(See blog on 9/17/17 for part one.)
The causes of teratogenesis (birth defects) are numerous, complex, and, in most cases—60 percent, overall—unidentifiable.
Mutant genes cause about 7.5 percent of birth defects; chromosomal abnormalities account for 6 percent; maternal illnesses, such as rubella and diabetes, contribute another 3.5 percent; and environmental substances and factors, such as an occupational chemical or a pharmaceutical drug, or maternal nutrition or alcohol intake, create 3 percent. “Multifactorial” or “ecogenetic” causes, which involve an interaction between hereditary tendencies and non-genetic, usually undefined, factors, account for another 20 percent.
According to the eminent teratologist and pediatrics professor, Robert L. Brent, a particular agent is a teratogen if it fits some of the following criteria:
1) The reported human epidemiological studies indicate an association with a unique group of malformations or an association with an increase in malformations.
2) Human epidemiological studies consistently indicate that the exposed population has a higher incidence of the malformation than the control population does.
3) Scientists have developed an animal model for the observed malformations using exposures to the agent in the therapeutic range.
4) Teratogenic and embryotoxic effects in the animal model have a dose-response relationship in the therapeutic range.
5) A reasonable biologic explanation for the teratogenic results or an understanding of the mechanism of teratogenesis exists.
None of Brent’s criteria applied to Bendectin. Nonetheless, because an estimated 30 million pregnant women had used the drug, and the natural incidence of birth defects is 3 percent, chance alone guaranteed that about 900,000 malformed infants had been born to Bendectin-exposed mothers. Furthermore, limb reduction defects, like those of David Mekdeci [case discussed in part one], spontaneously afflict one in 3,000 newborns. Again, chance would account for 10,000 infants with limb reduction defects being born to Bendectin mothers.
Melvin Belli and other plaintiffs’ lawyers did not concern themselves with such biologic uncertainty. Indeed, they counted on convincing emotionally susceptible jurors to overrule it. But, scientifically, they faced an uphill battle, which steepened as epidemiological investigations accumulated.
Epidemiology is the study of the occurrence of a disease—or, in this case, a defect—in a defined population. Typically, the epidemiologists who studied Bendectin identified congenital abnormalities in infants born during a certain time at a certain hospital and, after allowing for confounding factors, assessed the causative risk of the drug’s exposure. They compared the prevalence of certain malformations among Bendectin-exposed infants with the prevalence among unexposed controls, or interviewed mothers with malformed infants about their drug use during pregnancy and compared rates of Bendectin exposure with different types of malformations.
To establish causation between Betty Mekdeci’s Bendectin use and her son’s malformations, the Belli team relied upon two key expert witnesses, neither of whom was an epidemiologist. Australian gynecologist William McBride had been among the first to link thalidomide to limb malformations, and, in 1972, founded his own birth defects research foundation in Sydney. Alan K. Done was a Utah pediatrics professor who professed an expertise in teratology. Among the pieces of “evidence” that Done used to construct a teratogenic theory, and to ignore the clear weight of science, were McBride’s studies in rabbits and chicks, which purportedly showed Bendectin-induced deformities, and his own questionable analysis of the drug’s chemical structure.
After the Mekdeci verdict, an all-out anti-Bendectin campaign waged for three years. Besides the litigation, Ralph Nader’s Public Citizen health group repeatedly petitioned the government to ban the drug, and members of Congress, second-guessing the FDA, pressured the agency to conduct or sponsor more animal or epidemiological studies and to persuade Merrell to do the same.
By 1983, Bendectin had been the subject of more than twenty epidemiological studies, none of which demonstrated a significant correlation between exposure to the drug and any birth defect. Dr. Brent analyzed these studies in commentaries for the journal, Teratology, concluding that Bendectin was a “litogen” and a “tortogen,” but not a teratogen. His informed opinion did not prevail in court, however. On May 27, 1983, a District of Columbia jury ruled that Bendectin had caused twelve-year-old Mary Oxendine’s limb deformities.
Mary Oxendine was born with a right arm shorter than her left, and a right hand described by one of her lawyers as “lobster-clawed,” with two fingers missing and the other three webbed, but later surgically separated. During her pregnancy, Mary’s mother, Joan, had taken Bendectin and Provera®, a drug used to prevent miscarriage. After reading The National Enquirer exposé planted by Belli, Joan Oxendine began looking for an attorney. She found Barry Nace, a tough, aggressive, and physically imposing trial lawyer whose Bethesda, Md. firm specialized in medical malpractice.
Nace filed suit against Merrell Dow and Upjohn, the maker of Provera, in the D.C. Superior Court. Because Upjohn, which later settled with the plaintiffs, refused to join Merrell Dow’s motion to remove the case to the Cincinnati court, it was tried in Washington. The sight of young Mary and the testimony of the ubiquitous Alan Done convinced the jury to award the Oxendines $750,000 in compensatory damages. This was Merrell Dow’s first unequivocal defeat.
On June 9, 1983, Merrell USA president Dave Sharrock announced that the company was ending production of the morning-sickness drug, despite having “absolutely no doubt of its safety and effectiveness.” The burdens of marketing Bendectin, he said, “have become just too heavy.”
Merrell Dow now faced more than 300 lawsuits in the United States alone. In three years, its monthly liability insurance premium had tripled to $1 million, while sales of Bendectin, which, at its peak, earned $15 million a year, steadily dropped. Twice, the company offset the decline with increased prices, but it now anticipated that annual sales would not exceed the drug’s costs. Faced with a patient dropoff, as well as staggering litigation-related expenses, Sharrock pronounced Bendectin economically dead.
Jim Newberne, who testified at the Mekdeci trial, agreed with the decision.
“I thought it was too much baggage to carry,” he said. “[Despite the drug’s safety,] we were going to get hit with these lawsuits anyhow, which, in time, could’ve bankrupted the company.”
But Al Sjoerdsma, the purist scientist, didn’t care.
Dave Sharrock should never have given up, he said.
The Bendectin lawsuits were so outrageous. . . . There didn’t seem to be any commonality, no distinctive defect being claimed. It was up to them to prove there was something there, not for us to prove there was nothing.
Part Three of the Bendectin story will appear on 9/24/17.