SILVER SPRING, Maryland—Members of the Oncologic Drugs Advisory Committee (ODAC) unanimously recommended that the Food and Drug Administration grant accelerated approval to Fragmin (dalteparin sodium, Pfizer) for the extended treatment of symptomatic venous thromboembolism (VTE), proximal deep vein thrombosis (DVT), and/or pulmonary embolism (PE) to reduce the recurrence of VTE in patients with cancer.
The recommendation came after a long discussion with Pfizer and FDA representatives about whether some data presented by the company was, in fact, an important safety warning. After that question was resolved, the panel voted 12-to-0 that the totality of safety and efficacy results presented by Pfizer warranted approval of the company's supplemental marketing application. "I think the overall risk-benefit can be dealt with by some labeling initiatives," said William Hiatt, MD, professor of medicine, University of Colorado, and a member of FDA's Cardio-Renal Advisory Committee, who served as a voting consultant during ODAC's Fragmin deliberations.
Fragmin is a low-molecular-weight heparin(Drug information on heparin) whose antithrombotic properties derive from enhanced inhibition of Factor Xa and thrombin by antithrombin. In humans, the drug preferentially increases the inhibition of coagulation Factor Xa while only slightly affecting clotting time. Fragmin first received FDA approval in 1994 for the prophylaxis of DVT that might lead to PE in patients undergoing abdominal surgery.
Venous thromboembolism occurs in about 1 in 200 cancer patients. Cancer increases the risk of VTE up to 7 times and the risk of a recurrent clot 3.2 times, compared with noncancer patients. Said Craig Eagle, MD, head of Pfizer Worldwide Medical Oncology: "We note that there is no FDA-approved medication for the prevention of recurrent VTE in cancer patients, and low-molecular-weight heparin has the potential to confer clinical benefit in the management of VTE."CLOT Study
To support its application, Pfizer presented data from CLOT (Comparison of Low Molecular Weight Heparin vs Oral Anticoagulant Therapy for Long-term Anticoagulation in Cancer Patients With Venous Thromboembolism), a multinational, multicenter, randomized, open-label trial published in 2003.
The trial equally randomized 676 cancer patients with proximal DVT and/or PE to receive either Fragmin plus oral anticoagulant (OAC) or OAC alone for 6 months or until death. The majority of patients had solid tumors; only 40 (11.8%) in the Fragmin arm and 30 (8.9%) in the OAC-only group had hematologic malignancies.
The primary endpoint was objectively documented, symptomatic recurrence of DVT and/or PE. Secondary endpoints were symptomatic DVT, PE, or central venous thrombosis (CVT) of the upper limbs, neck, or chest; any bleeding; major bleeding; and death. Patients were followed for survival up to 12 months. The efficacy results were based on the intention-to-treat population and the safety findings on those actually treated (three individuals in the OAC-only arm did not receive treatment).
