# Presentation: 181773

## FDA PresentationODAC Meeting July 24 2007

- NDA 22042
- Applicant: Eli Lilly
- Evista®
- (Raloxifene Hydrochloride)

## Evista® Review Team

- 			**	****Primary Reviewers****	****	****Team Leaders**
**Medical****	****	****	****Patricia Cortazar****	****	****	****John R Johnson**
**	****	****	****	****Bhupinder S Mann**
**Statistical****	****	****Kun He****	****	****	****	****Raji Sridhara**
**Clinical Pharmacology****	****Julie Bullock****	****	****	****Brian Booth**
**CMC****	****	****	****Sarah Pope****	****	****	****Ravi Harapanhalli**
**Project Manager****	****	****Patricia Garvey**
**DSI****	****	****	****Lauren Iacono-Connors****	****	****Leslie Ball**

## Raloxifene Proposed New Indication:Women with Osteoporosis

- “The reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis”
- Supporting trials:** **
- RUTH, MORE and CORE

## Raloxifene Proposed New Indication: Women at High Risk for Breast Cancer

- “The reduction in risk of invasive breast cancer in postmenopausal women at high risk for breast cancer”
- Supporting trial:
- STAR

## Issues to Consider before Approval 

- Safety and efficacy of raloxifene
- Clinical Benefit:
- Reduction in the incidence of invasive breast cancer
- Risks:
- Adverse events associated with raloxifene exposure
- Deep vein thrombosis
- Pulmonary embolism
- Death due to stroke

## Approved Drug: Nolvadex (Tamoxifen Citrate)

- “NOLVADEX is indicated to reduce the incidence of breast cancer in women at high risk for breast cancer.”
- NSABP BCPT P-1 Eligibility:
- Age 35 to 59 years with projected 5-year risk of invasive breast cancer ≥ 1.66%
- Age ≥ 60 years
- Lobular Carcinoma *in situ*

## Raloxifene: Placebo-controlled Trials

| 
Trial  | Patient population 
(postmenopausal)  | 
Primary Endpoint |
| --- | --- | --- |
| RUTH  | High risk  of coronary events  | Major coronary events
Invasive breast cancer |
| MORE  | Osteoporosis | Vertebral fracture
BMD (lumbar spine & femoral neck) |
| CORE  | Osteoporosis  | Invasive breast cancer |

## Raloxifene Placebo-controlled Trials:

| Trial | Treatment Arms | Exclusion Criteria  |
| --- | --- | --- |
| RUTH | Raloxifene 60 mg
Placebo | H/O myocardial infarction (MI), percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG) within 3 months
H/O of venous thromboembolism (VTE) |
| MORE | Raloxifene 60 mg
Raloxifene 120 mg
Placebo | Cerebrovascular accident (CVA) within 10 yrs
H/O VTE |
| CORE | Raloxifene 60 mg
Placebo | Same as MORE except prior CVA not excluded |

**Raloxifene Placebo-controlled Trials:**
**Treatment Arms & Exclusion Criteria **

## RUTH:  Invasive Breast Cancers

- Invasive breast cancers:
- Raloxifene 			40 	(N = 5,044)
***IR per 1,000 person-years ******	******1.50***
- Placebo 			70 	(N = 5,057)
***IR per 1,000 person-years ******	******2.66***
- Absolute risk difference 	1.16
- Breast cancers diagnosed at stage ≤  II A
- Placebo 			92%
- Raloxifene 			83%

**IR: Incidence Rate**

## RUTH: Comparison of Safety and Efficacy

| 
Events | Raloxifene
 IR | Placebo
IR | Absolute
Risk
Difference | Relative Risk 
(95% CI) |
| --- | --- | --- | --- | --- |
| Invasive breast cancer  | 1.50 | 2.66 | -1.16 | 0.56 
(0.37, 0.84) |
| Clinical Vertebral fractures | 2.40 | 3.70 | -1.30 | 0.65
(0.47, 0.90) |
| Death due to Stroke  | 2.20 | 1.47 | +0.73 | 1.50 
(0.98, 2.30) |
| Stroke  | 9.46 | 8.60 | +0.86 | 1.10 
(0.91, 1.32) |
| Deep vein thrombosis  | 2.44 | 1.78 | +0.66 | 1.37 
(0.94, 1.99) |
| Pulmonary embolism  | 1.35 | 0.91 | +0.44 | 1.49 
(0.89, 2.49) |

**RUTH: Comparison of Safety and Efficacy**

## MORE:  Invasive Breast Cancers

- Invasive breast cancers:
- Raloxifene 			11 	(N = 2,576)
***IR per 1,000 person-years ******	******1.26 ***
- Placebo 			38	(N = 2,557)
***IR per 1000 person-years ******	******4.36***
- Absolute risk difference 	3.10
- Breast cancers diagnosed at stage ≤ II A
- Placebo 			96%
- Raloxifene 			90%

## MORE: Comparison of Safety and Efficacy

| 
Events  | Raloxifene
IR | Placebo
IR | Absolute
Risk
Difference | Relative Risk
(95% CI) |
| --- | --- | --- | --- | --- |
| Invasive breast cancer  | 1.26 | 4.36 | -3.10 | 0.29
(0.13, 0.58) |
| Clinical Vertebral Fractures | 7.08 | 12.27 | -5.19 | 0.58
(0.42, 0.80) |
| Death due to Stroke  | 0.51 | 0.69 | -0.18 | 0.74
(0.23, 2.52) |
| Stroke  | 5.16 | 6.42 | -1.26 | 0.80
(0.57, 1.14) |
| Deep vein thrombosis  | 2.50 | 0.92 | +1.58 | 2.72
(1.27, 6.68) |
| Pulmonary embolism  | 1.25 | 0.46 | +0.79 | 2.72
(0.92, 10.85) |

**MORE: Comparison of Safety and Efficacy**

## CORE:  Invasive Breast Cancers

- Invasive breast cancers:
- Raloxifene 			19 	(N = 2,716)
***IR per 1,000 person-years ******	******2.43***
- Placebo 			20 	(N = 1,274)
***IR per 1000 person-years ******	******5.41***
- Absolute risk difference 	2.98
- Breast cancers diagnosed at stage ≤ II A
- Placebo arm			94%
- Raloxifene arm		90%

## CORE: Comparison of Safety and Efficacy

| 
Events  | Raloxifene
IR | Placebo
IR | Absolute
Risk
Difference | Relative Risk
(95% CI) |
| --- | --- | --- | --- | --- |
| Invasive breast cancer  | 2.43 | 5.41 | -2.98 | 0.45
(0.23, 0.89) |
| Clinical vertebral fractures | 8.28 | 8.56 | -0.28 | 0.97
(0.62, 1.53) |
| Death due to Stroke  | 0.76 | 0.27 | +0.49 | 2.81
(0.34, 12.9) |
| Stroke  | 6.24 | 3.75 | +2.49 | 1.65
(0.92, 2.98) |
| Deep vein thrombosis  | 2.17 | 1.07 | +1.10 | 2.01
(0.68, 5.95) |
| Pulmonary embolism  | 1.15 | 0.00 | +1.15 | NA |

**CORE: Comparison of Safety and Efficacy**

## Summary of Benefits vs. RisksRaloxifene Placebo-controlled Trials

**RUTH:**** ****	****Benefit equals Risk**
- Benefit: ARR of **1.16** IBC per 1,000 P-Y and osteoporosis prevention and treatment
- Risk**:** equal increase in thromboembolic AEs IR
**MORE:****	****Benefit more than Risk**
- Benefit: ARR of **3.10** IBC per 1,000 P-Y and osteoporosis prevention and treatment
- Risk**:** smaller increase in thromboembolic AEs IR
**CORE:****	****Risk outweighs Benefit**
- Benefit: ARR of **2.98** IBC per 1,000 P-Y and osteoporosis prevention and treatment
- Risk: larger increase in thromboembolic AEs IR

**ARR: absolute risk reduction, IBC: invasive breast cancer, P-Y: person-years, **
**AE: adverse events, IR: incidence rate**

## Raloxifene: Risk vs. BenefitRaloxifene Placebo-controlled Trials  

- Reduced risk of invasive breast cancers
**Variability of raloxifene effect size:**
**Number of women needed to treat (NNT) for one year to prevent one invasive breast cancer:**
**RUTH ****	****862 (Women with ****≥****4 CV risk score)**
**MORE ****	****323 (Women with osteoporosis)**
**CORE ****	****335 (Women with osteoporosis)**
**NSABP P-1 ****	****300 (Women ****≥35 y old, ****at high risk)**
- Increased risk of thromboembolic adverse events
- Comparison of Risk vs.** **Benefit:
**Reduction in invasive breast cancer incidence and osteoporosis prevention and treatment benefit vs. increased risk of thromboembolic AEs**