SCLC + NSCLC patients.  
The largest of these studies was 2001-0145, an adequately designed study intended to show the superiority of ESA on survival, where the hazard ratio for survival excluded more than a 12% increased risk of death.

## Tumor Types: Survival and Tumor Promotion

**Tumor****	****Study****	**** N    ****Adverse Effects**
- NSCLC	CAN-20	 70	↓ OS
- 	980297*	222	OS HR 0.86 (0.62, 1.18)
- 			PFS OS 0.92 (0.68, 1.23)
- Breast	BEST	939	↓ OS
- 	BRAVE	463	OS HR 1.09 (0.88, 1.35)
- 			PFS HR 1.09 (0.90, 1.31)
- 	PREPARE	733	↓ OS†   ↓ RFS†
- Head/Neck	ENHANCE	351	↓ OS    ↓ LR PFS
- 	DAHANCA	522	↓ OS†    ↓ LRC
- Lymphoid	161	344	↓ OS
- Cervical	GOG-191	114	↓ OS†
- Mixed	103	989	↓ OS

- *=NSCLC subset

- †=trend

**Notes:**
In contrast, the following tumor types have had data submitted to FDA that either show trends to or have statistically significant increased tumor promotion and/or decreased survival.
(CLICK) In NSCLC, the CAN-20 study in patients receiving neither chemotherapy nor radiotherapy demonstrated decreased survival in patients receiving ESAs.  
Study 980297 was shown in the previous slide, and enrolled patients with both NSCLC and SCLC.  
Subset analysis performed on the study has not shown a statistically significant survival difference.
(CLICK) In Breast cancer, the BEST study in patients with metastatic breast cancer showed decreased survival.  
In the BRAVE study in patients with metastatic breast cancer, no statistically significant decrease in survival was observed.  
A major difference between the BEST and BRAVE study was that the BRAVE study enrolled patients receiving any line of chemotherapy, while the BEST study enrolled patients receiving 1st line chemotherapy.  
In the neoadjuvant setting, as previously discussed, the PREPARE study has shown trends to decreased overall survival and decreased relapse free survival.
(CLICK) in head and neck cancer, both the ENHANCE and DAHANCA studies enrolled patients receiving radiotherapy.  
Both studies have shown evidence of worsened tumor control.  
The ENHANCE study showed decreased overall survival, while the DAHANCA study had a trend to decreased survival
(CLICK) in patients with a heterogeneous group of lymphoid malignancies, the 161 study demonstrated decreased overall survival.
(CLICK) in patients with cervical cancer, the GOG-191 study previously discussed showed a trend to decreased overall survival.
(CLICK) in patients with a heterogeneous group of non-myeloid malignancies not receiving chemotherapy or myelosuppressive radiotherapy, the 103 study demonstrated decreased overall survival.

## Other Tumor TypesESA Adverse Effects not determined

- Tumor Types
- GI
- GU
- Ovarian
- Uterine
- Germ Cell

- Leukemia
- CNS
- Renal Cell
- Melanoma
- Sarcoma

**Notes:**
This slide illustrates other major tumor types where the adverse effects of ESAs have not been adequately investigated in randomized, controlled trials with data submitted to and analyzed by FDA.

## Outline

- Background
- Regulatory History
- Benefits vs Risks
- Adverse Findings in Oncology Trials
- Updates since 2007 ODAC
- Adverse Findings in 2 Additional Trials
- New FDA Analyses
***Post ODAC 2007 Actions***
- Risk Evaluation and Mitigation Strategies (REMS)

**Notes:**
Now we will discuss events occuring after ODAC in May 2007

## 2007-2008

**May**

**Feb**

- FDA-Sponsor Meetings

**Jun**

**Jul**

**Aug**

**Sep**

**Oct**

**Nov**

**Dec**

**Jan**

- ODAC 2007

- Labeling Revision Request

**MedGuide **submitted

- 145 study (SCLC) CSR/Data submitted

_**Revised**_** Label DHCP**

**GOG-191 PREPARE** Results, CSR/Data Submitted  Labeling Updates initiated

- Additional Study CSR/Data submitted

- CMS NCD proposed

**GOG 191 PREPARE** FDA   Press Release

_**2007-2008**_

**Notes:**
Now we will examine a timeline of events that have occurred since ODAC in May 2007.  Marked on this figure are the months since May 2007.
(CLICK) In May 2007, after ODAC, a request for labeling revisions which addressed recommendations from ODAC 2007 was sent by FDA to the Sponsors.
(CLICK)  In May 2007, the Centers for Medicare and Medicaid Services proposed a national coverage decisions on ESAs in oncology.
(CLICK) In June and August 2007, meetings occurred between FDA and Sponsor regarding modification of ongoing trials to increase the accrual rate. Proposals for new trials were also discussed.  Additional meetings have also occurred regarding myelodysplastic syndrome and the erythropoetin receptor.
(CLICK) In October and December 2007, clinical study reports and datasets were submitted on study 2001-0145 in SCLC
(CLICK) In October 2007, a Medguide was requested by FDA.  A Medguide is a required sheet of information on a drug that must be provided to the patient.
(CLICK) In November 2007, as well as last Friday, revised labeling and “Dear Health Care Provider” letter were approved by FDA
(CLICK) As previously stated, in late November and December 2007, FDA was notified of adverse results from GOG-191 and PREPARE.  Clinical study reports and data sets were submitted for the studies, and updated labeling was initiated which included the study results. 
(CLICK) In early January 2008, FDA issued a press release describing the results of GOG-191 and PREPARE
(CLICK) From December 2007 to February 2008, datasets on completed studies to support labeling and re-analysis were submitted, along with clinical study reports and data sets on numerous other studies.  We will be mentioning these other studies again in subsequent slides.

## CMS NCD

- ESA use is indicated when ...
- Hgb is < 10 g/dL prior to initiation/maintenance of ESA treatment
- Hgb <10 g/dL four weeks after initiation of ESA AND rise in Hgb is > 1 g/dL
- Must submit most recent Hgb levels at least as often as prior to each ESA claim for reimbursement
- Stop ESA 8 wks post chemo
- NCD Dose adjustment guidelines

**Notes:**
This is a summary of the National Coverage Decision by Centers for Medicare and Medicaid Services issued in May 2007.
ESA use is indicated when ... 
Hemoglobin is less than 10 prior to the initiation or maintenance of ESA treatment
ESA use is indicated when ... 
Hemoglobin continues to be less than 10 four wks after initiation of an ESA AND rise in Hgb is > 1
Clinicians must check Hgb levels at least as often as prior to each ESA dose to ensure reimbursement
Stop ESA 8 wks post chemo
Dose adjustment guidelines were issued by the National Coverage Decision

## Boxed Warning

- ESAs ↓ OS and/or time-to-tumor progression in clinical studies in breast, NSCLC, head & neck, lymphoid, & cervical Ca when dosed to target Hgb ≥ 12 g/dL.
- Risks of ↓ OS & tumor progression not excluded when ESAs are dosed to target Hgb < 12 g/dL.
- To minimize these risks, and the risk of serious CV events/TVEs, use the lowest dose needed to avoid RBC transfusions.
- Use only for treatment of anemia due to concomitant myelosuppressive chemo.
- Discontinue following the completion of a chemo course.

**Notes:**
This is the Boxed Warning issued last Friday.  
The portions included on the slide includes the relevant oncology section of the box.
(CLICK) Now read off of the slide.

## Risks of ESAs

- 6 studies→ statistically significant evidence of         ↑ tumor promotion and/or ↓ survival
- BEST (Breast)*
- ENHANCE (Head/Neck)
- DAHANCA (Head/Neck)
- 161 (Lymphoid Ca)*
- CAN-20 (NSCLC)
- 103 (Anemia of Cancer) (Many tumor types)
- 2 studies→ trends of ↑ tumor promotion and/or ↓ survival
- PREPARE (neoadjuvant breast)*
- GOG 191 (cervical cancer)†

- * = pts receiving chemo

- †=pts receiving chemoRT

**Notes:**
So to summarize the current data on the risks of ESAs in oncology:
6 studies show statistically significant evidence of ↑ tumor promotion or ↓ survival.  
The studies and the types of cancers are listed here.

2 additional studies show trends of ↑ tumor promotion or ↓ survival, and data from these studies have been presented to FDA since the previous ODAC in May 2007.   These are the PREPARE and GOG-191 studies, as previously discussed.

## Analyses presented by ...

- Treatment Type
- chemo-induced anemia vs RT vs no anticancer Rx
- Tumor Type
- Achieved or target Hgb
- Examples of ↑ Risk present across these factors
- Is there an oncology setting where ESAs do not have ↑ risk?

**Notes:**
This presentation has offered analyses on the risk of ESAs when trials that have observed increased risk have been categorized by treatment type, tumor type, and achieved or targeted hemoglobin.

In the next 3 slides, these analyses will be summarized.

(CLICK) Examples of increased risk has been observed across these factors.

(CLICK) Which would lead to the question : is there an oncology setting for ESAs that does not have an increased risk?

## SummaryTreatment Type

- ↑ Risk present in
- chemo-induced anemia (4 studies)
- RT (2 studies)
- No anticancer Rx (2 studies)

**Notes:**
In looking at trials with increased risk and categorizing them by treatment type, we have observed an increased risk present in 4 studies in chemotherapy induced anemia (which is the labeled indication), 2 studies in patients receiving radiation therapy (an off label use), and in 2 studies in patients receiving no chemotherapy or myelosuppressive radiotherapy (an off label use).

## SummaryTumor types

- SCLC
- 3 trials without survival difference
- Results in SCLC unlikely to be applicable to other tumor types
- No data in numerous tumor types

**Notes:**
In looking at trials with increased risk and categorizing them by tumor types, 
A safety signal in survival was not observed in 3 trials in SCLC
Results in SCLC, an aggressive neuroendocrine tumor, are unlikely to be applicable to other tumor types; for example, epidermal tumors.
No data from randomized, controlled trials has been submitted to and analyzed by FDA on the risk of ESAs in numerous other tumor types

## SummaryTumor types

| Tumor Type | # studies with ↓ OS and/or ↑ tumor promotion |
| --- | --- |
| Head/Neck | 2 |
| Breast |              1 (Stg IV)
               1* (neoadj) |
| NSCLC | 1 |
| Lymphoid | 1 |
| Cervical |  1* |
| Heterogeneous | 1 |

- SummaryTumor types

- *=trend

**Notes:**
These are the tumor types in which decreased overall survival and/or increased tumor promotion have been observed.
There are 2 such studies in head and neck cancer, 1 study in metastatic breast cancer, 1 study in neoadjuvant breast cancer, 1 study in non-small cell lung cancer, 1 study in lymphoid malignancies, 1 study in cervical cancer, and 1 study in patients with a variety of non-myeloid malignancies.

## SummaryAchieved vs Target Hgb

- No adequately designed studies have been completed with target Hgb < 12
- 2 studies (161 and 103) where the achieved median Hgb < 12 showed ↓ OS
- Safety of target Hgb < 12 is not established

**Notes:**
Now lookg at achieved vs targeted hemoglobins
No adequately designed studies have been completed with target Hgb < 12
In looking at trials with increased risk by achieved or targeted hemoglobin, we note that despite targeting a hemoglobin greater than or equal to 12, both the 103 and 161 trials achieved median hemoglobin of less than 12. 
In both of these trials, patients receiving ESAs had decreased survival.
Therefore the safety of ESAs when used to target Hgb < 12 is not established

## Conclusions

- ESAs=supportive care agents→establishing safety is necessary
- Efficacy of ESAs: ↓ RBC transfusions
- 8 post-approval studies: ↓ OS, ↓ locoregional control/RFS
- Numerous studies: ↑ TVE risk
- ESAs do NOT ↑ survival, and may ↑ tumor growth
- Reconsideration of risk:benefit ratio of ESAs
- Results from adequately designed ongoing or proposed studies will not be available for several years

**Notes:**
So, to conclude, ESAs are supportive care agents and therefore establishing safety is necessary.

(CLICK) the Efficacy and the approval basis of ESAs in oncology is to reduce the proportion of cancer pts on chemo receiving RBC transfusions

(CLICK) 8 Post Approval Studies have provided evidence of ↓ OS and/or ↓ locoregional control or relapse free survival

(CLICK)  numerous studies in both oncology and nononcology settings have demonstrated an ↑ TVE risk

(CLICK) ESAs do NOT increase survival, and may promote tumor growth

(CLICK) Based on the 8 studies mentioned above, there should be a reconsideration of the risk to benefit ratio of ESAs in cancer pts.

(CLICK) Results from adequately designed ongoing or proposed studies will not be available for several years, and we will be discussing this further.

## Outline

- Background
- Regulatory History
- Benefits vs Risks
- Adverse findings in oncology trials
- Updates since 2007 ODAC
- Adverse findings in 2 additional trials
- New FDA Analyses
- FDA Actions
***Risk Evaluation and Mitigation Strategies (REMS)***

**Notes:**
Now we will discuss different Risk Evaluation and Mitigation Strategies for ESAs in the oncology indication.

## Risk Evaluation and Mitigation Strategies (REMS)

***Risk Evaluation ******→ strategies to further characterize risks***
***Meta-analysis of completed trials ***
***Assessment of individual studies***
- Risk Mitigation → strategies that apply to current use

**Notes:**
Risk-management proposals can be further divided into proposals for risk evaluation, which are strategies to further characterize risks, including meta-analysis of completed trials, and assessment of individual studies.  
Proposals for risk mitigation are strategies that apply to the current use of ESAs.  
Let’s start with risk evaluation.

## Risk EvaluationMeta-Analysis

- Meta-analysis is problematic to definitively rule out risks of ESAs
- No studies have demonstrated superior OS or PFS for an ESA-containing arm

**Notes:**
In examining various meta-analyses in literature and offered by the sponsors, meta-analysis remains a problematic technique to definitively rule out risks of ESAs.

No completed oncology studies have definitively demonstrated superior OS or PFS for an ESA containing arm.

## Risk EvaluationMeta-Analysis

- Can obscure safety signals from individual studies
- Results depend on the studies included
- Earlier meta-analyses suggested statistical significance on OS favoring ESAs
- Later meta-analyses suggest statistical significance on OS favoring controls
- Issues on appropriate allocation of alpha
- Heterogeneous trials w/ variable quality, variable lengths of follow up, variable target Hgb, and heterogeneous tumor types

**Notes:**
Meta-analysis can obscure safety signals from individual studies

(CLICK) Meta analysis results depend on the studies included
Earlier meta-analyses suggested statistical significance on OS favoring ESAs
Later meta-analyses suggest statistical significance on OS favoring the controls

(CLICK) Cumulative and retrospective meta-analyses have issues on the appropriate allocation of alpha

(CLICK) Meta-analyses include Heterogeneous trials with variable quality, variable lengths of follow up, variable target Hgb, and heterogenous tumor types

## Risk Evaluation Individual Studies

- ODAC 2004 Recommendations on optimal trial design
- Studies satisfying these recommendations

**Notes:**
Now moving on to individual studies.  
We will now examine the elements of optimal trial design to assess and exclude increased risk as recommended by the previous ODAC in 2004.
We will also describe completed, ongoing, or proposed studies that nearly or completely meet these recommendations.

## ODAC 2004 Recommendations

- Double Blind, Placebo-Controlled Trials
- Preferred Primary Endpoint: Survival
- Adequately powered trials to detect survival differences
- Routine Assessment of Tumor Progression
- Homogeneous Tumor Type
- Assessment of TVEs → prospectively defined endpoint

**Notes:**
These were the major highlights of the 2004 ODAC recommendations regarding optimal trial design to exclude increased risks with ESAs:
(CLICK) Trials be Double Blind + Placebo-Controlled
(CLICK)  Preferred Primary Endpoint be a Survival endpoint
(CLICK) Trials be Adequately powered to detect survival differences
(CLICK) Trials have a Routine Assessment of Tumor Progression
(CLICK)  Trials include a Homogenous Tumor Type
(CLICK) The assessment of TVEs should be a prospectively defined endpoint.  

## Risk Evaluation Individual Studies

- Studies, meeting ODAC 2004 recs, designed to detect & exclude an upper limit of risk
- EPO-ANE-3010 (Stg 4 breast cancer)
- Poor accrual: 236/1000 pts accrued since March 2006
- N93-004 (SCLC)
- Prematurely terminated 7/01 for slow accrual w/224 pts
- 2007-0782 (advanced breast, lung, colorectal cancer)
- Proposed since ODAC 2007, not initiated
- Studies, meeting ODAC 2004 recs, designed to detect a superior outcome w/ ESAs
- 2001-0145 (SCLC)
- Finished accrual 7/06 w/596 pts

**Notes:**
These are studies that nearly satisfy all of the 2004 ODAC recommendations.  They are divided into two categories, studies designed to detect and exclude an upper limit of risk, and studies designed to detect a superior outcome with ESAs.
Starting with the first category:
(CLICK) EPO ANE 3010 is a study in metastatic breast cancer, and has had problems with poor study accrual, and is presently enrolling patients.
(CLICK) N93-004 is a study in SCLC, and prematurely terminated in July 2001 for slow accrual.  We have previously presented the results of this study.
(CLICK) Study 2007-0782 was proposed by Amgen after ODAC 2007, and proposes to enroll patients with advanced breast, lung, and colorectal cancer.  This study has not yet been initiated.
Now moving onto the the second category,
(CLICK) Study 2001-0145 in SCLC finished patient accrual in July 2006, and we have previously presented the results of the study.

## Data submitted to FDA by Sponsors12/20/07-3/5/08

- Clinical Study Reports received on 18 studies
- 35,642 pages total
- Datasets received on 30 studies
- None of these 30 studies are specifically designed to detect and exclude increased risks of death

**Notes:**
A very large amount of data has recently been submitted to FDA from numerous studies, some of which you have seen in the Sponsor’s presentation.  
FDA had informed the sponsors prior to data submission that FDA would not be able to review this data prior to this ODAC.
Clinical study reports have been received on 18 studies, totaling over 35,600 pages.
In addition, data sets have been received on 30 studies.

The date of 12/20/07 was selected by FDA as a cutoff date in order to prepare for ODAC.   
None of the these submitted studies were specifically designed to detect and exclude increased risks of death.

Comments
Updated as of 3/11/08.  
CSRs actually received include GBR-7 (500), RTOG (1002), CAN 17 (2578), Blohmer (275), GOG 191 (34 pgs), Moebus (447), BEST update (1388), PREPARE (135), CAN-20 (1606), GER-22 (587), CAN-15 (1385+119), INT-10 (1851), 2001-0145 (14,145), 990114 (1921), 980297 (1250), 2002-0149 (1489), 2003-0232 (1948), 980291 (1665+1317)=35642 pages

Datasets actually received include PREPARE, GOG-191, Blohmer, CAN 17, GBR 7, Moebus, J+J PAS supplement [includes BEST Update, I88-036, I88-037, J89-040, CC2574-P- 174, EPO INT 1, EPO INT 2, EPO INT 3, EPO INT 10, N 93-004, PR 98- 27- 008 (NCCTG)], CAN-20, GER-22, CAN-15, RTOG, INT-45, INT-47, INT-49, 2001-0145, 980291, 990114, 980297, 2002-0149, 2003-0232

## Data submitted to FDA by Sponsors12/20/07-3/5/08

- FDA is aware that some of these studies do not report statistically significant **↑**** **risk of tumor promotion and/or ↓ survival
**Absence of evidence of ****↑ risk ****is **_**not**_** evidence of absence**

**Notes:**
FDA is aware that some of these studies do not report a statistically significant ↑ risk of tumor promotion and/or decreased survival

FDA reminds the committee that the absence of evidence of increased risk in studies that are not designed to detect and exclude increased risk does not mean that there is definitive evidence that such risks are not present.

## Risk Mitigation proposals

- Risk Evaluation → strategies to further characterize risks
- Meta-analysis of completed trials
- Assessment of individual studies
***Risk Mitigation ******→****** strategies that apply to current use***

**Notes:**
Now we will move on to risk mitigation, which are strategies that apply to the current use of ESAs.

## Amgen Risk Mitigation Plan

- Physician Education
- Literature dissemination
- DHCP letters
- FAQ handout on ESAs, NCD, ODAC
- Support for CME
- Pt advocacy group communication
- Medication Guide*
- Assessment of risk communication to pts/ providers
- Labeling changes

- *=active negotiations occurring b/t FDA & Sponsor

**Notes:**
Now, apart from labeling changes, these are other proposals for risk mitigation.  We’ll start with the sponsor’s proposals, which include various forms of physician education: 
(CLICK) Dissemination of relevant published literature and labeling
(CLICK) Dear healthcare provider letters on ESAs.  A revised letter was approved by FDA last Friday.
(CLICK) Preparing a frequently asked questions document regarding ESA use, the national coverage decision by the CMS, and outcomes of 3 different ODACs.
(CLICK) Unrestricted educational support for independent continuing medical education training, education of members of the company speaker bureau, and providing materials on ESA safety issues at scientific booths at major biomedical meetings
(CLICK) Cancer patient advocacy group communications
(CLICK) At FDA’s request, a medication guide has been drafted by the sponsor.  We are currently collaborating on this
(CLICK) Assessment of risk communication to patients and providers
(CLICK) And labeling changes.  A revised label was approved by FDA last Friday.

## FDA Risk Mitigation Labeling changes

- Removal of the indication for chemotherapy-induced anemia?

**Notes:**
FDA is concerned that the sponsor’s proposals may not be sufficient to mitigate current risks.
FDA requests that the committee consider the following additional steps.  
One strategy for risk mitigation that the committee may consider is removal of the indication for chemotherapy-induced anemia.

## FDA Risk Mitigation StrategiesPossible Labeling changes

- If indication for chemotherapy induced anemia remains ...
- Limit to CIA in pts w/SCLC?
- “ESA is indicated for treatment of CIA in pts w/SCLC receiving myelosuppressive chemotherapy”

**Notes:**
If the indication for chemo induced anemia were to remain in the label, FDA asks the committee to consider whether the following additional labeling changes are appropriate to minimize risks to patients.  

Restrict the current indication to specific cancer types where safety has been adequately assessed, which at the current time includes small cell lung cancer.
Sample labeling could state the following: “ESA is indicated for treatment of CIA in pts w/SCLC receiving myelosuppressive chemotherapy”

## FDA Risk Mitigation StrategiesPossible Labeling changes

- If indication for chemotherapy induced anemia remains ...
- Limit to CIA in pts w/locally advanced or metastatic cancer?
- “ESA is indicated for treatment of CIA in pts w/locally advanced or metastatic cancer receiving myelosuppressive chemotherapy”

**Notes:**
The committee may consider restricting the indication to use in patients who may not be cured, for example, patients w/locally advanced or metastatic cancer.
Sample labeling could state the following: “ESA is indicated for treatment of CIA in pts w/locally advanced or metastatic cancer receiving myelosuppressive chemotherapy”

## FDA Risk Mitigation StrategiesPossible Labeling changes

- If indication for chemotherapy induced anemia remains ...
- State not indicated for neoadjuvant and/or adjuvant?
- “ESA is indicated for treatment of CIA in pts w/locally advanced or metastatic cancer receiving myelosuppressive chemotherapy.  ESA is _not_ indicated for use in pts receiving neoadjuvant and/or adjuvant chemo”

**Notes:**
The committee may consider stating that ESAs are not indicated for patients receiving neoadjuvant and/or adjuvant treatment.
Sample labeling could state the following: “ESA is indicated for treatment of CIA in pts w/locally advanced or metastatic cancer receiving myelosuppressive chemotherapy.  ESA is not indicated for use in pts receiving neoadjuvant and/or adjuvant chemo”

## FDA Risk Mitigation StrategiesPossible Labeling changes

- If indication for chemotherapy induced anemia remains ...
- State not indicated for breast and/or head/neck?
- 2 studies with adverse findings in Breast Ca
- 2 studies with adverse findings in Head/Neck Ca
- “ESA is indicated for treatment of CIA in certain pts with cancer receiving myelosuppressive chemotherapy.  ESA is _not_ indicated for use in pts with breast or head/neck cancer.”

**Notes:**
The committee may consider stating that ESAs are not indicated for patients in clinical settings where harmful effects have been demonstrated in at least 2 studies, for example, in breast and/or head and neck cancers.
Sample labeling could state the following: “ESA is indicated for treatment of CIA in certain pts w/cancer receiving myelosuppressive chemotherapy.  ESA is not indicated for use in pts with breast or head/neck cancer.”

## FDA Risk Mitigation StrategiesPossible Labeling changes

- If indication for chemotherapy induced anemia remains ...
- Based on currently available data, should labeling specify the hemoglobin at which ESA should be initiated?

**Notes:**
Finally, based on currently available data, the committee may specify a hemoglobin level at which initiation of ESAs is appropriate, assuming a patient is asymptomatic and has no comorbid conditions.

## FDA Risk Mitigation

- Required Informed Consent
- Restricted Distribution system
- Thalidomide (STEPS)
- Lenalidomide (RevAssist)
- Isotretinoin (iPLEDGE)

**Notes:**
Other proposals for risk mitigation from FDA are as follows:
Require an informed consent between the patient and physician describing the risk and benefits of ESAs and RBC transfusions.  
A similar process has been done with other drugs, but FDA experience with this tool is limited, and this process can be difficult to monitor and enforce.
Another proposal is for a restricted distribution system.
Examples of a restricted distribution system includes existing systems in place with thalidomide, lenalidomide, and isotretinoin.
Such a system could restrict ESA prescribing to providers who agree to educate patients on the risks and benefits of ESAs, and verify patient hemoglobins and use ESAs according to the label.  ESA distribution would be limited to inpatient and outpatient pharmacies that only accept prescriptions from these enrolled providers.  
Developing such a system is a complex process.

This concludes FDA’s presentation.