A leading drug manufacturer was accused yesterday of trying to step up sales of a cholesterol-lowering medicine called Atromid-S after a 13-year study had showed it to be causing hundreds of deaths annually.
The accusation was made by the nonprofit Health Research Group (HRG), which is affiliated with Ralph Nader, and by officials of the National Heart, Lung and Blood Institute and the Food and Drug Administration.
Their target, Ayerst Laboratories, conferred with the FDA last week about the charges but did not respond to a reporter's request for comment. Ayerst is a division of American Home Products Corp., which last year ranked 94th on the Fortune magazine list of the 500 largest industrial corporations.
An estimated 500,000 to 1 million Americans, most of them middle-aged men with high cholesterol levels, take Atromid-S, a trade name for clofibrate. In 1978, Ayerst grossed $24 million from 3.6 million prescriptions for the drug.
The participants in the study were European men. But if it applied precisely to a half-million American men who took Atromid-S for an average of 10 years, the HRG's Dr. Sidney M. Wolfe calculated, "5,500 excess deaths would occur" among them.
An internal study by the Heart Institute of the European mortality figures, cited by Wolfe in a letter to the FDA, concluded the figures were "strongly suggestive of an increased risk of cancer, liver, and gall bladder disease" in users of clofibrate.
The major finding of the European study, a cooperative venture of the World Health Organization (WHO), was published in November 1978 in the British Heart Journal. But last July, Ayerst produced an eight-page sales promotion brochure for Atromid-S.
In his letter to FDA Commissioner Jere Goyan, Wolfe charged that the stepped-up sales, campaign employed "false and misleading advertising" and urged Goyan to seek a criminal prosecution in a chronology he compiled, Wolfe recalled that in 1968, a year after the FDA approved Atromid-S for use in lowering cholesterol and other blood fats, the agency had forced Ayerst to write a "Dear Doctor" letter to correct a "misleading" claim of "a beneficial effect" on heart disease.
FDA spokesman Wayne L. Pines called the sales effort "misleading" and said that it did not represent "responsible behavior." But, he told a reporter, the agency's Bureau of Drugs judged that the complaint could not be successfully prosecuted.
Pines recalled that the Atromid-S case is not the first time the FDA has found Ayerst seeking to convert an adverse scientific study into a sales advantage.
He cited a 1976 FDA bulletin to health professionals that called Ayerst "irresponsible" for "clouding the issues" in a promotional letter to physicians mailed after studies had shown that another of its drugs, Premarin sharply increased the risk of cancer in the lining of the uterus. Premarin is a postmenopausal estrogen.
The WHO clofibrate study enlisted 15,745 healthy men -- residents of Edinburgh, Budapest and Prague -- who had not had heart attacks.
The two main groups of participants had high blood cholesterol levels. One group got colfibrate: the other got placebos, or dummy pills. The major finding was that the overall annual death rate in users, 4.9 per 1,000, was 29 percent higher than in nonusers, 3.8 per 1,000.
The annual rate of gall bladder operations in users, 2.1 per 1,000 was more than double that in nonusers, 0.9.
But the annual rate of fatal heart attacks in users, 1.6 per 1,000 was not significantly higher than in nonusers, 1.4 per 1,000.
And nonfatal heart attacks, in contrast to the other findings, were significantly lower in users, 4.6 per 1,000, than in nonusers, 6.0.
Dr. Marion Finkel, deputy director of the Bureau of Drugs, said the WHO report led the FDA to try "at the very least to greatly narrow the indications [accepted reasons] for use." This was to be done by tightening the official labeling, or prescribing instructions for doctors.
The FDA finally did write a strict label, including a special boxed warning. Ayerst published the new label as the last page of its sales promotion brochure, entitled "The Coronary-Prone Patient."
In August the FDA's advertising chief, Dr. Peter Rheinstein, met with Ayerst to raise objections to the brochure. In September, in a draft letter to Ayerst vice president Henry Perdue, Rheinstein termed some material in the brochure "false and misleading."
Also in September, according to minutes of a meeting with Ayerst, Rheinstein said that the brochure -- and medical journal advertisements similar to it -- gave "an unbalanced view of the product." He asked that the brochure be recalled from Ayerst salesmen who call on doctors and that further ads be canceled.
Heart Institute Director Robert Levy, in a letter to Wolfe, said that the brochure and ads had "apparently turned a lemon into lemonade" in their treatment of the WHO report.
On Oct. 5, Perdue notified Rheinstein that Ayerst had yielded to his demands.
Wolfe asked Commissioner Goyan not only to seek a criminal prosecution, but also to "neutralize the false and misleading promotion" with corrective ads, tougher labeling and leaflets warning clofibrate users of the 29 percent higher death rate.
At last week's meeting with Ayerst, the FDA's Pines said, the agency discussed two possibilities: leaflets for patients and an "extensive education effort" for physicians to follow up on Atromid-S bulletin the FDA sent out in August.
Depending on how these possibilities pan out, he said, "we will consider the need for further tightening of the labeling." Ayerst has until Jan. 10 to respond, Pines said.