The Food and Drug Administration plans to alert the nation's doctors this week to concerns arising from two recent studies of Bendectin, the only FDA-approved medicine for the "morning sickness" of early pregnancy, according to an advance copy of the agency's Drug Bulletin.
The bulletin, to be released within a few days, according to an FDA source, cites increased rates of a stomach deformity among infants whose mothers took Bendectin.
The release will come after nearly two months of negotiations with the manufacturer, Merrell Dow Pharmaceuticals Inc., which agreed in June to reveal the studies in a "Dear Doctor" letter requested by the FDA. But on July 20, Merrell Dow refused to send the letter, according to FDA documents.
In a phone conversation that afternoon, an agency memo shows, an FDA official told a Merrell Dow vice president "that the firm's last-minute refusal to carry out an agreement negotiated in good faith over a period of weeks was unfair to the agency."
Merrell Dow said it reversed itself because a third study, with a larger data base than the other two combined, showed no association between Bendectin and the deformity. The company had cited this study in its draft of the "Dear Doctor" letter before agreeing to send the letter.
Information from that third study is also included in the FDA bulletin, which emphasizes that available data neither proves nor disproves an association between Bendectin and the deformity.
"Nevertheless," the bulletin says, "the reported association . . . is of concern because it represents the first observation of a possible adverse fetal effect of Bendectin that has been reported from more than one study . . . . It is therefore important that all who may prescribe or receive Bendectin be kept as fully informed as possible about factors that might influence a decision to use it . . . ."
The defect, pyloric stenosis, constricts the stomach outlet soon after birth, reducing ability to eat, and can cause severe dehydration and malnutrition. If left untreated, it can be fatal in weeks. Short, safe surgery can remedy the defect, which occurs an estimated one to three times in each 1,000 live births.
Nearly 2 1/2 months ago, Merrell Dow surprised the FDA by saying it had halted Bendectin's production and distribution while still selling what it called "the most tested drug for pregnant women" to present users. The announcement attributed the production halt solely to "compelling non-medical reasons," particularly costs of defending about 300 lawsuits. But the documents disclose that at the time of the announcement, the FDA was about to require Merrell Dow to disclose the pyloric stenosis association in the official Bendectin labeling.
The bulletin is the FDA's first effort to convey strong caution about Bendectin in the 27 years in which an estimated 33 million women worldwide have received the drug. It advises avoiding all drugs in pregnancy because nausea and vomiting in the first trimester "can usually be managed without . . . any drug."
In the first study referred to in the bulletin, two Yale University epidemiologists said Bendectin may more than quadruple the risk of stomach malformation. The work was federally funded and published in mid-December.
That led the FDA to commission a second and as yet unpublished study, by the Boston Collaborative Drug Surveillance Program at Boston University Medical Center. By May, its early findings showed a 2.7 times greater risk of the deformity.
The third study, by Boston University's drug epidemiology unit and also not published, found no association between Bendectin and 325 cases of pyloric stenosis, compared with 60 cases in the other two studies. This study was disclosed June 16 at an obscure medical meeting in Canada.
Dr. Samuel Shapiro, head of the Boston University unit, said the study had no connection with the $200,000 paid the unit annually by Merrell to monitor adverse reactions to its marketed drugs.
On June 9, in announcing the production halt, Merrell Dow executive David B. Sharrock emphasized that "the burdens of marketing Bendectin have become just too heavy" and that "we have absolutely no doubt of its safety." A few hours later, Dr. Paul Leber, an FDA division director, asked Merrell Dow to issue the "Dear Doctor" letter, so physicians and women still using Bendectin could be "fully informed."
The next day, however, FDA Commissioner Arthur Hull Hayes Jr. reinforced the company stance, telling a national television audience that Merrell Dow made the decision "for financial reasons . . . . There is no new scientific evidence yesterday or today."
In a subsequent letter, Rep. Doug Walgren (D-Pa.) accused Hayes of "misleading" the public because Hayes did not mention the second study. Hayes replied that he believed that study had not been fully evaluated.
Merrell Dow, however, soon agreed to send the "Dear Doctor" letter, and on June 27, Dr. Robert L. Powell, its director of drug regulatory affairs, sent Leber a draft text. Leber rejected it two weeks later, writing Powell that it was "a less than fair representation of the possible significance" of the two studies.
"Had you not elected to cease the manufacture and distribution of Bendectin, we would have already asked you to change the current product labeling to reflect the concern raised by the two studies," Leber wrote. "Consequently, we ask that you send the precise text of our FDA draft."
Two days later, Powell said that "in a spirit of full cooperation," the company was agreeing to the FDA draft, except for minor changes readily accepted by the agency.
The agreement was derailed on July 20, when vice president George H. Ohye phoned Leber to say he had been directed to read the text of a telex message then sent over his name from the headquarters of Dow Chemical, owner of Merrell Dow.
After a review, the message said, "our research executive staff . . . concluded that the data do not support a finding that the association exists." Leber said in a memo that he protested the breach of agreement to Ohye and said he would at once urge the FDA to "make public our views about the association."
The next day, Dr. Robert Temple, Leber's boss, tried to turn the company around. Temple said he stressed to Ohye "our very strong concern" and the FDA's preference for a "Dear Doctor" letter. But Merrell Dow held fast, with Powell writing that the company "relied heavily" on the third study.
With that, Dr. Harry M. Meyer Jr., director of the FDA's National Center for Drugs and Biologics, and other top agency officials summoned Ohye and Merrell Dow's international medical director July 29 to renew the FDA's request for a "Dear Doctor" letter, with mailings to begin within a week.
The Merrell Dow executives asked for a recess to seek guidance. An hour later, they reported that the company was reconsidering. Then Powell phoned Meyer to blame the reported reconsideration on confused company communication and say it would not yield.
An FDA memo says Meyer ended the conversation by saying that the FDA "would go forward with its own plans."