(4) STATEMENT OF PETER BARTON HUTT ON LEGISLATION TO ESTABLISH FIVE YEARS OF PATENT TERM EXTENSION FOR LOPID (GEMFIBROZIL) October 8, 1987 This statement is submitted in support of legislation to provide five years of patent term extension for the prescription drug Lopid (gemfibrozil). drug law. For the past 28 years I have specialized in food and Food and Drug Administration. During 1971-1975 I served as Chief Counsel for the Presently I am a partner in the Washington, D.C. law firm of Covington & Burling. I am the co-author of the casebook used to teach food and drug law in law schools throughout the country and I have written numerous articles on food and drug law, including articles on regulation of new drugs and patent term extension. I. General Background. Lopid was developed by Warner-Lambert as part of a basic research program designed to discover, investigate, and obtain Food and Drug Administration (FDA) approval of new drugs to reduce serum cholesterol. Lopid was synthesized in 1968. Animal toxicity studies were begun in 1969, the same year that a patent application was filed in the United States. As is true with most new drugs, the investigation and FDA approval of Lopid took years. The investigational new drug (IND) plan was submitted to FDA in 1971 and, after extensive human study, the new drug application (NDA) was submitted in 1980. Ultimately, FDA determined that the NDA for Lopid was approvable on September 25, 1981, and in fact the NDA was approved on December 21, 1981. The investigational studies conducted on Lopid in humans demonstrated two effects. First, the drug reduced low density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol, and triglycerides, in the blood. Second, the drug also increased high density lipoprotein (HDL) cholesterol. LDL and VLDL cholesterol are widely regarded as the "bad cholesterol" which increases the risk of heart disease, and HDL cholesterol is regarded as the "good cholesterol" which reduces the risk of heart disease. When the status of Lopid was discussed with the FDA Endocrinologic and Metabolic Drug Advisory Committee in 1979, however, it became apparent that the Panel would not recommend approval of a "reduces the risk of heart disease" claim without more direct proof that, in fact, patients taking the drug experienced a reduction in morbidity or mortality. Accordingly, FDA declined to approve any claim for Lopid directly relating to heart disease. Instead, when the NDA was approved in December 1981, the only permitted claim was the very narrow use for adult patients with elevated triglycerides at risk for pancreatitis. More important, however, FDA informed Warner-Lambert that the drug would not be approved at all, even with the very narrow claim that was ultimately approved in December 1981, unless a "Phase IV" study (i.e., a study conducted after approval of an NDA) was immediately begun to demonstrate that - 3 use of Lopid results in decreased morbidity or mortality from heart disease. Lopid had already been the subject of a pilot study relating to heart disease in Finland, which has the highest male mortality rate from heart disease in the world. That study had shown a 70 percent reduction in the expected heart attack rate. In light of the fact that Warner-Lambert was made aware that FDA would require a large long-term Phase IV study, Warner-Lambert began negotiations in 1979 with the World Health Organization, the University of Finland, and the Health Ministry of Finland, to undertake a definitive heart attack prevention study in high risk patients in Finland. This study referred to as the Helsinki Heart Study undertaken specifically and solely to satisfy the FDA requirement for a Phase IV study on heart disease. - - was Although FDA approval of many NDAs has been conditioned upon Phase IV studies, the Lopid study was highly unusual and, to my knowledge, without prior precedent or subsequent duplication. It is the only Phase IV clinical study required by FDA to investigate an unapproved claim. It is also the largest Phase IV study to date, and the only one of which I am aware that was designed to address a major research issue, the effectiveness of raising HDL cholesterol. The FDA requirement for a Phase IV study was not an informal or inconsequential element of the FDA approval of the NDA for Lopid. It was a formal element of the NDA approval, on which the approval was specifically conditioned. Attached to this statement are the FDA approvable letter of September 25, 1981, and the FDA approval letter of December 21, 1981. The approvable letter states, on page 5, that: "Approval of this application is also contingent upon your commitment to conduct an appropriate Phase IV study of certain aspects of effectiveness and long-term safety of gemfibrozil. Satisfactory completion of the ongoing Finnish study would be expected to meet this condition." Similarly, the approval letter of December 21, 1981, states that: "In your October 8, 1981 letter, you stated Thus, the Phase IV study was a formal FDA condition for the III. The Drug Price Competition and Patent Term Restoration Act of 1984. The planning for the Helsinki Heart Study began in 1979, patients were screened and recruited in 1980, and the first group of patients entered this study in 1981. Most of the funding for the study was provided by Warner-Lambert, although complete responsibility for the conduct of the study was undertaken by the Helsinki Heart Council, an organization created specifically to insulate the study from any potential outside factors. Ultimately, after screening about 23,600 eligible males, the study included roughly 4,000 high risk patients. |