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12:00 AM
Apr 27, 2015
 |  BioCentury  |  Regulation

CVOT crossroads

Why patients, doctors want FDA to revisit its 2008 diabetes CV guidance

As data begin to trickle in from the wave of cardiovascular outcomes trials mandated in the wake of the Avandia rosiglitazone debacle, patients, physicians and some of FDA's own advisory committee members think the agency should either scrap the requirement for outcomes studies, or refocus them on issues that matter to patients and physicians.

On April 14, FDA's Endocrinologic and Metabolic Drugs Advisory Committee met to discuss results from the SAVOR and EXAMINE cardiovascular outcomes trials of the DPP-4 inhibitors Onglyza saxagliptin from AstraZeneca plc and Nesina alogliptin from Takeda Pharmaceutical Co. Ltd.

SAVOR and EXAMINE are the first two cardiovascular outcomes trials (CVOTs) completed under FDA's 2008 guidance that requires companies with diabetes drugs to rule out at least a 30% increase in the risk of major adverse cardiac events (MACE) after approval.

The guidance was issued after a 2007 meta-analysis by cardiologist Steven Nissen and epidemiologist Kathy Wolski at the Cleveland Clinic concluded there was an increased risk of myocardial infarction (MI) and CV mortality for patients treated with GlaxoSmithKline plc's Avandia. Readjudicated data from the RECORD outcomes study exonerated Avandia, yet the guidance remains.

Onglyza and Nesina showed no increased risk for MACE.

Data from two more cardiovascular outcomes studies are expected in June, and if these data show a similar result for MACE, two members of FDA's own advisory committee told BioCentury the agency should consider revising the guidance either to focus on class-specific cardiovascular concerns, or to allow a tiered approach to development in which newly approved diabetes drugs are reserved for low-risk patients unless or until their safety in higher-risk patients is assessed.

Alternatively, one patient-physician group thinks the agency should scrap the guidance in favor of postmarket monitoring tools like FDA's Mini-Sentinel system or a forthcoming diabetes patient registry.

Clearing the hurdle

SAVOR and EXAMINE used MACE as the primary endpoint, which included cardiovascular death, non-fatal MI and non-fatal stroke, compared with placebo.

Onglyza met the primary endpoint of SAVOR (HR=1.00; 95% CI: 0.89, 1.12), as well as the secondary endpoint of no increase in MACE-plus, which included hospitalization for heart failure, hospitalization for unstable angina and coronary revascularization (HR=1.02; 95% CI: 0.94, 1.11).

SAVOR enrolled 16,492 diabetes patients with a history...

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