Once-Promising Alcoholism Drug Runs Into FDA Roadblock

In a rare split from the recommendations of one of its advisory committees, the U.S. Food and Drug Administration (FDA) issued in July a “nonapprovable” letter to Lipha S.A. for its new-drug application for acamprosate.

Lipha, a French subsidiary of the German pharmaceutical giant Merck KGaA, had licensed the rights to market acamprosate to Forest Laboratories in October 2001 and had filed its new-drug application with the FDA in December 2001.

The FDA agreed to an expedited review in light of the significant need for new options for treating alcoholism and the low number of medications available for that purpose.

(The American pharmaceutical giant Merck and Co. has no connection to acamprosate.)

Acamprosate is available in 29 countries outside the United States, including most of Europe, China, Singapore, and Australia, as well as Central and South American countries. It has been prescribed to more than 1.5 million persons with alcohol abuse or dependence in those countries with no apparent pattern of serious side effects.

European data indicate that the drug has no potential for abuse or rebound effect after discontinuation. European data have also indicated that the drug effectively reduces craving for alcohol and can help maintain abstinence in dependent patients.

Nevertheless, according to a Forest Labs press release about the FDA’s decision, the FDA indicated to Lipha that in completing its review, it found that the data simply “did not adequately establish the safety and efficacy of acamprosate. The FDA has requested that at least one additional U.S. clinical trial evaluating safety and efficacy be conducted, as well as additional pharmacokinetic analyses and additional preclinical studies.”

The data in question, submitted as part of the new-drug application, were the sole subject for discussion at a May meeting of the Psychopharmacologic Drugs Advisory Committee (PDAC). During that meeting, the PDAC considered data from several clinical trials submitted by Lipha that appeared to be conflicting. In the trials conducted in European populations, safety and efficacy were well demonstrated, mostly in populations of “pure alcohol abusers” with severe abuse and dependence. However, clinical trial data from the United States, gleaned from an outpatient population containing a large proportion of polysubstance abusers, failed to show conclusively efficacy on primary outcome measures and indeed indicated that placebo was better on several secondary measures.

Several experts who testified, however, said that the European and American data were not directly comparable, because they were collected under different methodologies, with fundamentally different patient groups.

PDAC members voted 8 to 2 in favor of a recommendation that the drug was efficacious in preventing relapse in alcoholism, despite the apparent conflict between the European and American data.

It is rare for the FDA to go against the recommendation of one of its advisory committees, and as is its policy, agency spokespersons had no comment on the matter. ▪