I am delighted to comment on the science/science policy background of the proposal to extend the patent life of Gemfibrozil. As you know, I was a member of the National Heart Lung and Blood Institute of the National Institutes of Health from 1963 to 1981 and served as its Director from 1975 to 1981. Between 1973 and 1983 I also served as a special consultant to the Food and Drug Administration on anti-lipid drugs. Since leaving government I have been a consultant in the area of lipid lowering drugs to several pharmaceutical companies including Warner Lambert. My personal research interest and publications are all in the field of lipoproteins, lipid transport, lipid metabolism and approaches to atherosclerosis in relation to hyperlipidemia.

Let me begin by stating that it is virtually impossible to overemphasize the magnitude of coronary heart disease in the United States or the potential cholesterol reduction now appears to have in controlling it. Over the last several decades an increasing body of evidence has gradually accumulated suggesting a causative relationship between blood cholesterol levels and the number 1 killer disease in the United States, Coronary Artery Disease, a resultant of coronary artery atherosclerosis. This evidence includes studies in animals, as well as morphologic compositional studies of atherosclerotic plaques, and genetic, metabolic and epidemiologic studies in man.

In genetic studies we have powerful evidence that individuals who inherit high levels of LDL (the so called had cholesterol) or low levels of HDL (the so called good cholesterol) are at high risk for early and severe coronary artery disease. In addition, many prospective epidemiologic studies, like the landmark NHLBI-sponsored

Framingham study, leave little doubt that there is a powerful association between high cholesterol and risk of coronary artery

disease.

Despite all this, many viewed epidemiologic and genetic studies as providing merely circumstantial evidence and considered animal studies as not being necessarily relevant to man and demanded clinical trial evidence of the direct value of cholesterol lowering in man before any public health action against cholesterol was initiated. This indeed was the view point of a NAS report published in 1980. Because of all this controversy, the NHLBI Arteriosclerosis Task Force in 1971 and again in 1980 recommended, of highest priority, the initiative that resulted in the Lipid Research Clinic's Coronary Primary Prevention Trial. This trial begun in 1973 was reported in January 1984. It cost NHLBI an estimated 160 million dollars and involved almost 4,000 American hypercholesterolemic men, age 35-59. It demonstrated conclusively for the first time that intervening on cholesterol saves lives. For every 18 reduction in cholesterol in this study there was a 2% reduction in coronary risk, heart attack and heart death.

In 1985, armed with the now overwhelming body of evidence, an NIH Consensus Conference on Cholesterol Lowering concluded that there was an undeniable causal relationship between cholesterol and coronary artery disease and that those Americans with elevated cholesterols should have their cholesterols lowered cholesterol lowering saves

lives.

- 3

The question was no longer whether cholesterol lowering was beneficial, the questions were now more practical

who, when and how

to treat. Since 1986 and under the coordinating umbrella of the National Heart Lung and Blood Institute, NIH, a National Cholesterol Education Program has sought to get the facts about cholesterol to the health professional and the public.

This all is presented as background to the Gemfibrozil issue. In 1980 when Gemfibrozil was being evaluated by the FDA there was no consensus on the efficacy of cholesterol lowering and in fact a clinical trial involving a similar but different lipid lowering drug had just reported out serious side effects (the European WHO Primary Prevention Trial with Clofibrate). Many within FDA in fact wondered whether any new cholesterol lowering drugs should be approved until the efficacy of cholesterol lowering on CHD risk was proven. A compromise solution arrived at in late 1981 was to allow Gemfibrozil to be approved and marketed but with a very limited indication for the individuals with the highest blood lipid levels at risk for pancreatitis and with the company's commitment to perform a Phase IV (post-market surveillance) trial (the Helsinki Heart Study) of the efficacy of their drug in preventing CHD (no such requirement was previously made prior to approval of a lipid lowering drug nor has it been made since).

With the conclusion of the Lipid Research Clinics Trial and the NIH Consensus Development Conference, a tremendously increased interest in cholesterol lowering has occurred. FDA considered with

its advisory boards whether it should require cholesterol lowering agents to be shown not only to lower cholesterol, but to prevent CHD, before being approved and were advised that the costs involved in large-scale studies using death and heart attack as endpoints (The Helsinki Heart Study of 4,000 subjects will undoubtedly cost its sponsors over 30 million dollars) and the immature state of the art of noninvasive surrogates of coronary artery disease progression precluded this.

Thus Gemfibrozil was reviewed and approved in an atmosphere now gone. It was only approved with a requirement for a Phase IV study that has cost millions of dollars, a study that would not be asked for today. I am thus very sympathetic to the sponsor's plight; they have supported a difficult multicenter clinical trial asking an important basic research question and costing millions of dollars. To the best of my knowledge all of the major multicentre clinical trials evaluating the efficacy of lipid lowering in the past have been publicly funded.

Gemfibrozil's mechanism of action is different from other lipid lowering agents. It very effectively lowers triglyceride and often dramatically raises HDL. If the Helsinki Heart Study is positive we will have the first conclusive evidence of the value of increasing HDL. Now with the change in scientific perception and with the passage of the 1984 patent legislation, Warner Lambert finds itself about to lose Gemfibrozil's patent rights exactly at the time that their clinical trial is concluding. This all does not seem fair.

- 5

As far as I know, this entire course is unique. No other lipid lowering drug has required extensive Phase IV studies prior to

approval. No other drug has been caught in the window as pharmaceutical patent law changed.

Warner Lambert should be

congratulated on maintaining their commitment to science and to a scientific question of great magnitude.