Grassley Seeks GAO Input on Surrogates and Postmarketing Follow Up by FDA

In his letter to the Government Accountability Office [GAO], Sen. Grassley asks for an investigation into FDA’s use of surrogates for product approval and whether FDA has appropriately followed up drugs approved initially based on surrogate markers. He cites recent examples of Avandia and Vytorin as cases where the system hasn’t worked as intended.

Is he right?

Avandia was aproved on the basis of a surrogate marker, HbA1c, but the marker is a surrogate for the effects of chronic hyperglycemia on the body. It is not a proven surrogate for the outcome of heart disease, as Sen. Grassley implies.

The effects of chronic hyperglycemia in patients with Type 2 diabetes that are well established include heightened risks of diabetic microvascular disease, which is associated with diabetic nephropathy, retinopathy, and neuropathy and their sequelae. There is decent evidence that reduction in chronic hyperglycemia reduces the risk of these serious health outcomes.

There is also reasonable evidence for associations of chronic hyperglycemia with other diabetes sequelae that relate to microangiopathies. The evidence for an independent effect of chronic hyperglycemia in Type 2 diabetes on macrovascular diseases, which include heart disease, is much weaker. Therefore, to say that FDA failed in its duties by approving a drug based on its effects on hyperglycemia alone is disingenuous.

On the other hand, I’ve long supported large premarketing simple safety studies for drugs to be used chronically in large populations (see here, for example), so if Sen. Grassley’s intention is to try to make such studies a requirement, I support him. I just don’t support his implication that FDA shouldn’t have relied on reduction in HbA1c as a demonstration of efficacy. It was then and is now an adequate surrogate endpoint for many of the detrimental effects of chronic hyperglycemia due to Type 2 diabetes.

The other chosen example, Vytorin, is another poor one to use against the choice of a surrogate to claim efficacy. As I’ve explained in an earlier post, the ENHANCE study did not establish the lack of efficacy of Vytorin or Zetia, as Sen. Grassley implies. It merely demonstrated that in a highly selected population of patients with atypical hypercholesterolemia, the use of Zetia with statin failed to reduce progression of carotid intimal thickness, itself an unproven surrogate measure for the outcome of cardiovascular death or disability. Genuine cardiovascular outcomes studies with this class of drug are underway.

Was Sen. Grassley wrong to imply that makers of drugs used to lower LDL-C or raise HDL-C should be required to do hard outcomes studies prior to approval? Yes and no. For the statin class, there’s little doubt that using LDL-C as a surrogate is justified, given the benefits on heart disease risk reduction shown with several class members, at least in patients with established heart disease at baseline.

For other classes of drugs, including the class containing Zetia/Vytorin, I think he’s mostly right, with one exception. There are some diseases independently associated with high cholesterol in the blood that are amenable to treatment with drugs that lower blood cholesterol. However, these conditions are rare and typically affect only those patients with very high lipid levels.

So, generally speaking, I agree with the implication and with the sentiment. Drugs used to lower LDL-C that will be used primarily by people like me who hope to reduce their risk of heart disease should be studied rigorously in the premarket setting, and such study should include evaluation of their effects on disease outcomes, rather than unproven surrogates (both LDL-C and CIMT, in the case of Zetia/Vytorin).