FDA Review of Clinical Data Fragmin

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FDA Review of Clinical DataFragmin (Dalteparin
sodium injection) for treatment of VTE in cancer
patients

• Medical Officer Andrew Dmytrijuk, MD
• FDA/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
  studyanother 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
• 11 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
CLOT Study Results
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)
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Primary Endpoint Result
CLOT Study Results
Log rank p 0.002
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Time to First Recurrent VTE
CLOT Study Results
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)
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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 ? - 6
• Death without a recurrent VTE
• Fragmin 33 vs OAC 28 ? 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
CLOT Study Results
Log rank p 0.20
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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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CLOT Study Results

• Major Safety Observations
• Study drug discontinuations due to death
• Major bleeding
• Thrombocytopenia
• Liver enzyme/bilirubin elevations

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CLOT Study Results

• Study drug discontinuation due to death
• 17 Fragmin vs 7 OAC,
• however
• Overall mortality similar
• 39 Fragmin 41 OAC

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CLOT Study Results
Death rates by month of study drug
exposure median 176 days Fragmin 167 days OAC
Fragmin (N338) Fragmin (N338) OAC (N338) OAC (N338)
Study Period (Month) of Subjects Died Crude Death Rate of Subjects Died Crude Death Rate
lt1 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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CLOT Study Results

• Imbalance in study drug D/C due to death
• Possible safety signal
• Causes
• - imbalance in study drug exposure
• - variations in patient management
• - drug effect

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CLOT Study Results
Major Bleeding 6 Fragmin vs 4 OAC
Study weeks Fragmin Fragmin OAC OAC
Study weeks 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

• Thrombocytopenia
• Liver enzyme/bilirubin abnormalities

Lab Any grade Any grade Grade 3 Grade 3
Lab Fragmin OAC Fragmin OAC
Tpenia 11 8 6 3
ALT 40 31 4 2
AST 34 28 3 1
GGT 41 31 12 10
Bilirubin 13 11 4 2
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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

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• 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

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

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CLOT ITT Population
Dalteparin n 338 Dalteparin n 338 OAC 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 lt 30 9 3 6 2