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FDA Review of Clinical DataFragmin®

(Dalteparin sodium injection) for treatment of VTE in cancer

patients

Medical Officer: Andrew Dmytrijuk, MDFDA/Center for Drug Evaluation and Research

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Presentation

• Regulatory Background

• “CLOT” Study―Special Considerations

• Introduction to Questions

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Regulatory Backgound

Types of VTE Indications

– Prophylaxis:

• Primary prevention

• Lower anticoagulant drug dose

– Treatment:

• Secondary prevention

• Higher anticoagulant drug dose

Differing risk: benefit considerations

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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)

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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

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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

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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

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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

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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.

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CLOT STUDY―Special Considerations

“Randomized Comparison of Low Molecular Weight Heparin (Dalteparin) versus Oral Anticoagulant Therapy for Long Term Anticoagulation in Cancer Patients with Venous Thromboembolism”

Design Features

Results

Regulatory context

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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

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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

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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

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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.

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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

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Subject Disposition

Fragmin OACRandomized 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

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Primary Endpoint Result

Log rank p = 0.002

CLOT Study Results

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Time to First Recurrent VTE

PeriodFragmin

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

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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

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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

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Categories of Death & VTE OutcomesDifferential 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%

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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

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Time to VTE or Death

Log rank p = 0.20

CLOT Study Results

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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

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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

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Major Safety Observations

• Study drug discontinuations due to death

• Major bleeding

• Thrombocytopenia

• Liver enzyme/bilirubin elevations

CLOT Study Results

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Study drug discontinuation due to death

• 17% Fragmin vs 7% OAC,

however

• Overall mortality similar

• 39% Fragmin 41% OAC

CLOT Study Results

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CLOT Study Results

Death rates by month of study drug exposuremedian 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

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Imbalance in study drug D/C due to death

• Possible safety signal

• Causes:

- imbalance in study drug exposure

- variations in patient management

- drug effect

CLOT Study Results

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CLOT Study Results

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%)

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CLOT Study Results

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

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Summary of Safety Findings

CLOT Study Results

1. More Fragmin patients discontinued study drug due to death

2. Fragmin group experienced numeric excess in:

• Major bleeding

• Thrombocytopenia

• Liver enzyme/bilirubin elevations

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CLOT Overall SummaryDesign 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

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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

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Topics for Questions:

1. Assessment of CLOT safety findings

2. Robustness of CLOT study efficacy findings

3. Potential label considerations

4. Potential need for additional studies

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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