# Presentation: 710082

## FDA Review of Clinical DataFragmin® (Dalteparin sodium injection) for treatment of VTE in cancer patients

**Medical Officer: Andrew Dmytrijuk, MD**
**FDA/Center for Drug Evaluation and Research**

## Presentation

**Regulatory Background **
**“****CLOT” Study****―Special Considerations**
**Introduction to Questions**

## Regulatory Backgound

_**Types of VTE Indications**_
_**Prophylaxis**_**:**
**Primary prevention**
**Lower anticoagulant drug dose**
_**Treatment**_**:**
**Secondary prevention**
**Higher anticoagulant drug dose**
_***Differing risk: benefit considerations***_

## Regulatory Background

**Drugs with VTE Indications **
_**Prophylaxis:**_** **
**Heparin (unfractionated) **
**Lovenox (enoxaparin sodium)**
**Arixtra (fondaparinux sodium)**
**Fragmin (dalteparin sodium)**
**Warfarin **
_**Treatment:**_
**Heparin (unfractionated) with Warfarin**
**Lovenox (enoxaparin sodium)**
**Arixtra (fondaparinux sodium)**
**Innohep (tinzaparin sodium)**

## Regulatory Background

**Drugs with VTE  Indications**
**Specific population for prophylaxis**
**Broad population for treatment**
**Short term use of low molecular weight heparin drugs**
**At least two adequate and well controlled studies**
**Extensive historical experience with heparin/warfarin**

## Regulatory Background

***Guidance for Industry: ***
***Evidence of Effectiveness (May, 1998)***
**“****Usual requirement for more than one adequate and well-controlled investigation...”**
***or***
**“****Demonstration of effectiveness by a **_**single study**_** of a new use, **_**with independent substantiation**_** from related study data”**
***or***
**“****Evidence of Effectiveness from a single study”...*****another study unethical or impossible***

## Regulatory Background

**Whether a **_**single study + supportive data**_** *****or***** **_**single study alone**_**:**
**“****In all cases, it is presumed that the single study has been appropriately designed, that the possibility of bias due to baseline imbalance, unblinding, post-hoc changes in analysis or other factors is judged to be minimal and that the results reflect a clear prior hypothesis documented in the protocol.”**
** *****ie., robust study findings***

## Regulatory Background

**Fragmin is currently approved for:**
**Deep Vein Thrombosis**_** (DVT) prophylaxis**_** in patients:**
**undergoing hip replacement surgery **
**undergoing abdominal surgery**
**at risk for thromboembolic complications due to severely restricted mobility during acute illness**
***(5000 IU SC daily up to 8 - 14 days)***
** **_**Ischemic complication prophylaxis**_** in unstable angina and NQWMI when administered with ASA**** **
***(10000 IU SC every 12 hrs up to 8 days)***
***Not approved for treatment of DVT***

## Fragmin sNDA Proposed Indication and Dose

**“****Fragmin is also indicated for the extended treatment of symptomatic venous thromboembolism (VTE) (proximal DVT and/or PE), to reduce the recurrence of VTE in patients with cancer.”**
**200 IU/kg (max. 18,000 IU) SC for 1 month followed by 150 IU/kg (max. 18,000 IU) SC for 5 additional months.**

## CLOT STUDY―Special Considerations

**“****Randomized **_**C**_**omparison of **_**L**_**ow Molecular Weight Heparin (Dalteparin) versus **_**O**_**ral Anticoagulant **_**T**_**herapy for Long Term Anticoagulation in Cancer Patients with Venous Thromboembolism”***** ***
***Design Features***
***Results***
***Regulatory context***

## CLOT Design

**International, multicenter**
**Open-label**
**1:1 randomization****	**
**Fragmin vs OAC**
**Population: Cancer patients with acute proximal DVT and/or PE**
**Primary endpoint: comparison of time to first symptomatic recurrent VTE during 6 month study period**

## CLOT Design

_**Experimental**_**  (Fragmin group)**
**	****Initial Rx - **_**Fragmin 200 IU/kg**_** SC qd x 1 month**
**	****Extended Rx- Fragmin 150 IU/kg SC qd x 5 months **
_**Control**_** (OAC group)**
**	****Initial Rx - **_**Fragmin 200 IU/kg**_** SC qd x 5-7d + OAC**
**	****Extended Rx – OAC with INR 2-3 x 6 months**

## CLOT Design

_**Features:**_
**Open label**
**Study groups differed in anticoagulation monitoring**
**OAC group required regular blood INR monitoring**
**Potential impact upon symptom monitoring **
**“****Symptomatic VTE” primary endpoint required survival****―results susceptible to:**
**Death without VTE**
**Difficulty in VTE ascertainment near time of death**
**Initial Fragmin use in both study arms**
**Superiority to placebo/assumptions**

## CLOT Study Timeline & Protocol Changes

*** ******First patient enrolled: May 3, 1999***
*** ******September 13, 1999: Primary endpoint redefined from:***
*** ***_***Recurrent VTE & Major Bleeding***_*** ***
***to ***
_***Recurrent VTE***_
*** ******Sample size readjusted: 1999 and 2001***
*** ******Last patient completed: April 9, 2002.***

## CLOT Study Results

**Baseline Characteristics**
**Balanced between study groups**
**Median age 64 (22-89)**
**90% solid tumors**
**75% stage IV**
**10% no evidence of tumor**

## Subject Disposition

|  | Fragmin | OAC |
| --- | --- | --- |
| Randomized | 338 | 338 |
| Discontinued study drug | 158 (47%) | 172 (51%) |
| ---due to death | 56 (17%) | 24 (7%) |
| ---due to VTE | 21 (6%) | 47 (14%) |
| ---due to bleed | 10 (3%) | 19 (6%) |
| ---due to AE | 17 (5%) | 19 (6%) |
| ---other | 54 (16%) | 63 (19%) |

***CLOT Study Results***

## Primary Endpoint Result

**Log rank p = 0.002**

***CLOT Study Results***

## Time to First Recurrent VTE

| Period | Fragmin
n = 338 | OAC
n = 338 |
| --- | --- | --- |
| Weeks 1 – 4 | 11 (3%) | 33 (10%) |
| Weeks 5 - 28 | 16 (5%) | 20 (6%) |
| Total | 27 (8%) | 53 (16%) |

***CLOT Study Results***

## Time to First Recurrent VTE

***CLOT Study Results***

-  **Survival required to experience VTE symptoms**
** ****Mortality and VTE present competing risks **
** ****40% mortality at six months**
** ****Death rate 3X greater than VTE rate**
** ****Imbalances in VTE-death categorical outcomes**
** ****VTE-free survival similar between study groups**

## Categories of Death & VTE Outcomes

***CLOT Study Results***

| Outcome | Fragmin 
n = 338 | OAC
n = 338 |
| --- | --- | --- |
| Died but did not have recurrent VTE | 111 (33%) |  97 (28%) |
| Had recurrent VTE and then died |  20 (6%) |  40 (12%) |
| Had recurrent VTE and survived |  7 (2%) |  13 (4%) |
| None of the above | 200 (59%) | 188 (56%) |

***Subjects counted only once in each category***

## Categories of Death & VTE OutcomesDifferential Effects

***CLOT Study Results***

** **_**Death**_** followed a recurrent VTE: **
** ****	****Fragmin 6% vs OAC 12%; ****Δ**** = - 6%**
** **_**Death**_** without a recurrent VTE:**
**	****Fragmin 33% vs OAC 28%; ****Δ**** = + 5%**

## Categories of Death & VTE Outcomes

***CLOT Study Results***

** ****Inaccuracy in diagnosis of VTE near/at time of death may importantly impact results**
** ****VTE-free survival outcomes useful**
** ****	****- Straightforward clinical interpretation**
**	****- Resolves competing risk considerations**

## Time to VTE or Death

**Log rank p = 0.20**

***CLOT Study Results***

## Other Exploratory Efficacy Analyses

***CLOT Study Results***

-  **“****Time to treatment failure” (defined as time to recurrent VTE or discontinuation of study drug due to death) showed similar outcomes between study groups (log rank p = 0.65)**
**Post-hoc, exploratory subset analyses suggested no treatment effect among patients with:**
** ****nonmetastatic cancer**
** ****hematologic cancer**
** ****Hospitalization rates similar between study groups**

## Summary of Efficacy Finding Limitations

***CLOT Study Results***

-  **Robustness of primary endpoint called into question by:**
** ****Competing risks of death and VTE**
** ****Design features: differing patient management ****	****between study groups/symptom detection** 	**/open label**
** ****Variable results among sensitivity analyses**

## CLOT Study Results

** ****Study drug discontinuations due to death**
** ****Major bleeding**
** ****Thrombocytopenia**
** ****Liver enzyme/bilirubin elevations**

***CLOT Study Results***

## Study drug discontinuation due to death

**17% Fragmin vs 7% OAC, **
***	******	******	******	******however***
**Overall mortality similar**
**39% Fragmin 41% OAC**

***CLOT Study Results***

## Death rates by month of study drug exposure

***CLOT Study Results***

**Death rates by month of study drug exposure**
***median 176 days Fragmin; 167 days OAC***

|  | Fragmin (N=338) |  | OAC (N=338) |  |
| --- | --- | --- | --- | --- |
| Study Period (Month) | # of Subjects Died | Crude Death Rate  | # of Subjects Died | Crude Death Rate |
| <1 | 17 | 5.4 | 11 | 3.7 |
| 1-2 | 15 | 5.8 | 3 | 1.3 |
| 2-3 | 9 | 4.0 | 4 | 1.9 |
| 3-4 | 4 | 1.9 | 3 | 1.6 |
| 4-5 | 9 | 4.5 | 0 | 0 |
| 5-6 | 5 | 2.8 | 0 | 0 |

## CLOT Study Results

** ****Possible safety signal**
** ****Causes:**
**	****- imbalance in study drug exposure **
**	**
**	****- variations in patient management**
**	****- drug effect**

***CLOT Study Results***

## Major Bleeding: 

**Major Bleeding: **
**6% Fragmin vs 4% OAC**

| Study weeks | Fragmin |  | OAC |  |
| --- | --- | --- | --- | --- |
|  | At risk
n | Major Bleed
n | At risk
n | Major Bleed
n |
| 1 | 338 | 4 (1.2%) | 335 | 4 (1.2%) |
| 2 – 4 | 332 | 9 (2.7%) | 321 | 1 (0.3%) |
| 5 - 26 | 297  | 9 (3.0%) | 267 | 8 (3.0%) |

##  Thrombocytopenia

| Lab | Any grade |  | Grade ≥ 3 |  |
| --- | --- | --- | --- | --- |
|  | Fragmin | OAC | Fragmin | OAC |
| T’penia | 11% | 8% | 6% | 3% |
| ALT | 40% | 31% | 4% | 2% |
| AST | 34% | 28% | 3% | 1% |
| GGT | 41% | 31% | 12% | 10% |
| Bilirubin | 13% | 11% | 4% | 2% |

** ****Thrombocytopenia**
** ****Liver enzyme/bilirubin abnormalities**

## Summary of Safety Findings

***CLOT Study Results***

-  **1. More Fragmin patients discontinued study drug due to death**
** ****Fragmin group experienced numeric excess in:**
**Major bleeding**
**Thrombocytopenia**
**Liver enzyme/bilirubin elevations**

## CLOT Overall Summary
Design limitations:
	- open label
	- redefined primary endpoint
	- differing anticoagulation management in study groups
	- primary endpoint required survival
Efficacy:
	- treatment effect confounded by competing risks of 		death and recurrent VTE
	- treatment effect for Fragmin evidenced in the first 			month; no further gain in months 2-6
Safety:
	- excess study drug discontinuation due to death,
	- small excess in major bleeding, thrombocytopenia, 		liver test abnormalities

**Design limitations:**
**	*****- open label***
***	******- redefined primary endpoint***
***	******- differing anticoagulation management in study groups***
***	******- primary endpoint required survival***
**Efficacy:**
***	******- treatment effect confounded by competing risks of ******	******	******death and recurrent VTE***
***	******- treatment effect for Fragmin evidenced in the first ******	******	******	******month; no further gain in months 2-6***
**Safety:**
**	*****- excess study drug discontinuation due to death,***
***	******- small excess in major bleeding, thrombocytopenia, ******	******	******liver test abnormalities***

## CLOT Study in Regulatory Context
CLOT is a single study with important limitations in data interpretation
Short term regimens of Fragmin have proven efficacy and safety in other populations when used for VTE prophylaxis
Proposed indication and dose regimen is only for “cancer patients” with VTE
Safety and efficacy of proposed dose regimen has not been confirmed for broader population of patients with VTE

**CLOT is a single study with important limitations in data interpretation**
**Short term regimens of Fragmin have proven efficacy and safety in other populations when used for VTE prophylaxis**
**Proposed indication and dose regimen is only for “cancer patients” with VTE**
**Safety and efficacy of proposed dose regimen has not been confirmed for broader population of patients with VTE**

## Topics for Questions:
Assessment of CLOT safety findings

Robustness of CLOT study efficacy findings

Potential label considerations 

Potential need for additional studies

**Assessment of CLOT safety findings**
**Robustness of CLOT study efficacy findings**
**Potential label considerations **
**Potential need for additional studies**

## CLOT ITT Population

|  | Dalteparin n = 338 |  | OAC n = 338 |  |
| --- | --- | --- | --- | --- |
|  | n | % | n | % |
| ECOG 0,1 | 215 | 64 | 213 | 63 |
| Solid Tumor | 298 | 88 | 308 | 91 |
| Stage IV | 223 | 66 | 232 | 69 |
| Heme Ca | 40 | 12 | 30 | 9 |
| 30 ≤ CrCl ≤ 60 | 65 | 19 | 82 | 24 |
| CrCl < 30 | 9 | 3 | 6 | 2 |