# Presentation: 181771

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

## Questions

**1.****	****Safety:  The FDA review of the CLOT study cited a potentially important mortality safety signal related to the study drug discontinuation findings.  Discontinuation of the assigned study drug due to death was twice as common among patients receiving Fragmin as it was among patients receiving OAC.  The cause for this imbalance is unclear and not explained by findings within the CLOT study database.**

## Question 1

**   ****For example, the database did not show an excess in fatal hemorrhage among patients receiving Fragmin.  Post-hoc hypotheses, such as the possibility of informative censoring, have been proposed to account for the study drug discontinuation finding.  Regarding the excessive number of Fragmin discontinuations due to death:**

## Question 1

**  ****VOTE:  Do you regard the study drug discontinuation due to death finding as sufficient to preclude the approval of the application until the issue is resolved with additional clinical studies?**

## Question 2

**   ****Efficacy:  In order to rely on a single clinical study for definitive evidence of safety and efficacy, the primary endpoint result should be a robust finding.  Special considerations in evaluating the CLOT study’s primary endpoint result include the open label nature of the study, the differing anticoagulation management between the study groups, the endpoint’s competing risk with mortality, possible bias in VTE symptom detection and inconsistencies in exploratory analyses of the primary endpoint result.**

## Question 2

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**   ****VOTE:  considering these endpoint limitations, does the CLOT study provide substantial evidence of effectiveness?**

## Question 3

**   **_**Safety and Efficacy**_**:  If you provide favorable responses to the preceding safety and efficacy questions (“no” to safety question 1 and “yes” to efficacy question 2):**
**   ****VOTE:  Does the totality of the CLOT study’s safety and efficacy results provide a benefit to risk relationship sufficient to warrant approval of this supplemental marketing application?**

## Question 4

**   ****Label Considerations:  The CLOT study included predominantly patients with advanced (metastatic) cancer.  Exploratory subset analyses did not support an apparent treatment effect within the subsets of patients with hematological malignancies or patients with non-metastatic cancer.**

## Question 4

**a.  VOTE:  If marketing approval is recommended, should the product label limit the indicated patient population to a subset of “cancer patients” (for example, only patients with metastatic, non-hematologic cancer)?**

## Question 4

**b.  DISCUSSION:  If you vote to limit the indicated patient population, please discuss any important patient population limitations.**

## Question 5

**   ****Additional Clinical Studies:  The CLOT study was conducted among “cancer patients” and included predominantly patients with advanced (metastatic cancer).  Limitations in the study design were cited above.**

## Question 5

**   ****DISCUSSION:  If marketing approval is not recommended, please describe the types of clinical data the sponsor should submit to support approval, including any important study design considerations and the potential need for study of patients without cancer or the study of specific cancer patient populations.**