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

morningsickness

News that Catherine, Her Royal Highness the Duchess of Cambridge, is pregnant with her third child and again in the throes of hyperemesis gravidarum put me in mind of a drug that effectively treated severe vomiting during pregnancy for decades until litigation drove it off of the U.S. market. (Emesis means vomiting; gravidarum means pregnancy.)

***

I am speaking of Bendectin®, a drug that I have extensively studied and reported upon and with which my late father had an association after he retired from the National Heart Institute at the NIH after 20 years and became a leader in drug-discovery research with Richardson-Merrell, Inc. (RMI) and its corporate successors. (He set up, and became the first director of, a research institute in Strasbourg, France, for RMI before returning to the States.)

Often confused with thalidomide, the notorious sleeping pill that unquestionably caused birth defects when taken by women in their first trimester of pregnancy, Bendectin was proved in dozens of studies to be non-teratogenic: It did not cause any defects in babies born to women who had taken it to relieve the nausea and vomiting of pregnancy, also known as NVP. Despite hundreds of lawsuits, no U.S. court ever upheld on appeal a jury award on behalf of a plaintiff alleging injury by Bendectin treatment. The evidence of causation just wasn’t there.

I tell the full story of Bendectin’s demise by junk science over several chapters in my biography about my father, Albert Sjoerdsma, M.D., Ph.D., “Starting With Serotonin: How a High-Rolling Father of Drug Discovery Repeatedly Beat the Odds” (pub. 2008, www.improbablebooks.com). As he rose in the Merrell hierarchy, Dad eventually inherited Bendectin.

RMI’s Cincinnati subsidiary, William S. Merrell Co., synthesized and marketed the morning-sickness drug in the 1950s. In 1981, much to Al Sjoerdsma’s chagrin (I didn’t trust these guys.), Dow Chemical acquired Merrell National, Richardson-Merrell’s pharmaceutical operation, and formed a pharmaceutical division called Merrell Dow. In 1983, Sjoerdsma became president of the Merrell Dow Research Institute, which comprised all of the company’s research centers worldwide.

That same year, Merrell Dow—without Sjoerdsma on board—withdrew Bendectin from the U.S. market, citing exorbitant litigation defense costs. The generic version of the drug, known as Diclectin®, continued to be sold in Canada, however, and is still sold there today.

Thirty years later—2013—the U.S. Food & Drug Admin. approved Bendectin’s two ingredients, doxylamine succinate and pyridoxine hydrochloride, in 10 mg./10 mg. delayed-release tablets for the treatment of NVP in women who have not improved with changes in diet or with other non-medicine treatments. You might say that Bendectin never actually went away in the United States; it just went underground for a while. But I suspect that many people who know of the drug erroneously believe that it was withdrawn because it was unsafe.

The following is an edited excerpt of the Bendectin story from“Starting With Serotonin,” which I will present here in four parts, with the source endnotes deleted. (Buy the book, read the notes. 🙂 )Part One:

***

In the 1970s, allegations arose that Bendectin, then a popular time-released treatment for hyperemesis gravidarum and milder cases of NVP, caused birth defects.

Since the drug’s FDA approval in 1956, millions of pregnant women worldwide had taken two Bendectin tablets at bedtime and staved off debilitating hours of illness the next morning. NVP afflicts up to 85 percent of all mothers-to-be. When vomiting is severe—relentless, as it apparently is with the duchess—women can become dehydrated and vitamin-deficient and suffer metabolic consequences that may endanger their own health, as well as their unborn child’s. At a minimum, extreme cases that go untreated require hospitalization for IV fluids and nutritional replenishment.

Originally, Bendectin contained 10 mg. each of dicyclomine hydrochloride, an antispasmodic; doxylamine succinate, an antihistamine with antinausea properties; and pyridoxine hydrochloride, which is vitamin B6. Because all of these ingredients were already on the market, the FDA summarily approved manufacturer William S. Merrell Co.’s mixture, and follow-up clinical trials with Bendectin in the 1950s reinforced its decision. The drug gave anxious pregnant women complete symptomatic relief and caused no apparent harm. Bendectin was later marketed in more than twenty other countries, including Canada, Great Britain, France, Australia, and West Germany, under the brand names Debendox® and Lenotan®.

To pass [a new government-required review of efficacy of every ingredient in a drug], Merrell reformulated Bendectin in 1976 from three ingredients to two, dropping dicyclomine, which the FDA concluded did not significantly contribute to its efficacy. According to Merrell veterinary pathologist and toxicologist James W. Newberne, who later defended the drug’s safety record in court, dicyclomine “was an irritable bowel syndrome-inhibitor that they didn’t seem to need.”

TESTS OF BENDECTIN’S SAFETY

Hired in 1962 from Pittman-Moore Pharmaceuticals in Indianapolis, Jim Newberne ushered in the modern era of veterinary pathology at Merrell. Before his arrival, company scientists routinely sent animal-tissue samples out to clinical pathology laboratories for analysis. The rural Georgia native and former World War II Navy pilot became Merrell’s first “bona-fide pathologist.” [Dr. Newberne died in 2016.]

In 1967-68, Newberne and several of his colleagues performed Merrell’s first animal teratologic studies of Bendectin, and all proved negative. Tested in rabbits and rats, fetal exposure to the drug had no statistically significant effect on the incidence of birth malformations, or on pregnancy maintenance, litter size, or fetal weight.

Early post-thalidomide surveys of patients who had taken Bendectin and given birth also found no association with abnormalities. The only prospective teratologic study occurred in the mid-1960s, when two California researchers evaluated several antinauseants, including Bendectin, in pregnant women seen at Kaiser health plan clinics in the San Francisco area. Again, no teratogenicity emerged. Subsequent scrutiny in humans would be strictly epidemiological, and, thus, about statistical analysis of birth-defect causation. But these, too, supported Bendectin’s safety.

After approving the drug’s reformulation, and having received several dozen physician reports suggesting a link between its use and various birth defects, the FDA asked Merrell to add a warning label to its product, stating that, as with all drugs considered for use during pregnancy, it should be “used only when needed.” The company complied—even though Bendectin had a clean clinical slate, and chance alone could have accounted for the adverse reaction reports [ADRs].

An estimated 3 percent of all newborn infants have a congenital abnormality, about 60 percent of which cannot be explained. Nature does not guarantee a healthy baby.

MELVIN BELLI AND THE MEKDECI CASE

Despite such uncertainty, Melvin Belli, the then-much-in-the-news “King of Torts,” filed the first Bendectin lawsuit in June 1977 in an Orlando, Florida, federal court. Belli sued [Richardson-Merrell, Inc., the then-parent company] on behalf of Betty and Michael Mekdeci, whose son, David, had been born with a shortened arm, malformed hand, missing fingers, and a caved-in chest.

Since her son’s birth in March 1975, Betty Mekdeci had zealously sought an explanation for his developmental anomalies. To learn more about the many over-the-counter and prescription drugs she took during pregnancy, Mekdeci called the FDA repeatedly: Sympathetic employees urged her to target Bendectin.

As the trial approached, the King of Torts curried favorable press coverage. He hit a PR home run in October 1979 when The National Enquirer published a sensational “preview” trumpeting a “monstrous scandal that could be far larger than the thalidomide horror.” The tabloid article luridly charged that “untold thousands of babies are being born with hideous defects” because of a “vicious, body-twisting crippler.” After reading it, some frightened women, anxious to abort their pregnancies, rushed to consult their doctors, while others hired lawyers.

The FDA responded by emphasizing its own independent evaluation that no adequate clinical evidence existed to associate Bendectin with an increased risk of birth defects. It further noted that it was monitoring ADRs and reviewing several large ongoing epidemiological studies of mothers who had taken Bendectin. The agency stressed, however, that it was impossible to state, definitively, that any drug ingested during pregnancy is free of risk. Such a negative cannot be proved.

On March 21, 1980, the Mekdeci jury ruled in favor of Merrell, finding that Bendectin did not cause young David’s birth malformations, but it compromised the verdict by ordering the company to pay the Mekdecis $20,000 for their medical expenses. Although the judge threw out this sympathy award and ordered a new trial, the reversal did not stop the Belli legal team from touting a “victory” and signing up new clients in the United States and Europe.

DOW CHEMICAL’S ACQUISITION

An estimated 10 to 25 percent of all pregnant women in the United States had taken Bendectin for relief since its FDA approval. A plaintiff class could easily number in the thousands. Interested in acquiring Merrell National, the Dow Chemical Co., which was founded in 1897 in Midland, Mich., and made its mark in U.S. wartime industry, cautiously evaluated Merrell’s liability for its NVP drug.

Since 1979, Dow Chemical had been a defendant in class-action litigation over the herbicide, Agent Orange, which Dow and other chemical firms had manufactured and supplied to the U.S. military for use in Vietnam against enemy foliage cover. An astounding 600,000 U.S. veterans claimed to have been exposed and injured by the dioxin-containing agent. Dow did not want more litigation.

Any reservations that Dow officials may have had about Bendectin, however, were soon eased by the FDA, which held two days of public hearings about the drug in September 1980, reviewed all available scientific findings, and pronounced it safe.

On March 10, 1981, Merrell National became a subsidiary of Dow Chemical, but it never operated independently. Instead, Dow blended the new subsidiary with its Indianapolis pharmaceutical division to create the Cincinnati-based Merrell Dow Pharmaceuticals, Inc. Al Sjoerdsma would first become vice president of pharmaceutical research for . . . Dow Chemical, the company he distrusted. Resolutely focused on drug-discovery research, he intended to avoid “the business side,” as much as possible. He wanted nothing to do with the money people, whom he regarded with little more than disdain.

He also was dubious about Dow’s scientists. David Sheetz, a chemist, became head of Dow research. According to Sjoerdsma, Sheetz didn’t know pharmaceuticals.

David Sharrock, who had been president of Merrell National, would head Merrell Dow Pharmaceuticals U.S.A., an operating unit of the larger corporation.

Despite the Mekdeci jury’s verdict for the defense, by September 1981, forty-eight lawsuits against Merrell Dow were pending in federal courts. After a judge granted the company’s request to consolidate these claims in a single forum, hundreds of cases were transferred from both state and federal courts to a Cincinnati-based U.S. district court.

The term “junk science” was not yet in the U.S. jurisprudential lexicon. It would arise with the specious arguments advanced by expert witnesses testifying against Bendectin.

While Sjoerdsma never wavered in his belief that Bendectin was safe, he jumped into the fray only when his authority was implicated. Then, he predictably put his hard nose on science.

Part Two of the Bendectin story will appear on 9/20/17.

Ann, 9/17/17

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