A new congressional report charges that the maker of an antidepressant called Merital knew of at least 30 overseas deaths associated with the medicine, but failed to notify the Food and Drug Administration before it let Merital go on sale in the United States.
But the 95-page document -- approved unanimously by a House committee -- aims its sharpest charges at the FDA, calling its approval of Merital 2 1/2 years ago an example of the agency's failure to protect the public from prescription medicines that are both unsafe and ineffective.
Merital was introduced as an antidepressant that would be better tolerated by the elderly than the commonly prescribed tricyclic drugs to fight depression.
At the same time, the FDA's own files and the medical literature contained evidence of Merital's capacity to induce a variety of sometimes severe allergic reactions, the report said. Yet, it charged, the FDA overlooked the danger signals and thus was unable to alert physicians to be on the lookout for early signs of trouble.
Hoechst AG of West Germany was selling Merital in 31 countries by December 1978, when its U.S. subsidiary, Hoechst-Roussel Pharmaceuticals Inc. of Somerville, N.J., applied for FDA approval to sell the drug here.
The agency approved the drug on Dec. 31, 1984, and Hoechst-Roussel began to sell it in July 1985. An estimated 190,000 Americans had received Merital by January 1986, when Hoechst voluntarily ended sales worldwide in the face of increasing numbers of serious and sometimes fatal adverse reactions, the report said.
The report made the first public disclosure that at least 30 fatalities had become known to Hoechst, starting in 1977, before the U.S. approval. Several apparently involved allergic reactions, 10 involved drug-associated suicide and/or fatal overdose, three involved cardiac complications, and four involved hemolytic anemia, a rare disorder in which the immune system destroys red blood cells.
The report was prepared by the Human Resources and Intergovernmental Relations Subcommittee, whose chairman, Rep. Ted Weiss (D-N.Y.), held two hearings on Merital last year as part of a major inquiry. The full Government Operations Committee unanimously approved the report and released it July 19.
A Hoechst-Roussel spokesman who saw the report on Friday said he had no immediate comment.
The FDA said that "unfortunately, marketed drugs to help the seriously depressed are associated with numerous risks, some quite serious and potentially fatal.
"Merital was reviewed at unusual length -- six years. Cases of hemolytic anemia were known -- but none had been fatal -- at the time of approval. When a fatal case became known, FDA took immediate steps to strengthen the drug's labeling to reflect the changed risk-benefit ratio."
Health officials point out that all potent medicines carry the risk of side effects.
The report said, however, that the FDA's handling of the new antidepressant reflected in part a persistent failure to accord adequate attention to the safety records of drugs that, like Merital, were sold abroad before entering the domestic market. In the Merital episode, the report said, the pattern was aggravated by Hoechst's noncompliance with a wide array of reporting regulations, including one requiring the disclosure of deaths or other alarming reactions within 15 days.
For example, the report said, Hoechst neglected to tell the FDA in the pre-approval period that it had received reports of serious Merital-related side effects, and withheld from the agency unusual lab findings suggesting the potential to induce allergic reactions.
In the first three months of marketing -- July through September 1985 -- the subsidiary knew of "at least 100" reports of adverse effects that it did not provide to the FDA until early 1986, the report said.
Yet the agency took no action in response to Hoecht's reporting irregularities until the subcommittee called them to FDA's attention, the report said.
"FDA's continuing evasion of its law enforcement obligations undermine public confidence that the agency is receiving all the information it needs to make responsible assessments of the risks of new drugs," Rep. Weiss said in a statement accompanying the report.
At a May 1986 hearing, the FDA agreed -- under prodding by Weiss -- to review evidence turned up by his staff in order to decide whether Hoechst-Roussel should be prosecuted for noncompliance with the 15-day deadline for disclosure of alarming reactions. An agency investigation is under way.
A second Merital hearing two months later revealed subcommittee staff evidence that Hoechst-Roussel or its parent company had delayed reporting at least 17 overseas deaths among users of the antidepressant, including one that was delayed for six years.
Dr. A. John Nelson of Hoechst's U.S. affiliate in 1981 told the FDA advisory committee for antidepressants that "the safety of the drug is not in doubt."
The subcommittee report said: "At the very least, Hoechst's failure to reflect Merital's potential to induce hemolytic anemia fatalities in the drug's originally approved labeling rendered the drug misbranded within the meaning of the Food, Drug, and Cosmetic Act."
Also at the July 1986 hearing, Weiss told FDA Commissioner Frank E. Young that Hoechst AG had known in 1980 of the death in Italy of a woman on Merital who had developed hemolytic anemia. Yet, Weiss told Young, the U.S. subsidiary did not tell the FDA of the death until June 1986.
Under law, a sponsor must show the FDA that a drug is effective in its intended use with "substantial evidence," meaning at least two adequate and well-controlled studies. According to the report, however, the FDA approved the antidepressant drug although: Some agency reviewers found that two of the three studies upon which approval was based did not constitute reliable evidence of Merital's intended use in depression. The majority of studies submitted by Hoechst showed Merital to be no more effective than, or even inferior to, treatment with a placebo, or dummy pill.
The report said that as of the May 1986 hearing -- four months after Hoechst withdrew Merital -- "FDA was not aware that the drug was highly immunogenic; i.e., it induced drug-specific antibodies in a very high percentage of patients taking it.
"FDA's lack of awareness speaks not only to the agency's unfamiliarity with relevant publications in the world literature, but also to the sponsor's failure to make full and timely reports of this information," the report charged.
Subcommittee investigations of other no-longer-sold drugs have produced evidence that known side effects are sometimes overlooked during the drug approval process.
Oraflex, an Eli Lilly arthritis drug, was withdrawn from the market after the drug was connected to kidney and liver damage. The company pleaded guilty to 25 criminal counts for failure to report deaths in overseas use of the drug.
Zomax, a painkiller, was withdrawn from the market by Johnson & Johnson's McNeil Pharmaceutical subsidiary in the spring of 1983. In two days of hearings shortly afterward, the subcommittee found that the FDA had received reports of more than 2,000 allergic reactions, and that the responsible agency officials were unaware of most of those reports.
"Merital," Weiss said, "is but the most recent in a series of drugs -- including Oraflex and Zomax -- that the Committee of Government Operations has cited as evidence of the agency's need to anhance the public's protection from dangerous and unproven medicines."