FDAnews Drug Daily Bulletin

EMA Releases New Guidance on Deep Vein Thrombosis Trials

April 8, 2015

The European Medicines Agency is revising the way drugmakers conduct studies for drugs to treat blood clots, for the first time separating out the clinical requirements for different types of clots.

The updated guideline adds recommendations for testing drugs for superficial vein thrombosis, or clots that are close to the skin, as opposed to deep in the legs. Trials for sVT should enroll patients with extensive, symptomatic clots that are at least 5 cm long, the guideline says. Primary endpoints should focus on extension or recurrence of these clots — via documented extension or recurrence of superficial clots, or documented symptoms of deep vein clots or nonfatal clots in the lungs.

Noninferiority trials for these near-surface clots should use clot-related deaths as a primary endpoint, while superiority designs should look at all-cause deaths, the EMA recommends.

The agency generally wants study drugs evaluated against active comparators in Phase III trials, but leaves drugmakers the choice of which comparator to use in certain patient groups.

Sponsors treating patients with first-time clots, for example, may use either direct oral blood thinners or some combination of an oral vitamin K antagonist and an anticoagulant, such as low molecular weight heparin. Sponsors should follow these patients for the first time for three months to a year, the EMA says. For patients who are at high-risk of recurrence, the treatment period should be at least six months with one month of follow-up.

For special patient populations whose clots resulted from another condition, such as pregnancy or cancer, however, low molecular weight heparin is the best choice, the EMA says, and this should be continued for at least five days, or until coagulation levels are in normal range.

Safety Endpoints

The EMA also recommends a number of secondary safety outcomes, including stroke, heart attack, death resulting from clots, fatal lung clots or sudden, unexplained deaths for which lung clots can’t be ruled out. Sponsors should use autopsy and doctors’ reports to determine these events and categorize deaths as “nonvascular,” “vascular” or “unknown etiology.”

All patients should be followed for bleeding complications over the same time period, regardless of stratification, the EMA says.

The guideline updates definitions for different types of bleeding that sponsors should use as primary safety outcomes. For example, “major bleeding” is defined as an intracranial, intraocular, intraspinal, pericardia, retroperitoneal, intra-articular or intramuscular event that causes hemoglobin to drop more than 2 g/dL, requires transfusion of two or more units of blood and necessitates surgery or is fatal.

When it comes to diagnosing clots, the EMA recommends commonly used methods such as bilateral compression ultrasonography or pulmonary angiography, as well as newer methods, such as computed tomography venography and magnetic resonance venography.

CTV is similar to ultrasound in diagnosing deep vein thrombosis and allows clinicians to see the pelvic and deep femoral veins, leading to detection of an additional 3 percent of cases, the agency notes.
Comments are due to CVSWPSecretariat@ema.europa.eu by Sept. 30. View the guideline at www.fdanews.com/04-01-15-EMAbloodclotsguidance.pdf. — Lena Freund