The only accepted treatment for Type I diabetes is insulin therapy, and many patients with Type II diabetes also receive insulin. The experience of Amylin Pharmaceuticals Inc. at last week's FDA advisory panel meeting indicates that as companies work to develop new hypoglycemic agents for use with insulin, they will face complex treatment issues that may have to be addressed in separate trials. In particular, companies may find that they need to run one kind of trial to show efficacy, and another type of trial to explore how to use new compounds in combination with insulin in real life.

Despite enthusiasm shown by the panel members for AMLN's Symlin pramlintide, the Endocrinologic and Metabolic Advisory Committee voted against approval to treat Type I and Type II diabetes as an adjunct to insulin. While the panel concluded that AMLN demonstrated that pramlintide has efficacy as measured by decreases in glycosylated hemoglobin (HbA1c) in both Type I and Type II patients, it also said the company did not provide sufficient information to guide physicians in the use of pramlintide as an adjunct to insulin.

The panel also concluded that AMLN did not provide adequate safety data, largely based on concerns about the elevated incidence of hypoglycemia in patients during the first four weeks of therapy.

Pramlintide is a synthetic analog of amylin, an endogenous pancreatic hormone, that reduces glucose production and reduces gastric emptying time.

The panel's concerns about guiding physician use of insulin and pramlintide raised in acute form the issue many companies face in designing clinical trials: demonstrating efficacy versus re-creating real-world conditions. But the situation is far more complicated in trials using insulin, because patients vary their insulin dosing on a daily basis, while most drugs are given in fixed doses (e.g., 20 mg/day) or fixed ratios based on weight (e.g., 20 ug/kg).

Joseph Cook, chairman and CEO, emphasized that the company's first burden was to demonstrate the efficacy of pramlintide. And Joann Data, senior vice president of regulatory affairs and quality assurance, argued that "there is no one trial design that can address all the issues" of efficacy and dosing.

According to Data, the process of developing a product for use in a chronic condition consists first of establishing efficacy and second of establishing the optimal way to use the product. She added that fine-tuning of dosing often is performed in Phase III or early Phase IV studies.

Running the trials

Endogenous insulin increases uptake of glucose from the bloodstream by peripheral cells.