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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).

For the past 28 years I have specialized in food and

drug law.

During 1971-1975 I served as Chief Counsel for the

Food and Drug Administration.

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.

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 exten

sive human study, the new drug application (NDA) was submitted in 1980. Ultimately, EDA determined that the NDA for Lopid was approvable on September 25, 1981, and in fact the NDA was

approved on December 21, 1981.

[blocks in formation]

density lipoprotein (LDL) cholesterol, very low density

lipoprotein (VLDL) cholesterol, and triglycerides, in the


Second, the drug also increased high density lipopro

tein (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 EDA

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 with

out more direct proof that, in fact, patients taking the drug experienced a reduction in morbidity or mortality. Accordingly,

EDA 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


More important, however, EDA 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 (1.e., a study conducted after approval of an NDA) was immediately begun to demonstrate that


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 EDA 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 require

ment for a Phase IV study on heart disease.

Although EDA approval of many NDAs has been condi

tioned 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 EDA to investigate an unapproved claim.


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.


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


"In your October 8, 1981 letter, you stated
that the Phase IV studies that we requested
as a condition for approval had been under-

Thus, the Phase IV study was a formal FDA condition for the

NDA approval.

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


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