9/24/17: BENDECTIN®: THE TRUE STORY; A Safe Treatment for Nausea and Vomiting of Pregnancy, Part Three of Four

morningsickness

(Parts one and two appeared 9/17/17 and 9/20/17, respectively.)

When they targeted abnormalities, the epidemiologists who studied Bendectin usually looked at limb reductions and malformations; cleft lips and cleft palates; and heart defects. One study, however, focused on an intestinal condition, and, in an ironic and roundabout way, caught Sjoerdsma’s reluctant attention.

PYLORIC STENOSIS

Pyloric stenosis is a narrowing of the gastric pylorus, the passage at the lower end of the stomach that opens into the duodenum, the first section of the small intestine. Caused by congenital muscular hypertrophy, the condition occurs in one to three newborns per thousand—more often in males than females, and in familial lines—and develops several weeks after birth. Manifested by frequent projectile vomiting, pyloric stenosis can be easily corrected with minor surgery.

In December 1982, two Yale epidemiologists published the results of a case-control study that suggested an “association” between Bendectin exposure in utero and infantile pyloric stenosis. Drs. Brenda Eskenazi and Michael B. Bracken interviewed thousands of mothers who gave birth to babies between 1974 and 1976 at certain Connecticut hospitals. Although their data supported a Bendectin “risk factor,” they did not show a direct drug-to-defect causal relationship.

In response to the Yale report, the FDA commissioned a second pyloric stenosis study from Hershel Jick of the Boston Collaborative Drug Surveillance Program at Boston University Medical Center. In an earlier FDA-supported investigation, Jick and his colleagues had assessed the prevalence of major congenital disorders among infants born to a cohort of mothers in Seattle who had taken a variety of drugs during early pregnancy. They found no association between Bendectin and any birth defects, but they did not examine pyloric stenosis because the condition is not present at birth.

 I thought Hershel Jick was a damn good man, and I believed him. He said there was nothing there.

To identify its Seattle cohort, the Jick team used the automated pharmacy and hospital records of maternity patients enrolled in a prepaid group health plan. It returned to these databases to probe the alleged Bendectin-pyloric stenosis connection. By May 1983, the team’s early unpublished findings showed that, although the total number of infants with pyloric stenosis was exceedingly small, those exposed to Bendectin had a greater risk of developing it than unexposed infants did.

Had Sharrock not halted Bendectin production, the FDA reportedly would have required a disclosure of the pyloric stenosis association in the drug’s labeling. In June, unbeknownst to Sjoerdsma, the FDA began negotiating with Merrell Dow to send out a “Dear Doctor” letter, warning physicians of this alleged adverse effect. When Sjoerdsma found out, inadvertently, in July about the letter, he was furious.

The damn thing had gone around me and up to Orrefice’s desk. [Paul Orrefice was chairman of Dow Chemical.] I didn’t hear about it until 11 o’clock at night. I was talking with Bill Kuhn [a pharmacologist who handled many administrative matters], and Bill mentions that we’re working on the “Dear Doctor” letter, and George Ohye’s going to be talking with the FDA about it the next day. I said, “What ‘Dear Doctor’ letter?”

I said, “Bill, there’s no way we’re going to send a letter out to every doctor in the country warning them about pyloric stenosis. We’ve got to stop it.” He says, “You can’t do that.” And I said, “The hell I can’t. I’ll blow everybody out, including Orrefice.”  Which I did. That was when I was in my prime, at moments like that. . . . .

The next morning, Kuhn gets in touch with Ohye, who’s at the FDA, discussing the letter. I get on the phone with him, and I say, “George, you’re going to kill the letter.” He says, “We can’t do that.” And I said, “You’re goddamned right we can.” He said, “Well, what are we going to do?” I said, “If they want a letter, let them send out a letter.” . . . This was an example of how people in industry—especially, Cincinnati-based industry—bowed and scraped to the FDA. The FDA eventually sent out a letter or a bulletin that didn’t say anything. It was watered down, buried. It was typical government.

According to The Washington Post, Ohye telephoned the FDA’s Dr. Paul Leber on July 20, 1983, and read him a Telex message, sent from Dow Chemical headquarters over Ohye’s name. It said, in part, that after a review, “our research executive staff . . . concluded that the data do not support a finding that [the] association exists.” Publicly, the company would claim that it reversed itself because the early results of a third case-control study had found no risk of the defect.  But Merrell insiders knew better.

I hadn’t approved the letter. I never even saw the damn thing. . . . I’m in charge of research. I make this decision.

Sjoerdsma unquestionably thought “the business” had undercut his authority, but he also adamantly and swiftly disregarded the two studies. Why?

I just didn’t believe it. There was no biochemical rationale for it. But let’s say it was true . . . pyloric stenosis is no big deal. It’s something you’d see right away and can cure with minor surgery. You can diagnose it immediately and operate and fix it. It’s not as though you’ve got a permanent defect. My feeling was it was either minor, or not true. Pyloric stenosis was just another one of these kind of unbelievable effects.

The results of Jick’s Seattle study and the third study, which Boston University’s drug epidemiology unit conducted, were published in 1984. Jick found a “positive association” between first-trimester Bendectin use and pyloric stenosis—again, without a causal interpretation—while BU found no increased risk. In seeking to explain the conflict, Jick’s team postulated, ironically, that perhaps “the severe nausea of pregnancy” induced pyloric stenosis. Certainly, it noted, no biologic basis existed for the connection.

More problematic for Jim Newberne was an earlier FDA-commissioned study at the University of California’s Primate Research Center. According to Sjoerdsma, Andrew G. Hendrickx, a prominent primate teratologist, gave Bendectin or a placebo to pregnant monkeys, “whose gestation period was roughly five months, and did an interim sacrifice [at 100 days] of a certain number of the fetuses. I think they took five treated and five placebo, something like that. And they found septal defects in the hearts of the treated animals’ fetuses. Holes in the heart.”

Hendrickx called Newberne, his good friend and Teratology Society colleague, to alert the problem. The Merrell pathologist was then in weekly contact with the FDA and other regulatory people, worldwide, about Bendectin.

Jim came into my office with this long face. He says, “Al, I don’t know what to do. They think Bendectin is having an effect on the heart.” He showed me this stuff. . . . He couldn’t understand it because this defect had never been reported in human infants. I said, “Jim, all I know is, wait until the end of the 150 days [full pregnancy] and see what you get.” Well, they didn’t find anything. Zero.

When Hendrickx conducted a more elaborate study to verify the earlier results, Newberne insisted “that these monkeys go to term.” Full-term, newborn monkeys did not exhibit the interventricular septal “defect,” which, he learned, serves a function while the heart is embryonic, but heals before birth.

Sjoerdsma was not surprised.

***

The conclusion of this series on the Bendectin story will appear 9/27/17.

Ann, 9/24/17

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