Full article reprinted from "The Pink Sheet" DAILY July 7, 2009
Even before the synthetic insulin/cancer scare emerged, the pharma industry had realized that the diabetes market was a safety minefield. They are getting a better map of the terrain, starting with the cardiovascular effects of type 2 diabetes medications. All new type 2 diabetes drugs must now meet rigorous criteria set by FDA in cardiovascular safety guidance in December. Read on...
Full article reprinted from "The Pink Sheet" DAILY July 7, 2009
At least some CV issues were resolved with the release of new trial data at the American Diabetes Association meeting in June. For one, GlaxoSmithKline announced results from the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes trial, otherwise known as RECORD. The prospective study upheld the safety of Avandia, but commercially speaking, the story may be over.
The meeting also showcased updates from two landmark outcomes studies - the Veterans Affairs Diabetes Trial and the Action to Control Cardiovascular Risk in Diabetes study. The data show that intensive lowering of hemoglobin A1C can dramatically cut cardiovascular risk in many patients.
But in the VADT, intensive control was associated with twice the risk for cardiovascular events for those who had diabetes for over 21 years. In other words, the sicker patients were, the less they benefited from treatment. To help make sense of the new data for industry, "The Pink Sheet" DAILY interviewed Mary Parks, director of FDA's Division of Metabolism and Endocrinology Products.
"Pink Sheet" DAILY: In RECORD, GlaxoSmithKline tested a general diabetic population, defined as aged 60, on average, with diabetes for six to eight years. How does the FDA define the general diabetic population?
Parks: I don't have a definition for the general population in diabetes. The reason why is that you are talking about a disease that affects 24 million in the U.S. It affects young and old, across many demographics.
"Pink Sheet" DAILY: Some interpret the RECORD data as vindicating Avandia. What is FDA's point- of-view?
Parks: I don't think we can comment because we haven't received complete results for RECORD. Until we receive and review it, I don't think I can tell you how it would impact Avandia or if there would be any policy change on diabetes drug development.
"Pink Sheet" DAILY: After the RECORD results came out, some doctors criticized Steve Nissen for pushing a flawed meta-analysis that resulted needlessly in the onerous CV guidance. How do you respond?
Parks: I think it's a false assumption that one trial, one drug, shaped this [guidance]. That certainly wasn't the case.
"Pink Sheet" DAILY: What were the most important take-home messages for you from VADT and ACCORD?
Parks: I think the important message is that CV risk reduction in the diabetic population requires multiple risk reduction. You have to target things such as blood pressure, lipids, smoking cessation, all of the established risk factors for heart disease. And glycemic control alone is probably not going to have as great of an impact on macrovascular risk reduction. Its greatest impact will more likely be on specific diabetes complications resulting from hyperglycemia, such as diabetic nephropathy or retinopathy.
"Pink Sheet" DAILY: ACCORD and VADT reached different conclusions on the link between hypoglycemia and higher mortality. How do you explain that?
Parks: Remember these are two different patient populations, even though they were looking at the same question- intensive versus more conventional glycemic control. You had in one study [VADT] a much higher risk population- older patients with longer disease and more insulin use. That may have contributed to the differences in findings.
"Pink Sheet" DAILY: What are the implications of the finding from both ACCORD and VADT that it is potentially dangerous to give sicker patients too many drugs in order to lower blood glucose?
Parks: These trials are perhaps only confirming what in clinical practice a lot of people have already put into place. If you take an 80-to 90-year-old diabetic, it may not be in their best interest to be so aggressive at getting their blood sugar down so low that they are at risk for hypoglycemia.
"Pink Sheet" DAILY: What does that mean in terms of involving sicker patients in trials to satisfy the FDA cardiovascular safety guidance?
Parks: A sicker patient doesn't necessarily mean an 80-to-90 year-old patient. I think you need to recognize VADT and ACCORD ask very different questions from what FDA guidance requires companies to do. VADT and ACCORD were asking specifically if intensive glycemic control versus less intensive glycemic control will make a difference in CV outcomes trials. For FDA trials, that is not what we require companies to do. If anything, they [drug developers] want to have balance in glycemic control and other CV risk factors so that it will be easier to interpret what exactly is going on with the drug.
"Pink Sheet" DAILY: The guidance for type 2 diabetes drugs suggests that companies need to have a minimum number of cardiovascular events in trials, which means involving sicker patients. Would that requirement be affected by the new trial results?
Parks: The guidance doesn't outline a number of events. There is no percentage, no minimum number of events. The number is actually the goalpost, the upper bound of the 95 percent confidence interval. We don't talk about how many events are needed or even annual event rates.
Obviously, to make it within a reasonable timeframe, they want to enroll sicker patients with enough CV risk to be able to rule out that upper bound. But there is no minimum requirement for cardiovascular events.
"Pink Sheet" DAILY: Are there any implications then of ACCORD and VADT for trials or the guidance?
Parks: I think those results have implications on guidelines for managing diabetes and to that extent, that will probably impact on trials- whether companies want to put in stopping rules or dose adjustments in treatment algorithms for glycemic control, when to add on a therapy, when to consider that a patient requires additional therapy, will be based on those findings.
- Emily Hayes
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