ODAC Recommends That FDA Approve New Indication for Fragmin to Reduce VTE Recurrences in Ca Patients

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 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).

CLOT researchers reported a 52% reduced risk of recurrent VTE in the Fragmin-treated patients (P = .0017), and a 49% reduced risk of recurrent DVT, PE, or CVT (P = .003), compared with OAC alone. They found no significant difference in time to first major bleeding between the two groups, but a significant difference (P = .05) favoring Fragmin in time to any bleeding, either major or minor. There was no significant difference in survival between the two groups, either at 6 months or 12 months.

FDA Review

The FDA review team noted that most of the reduced risk of recurrent VTE in the Fragmin patients occurred in the first month of CLOT, at a time when they were receiving a higher dose of the drug than in the remaining 5 months. Moreover, the two study arms had similar VTE-free survival rates, and the time to VTE or death, while favoring the Fragmin patients, was not significant (P = .20).

FDA also raised what it called a "potentially important mortality safety signal" found during its analysis of the CLOT data. "Discontinuation of the assigned study drug due to death was twice as common among patients receiving Fragmin as it was among patients receiving OAC alone," the agency said in a document framing its questions to ODAC. "The cause of this imbalance is unclear and not explained by findings within the CLOT study base." FDA presented a chart of the death rates by month on the study drug, which showed a greater number of deaths among the Fragmin patients in each of the trial's 6 months.

'There Is an Answer'

The ODAC committee spent some time trying to resolve the issue until one of Pfizer's biostatisticians addressed it. "FDA is completely right to see this as a signal and to ask the question," said Michael Gaffney, PhD, the company's senior director for statistical research and consulting. "Where we disagree completely is that the data from the CLOT study do not provide an answer. There is an answer."

Dr. Gaffney explained that the mortality imbalance is due to censoring of patients who died on treatment. Because Fragmin does not require laboratory monitoring and for other reasons, it can usually be given to patients with terminal cancer until they die, unlike OAC, which must generally be discontinued as cancer patients approach death. Thus, more patients in the OAC arm discontinued the study drug before death due to reasons related to clinical management, and more patients on Fragmin were taking the drug when they died.

Another bias in the "on treatment" mortality analysis, he said, relates to the frequency of recurrent VTEs, which was reduced in the Fragmin patients. Study drug was discontinued for patients who developed recurrent VTEs, and since more OAC patients developed VTEs, they were more likely to discontinue treatment and thus be censored from the "on treatment" mortality analysis.

"So there is no mortality difference," Dr. Gaffney said. "There is an explanation from the data and the committee has got to understand that."

Following the committee's vote to recommend accelerated approval for Frag-min, ODAC members also voted 10-to-2 against recommending that the labeling for the drug limit its use in certain subsets of cancer patients.

FDA noted in its medical review of Fragmin that patients in the CLOT study predominantly had metastatic cancers and that exploratory subset analyses did not support an apparent treatment effect in the relatively few patients with hematologic malignancies or nonmetastatic cancer. Most ODAC panel members, however, rejected the agency's suggestion that Fragmin's labeling should exclude use of the drug in some cancer patients.

"I would like further analysis from the company," said ODAC member Alexandra M. Levine, MD, medical director of the University of Southern California Norris Cancer Hospital. "But I would not vote so based on the [FDA's] subset analysis, which is not valid."