I learned over the weekend that a historic figure in science-based medicine has died. If you know anything about the history of the Food and Drug Administration (FDA), you will know this woman’s name, Frances O. Kelsey, MD, PhD. It turns out that Dr. Kelsey died on Friday at the age of 101. Somehow I missed the news on Friday, but once the story showed up in my news feeds over the weekend, I knew I had to make her today’s topic. Here’s the short version:
The sedative was Kevadon, and the application to market it in America reached the new medical officer at the Food and Drug Administration in September 1960. The drug had already been sold to pregnant women in Europe for morning sickness, and the application seemed routine, ready for the rubber stamp.
But some data on the drug’s safety troubled Dr. Frances Oldham Kelsey, a former family doctor and teacher in South Dakota who had just taken the F.D.A. job in Washington, reviewing requests to license new drugs. She asked the manufacturer, the William S. Merrell Company of Cincinnati, for more information.
Thus began a fateful test of wills. Merrell responded. Dr. Kelsey wanted more. Merrell complained to Dr. Kelsey’s bosses, calling her a petty bureaucrat. She persisted. On it went. But by late 1961, the terrible evidence was pouring in. The drug — better known by its generic name, thalidomide — was causing thousands of babies in Europe, Britain, Canada and the Middle East to be born with flipperlike arms and legs and other defects.
It’s important to understand the context. When Dr. Kelsey received the application for Kevadon, the laws governing drug approval and the power of the FDA were very different than today, and the FDA was a very different agency. Back then, all the FDA was charged with doing was to make sure that the drugs it approved were safe. It’s worth reviewing the history of the FDA up to 1960, when that fateful application for approval from the Merrell Company first crossed the desk of a new medical officer, who also happened to be a woman in what was then most definitely a man’s world in science.
Before 1906, there was no federal law protecting the public from dangerous drugs or food. The decades leading up to that year were a golden age of quackery, with all sorts of patent medicines being sold by wandering salespeople and Bayer sold Heroin as a non-addictive morphine substitute and cough suppressant. Pharmaceutical companies didn’t have to demonstrate safety or efficacy of their drugs before marketing them. It is an age that quacks, understandably, pine for. In 1906, Congress passed and President Theodore Roosevelt signed the Pure Food and Drug Act of 1906. Then, as now, such regulation was not easy to pass. It took muckraking and exposes such as The Jungle by Upton Sinclair to rally support for such a law.
The original law was relatively modest, its main purpose being to ban the foreign and interstate traffic in adulterated and mislabeled food and drug products. It required that active ingredients be placed on the label of a drug’s packaging and that drugs could not fall below purity levels established by the United States Pharmacopeia or the National Formulary. Originally, the law was enforced by the Bureau of Chemistry in the Department of Agriculture, a bureau that didn’t become the Food and Drug Administration until 1930. Originally, the law didn’t require approval of drugs before they could be marketed, and the burden of proof was on the government to demonstrate that a food or drug was adulterated or unsafe.
Clearly, the law had relatively little in the way of teeth back then. For instance, in 1910 the government seized a large quantity of a product called Johnson’s Mild Combination Treatment for Cancer, whose manufacturer falsely claimed it could cure cancer. In the legal action that followed the Supreme Court ruled that the false claims of effectiveness were not within the Pure Food and Drugs Act. To address this weakness, Congress enacted the Sherley Amendment in 1912, which prohibited labeling medicines with false therapeutic claims. Unfortunately, the burden of proof on the government under the Sherley Amendment was high:
“To establish fraud, the bureau had to show that the manufacturer knew the product was worthless, and this proved difficult in many cases,” Swann says. For example, Lee Barlett, a former shirt salesman from Pittsburgh, promoted a medicine called Banbar as being effective for diabetes. Banbar was an extract of horsetail weed. The government took Barlett to court for selling a misbranded drug and even showed the death certificates of people with diabetes who had taken Banbar. But the jury ruled in Barlett’s favor.
The next major change in the Pure Food and Drug Act came in the 1930s. By the early 1930s, it was widely recognized that the Pure Food and Drugs Act of 1906 was obsolete, but there was no agreement over how to modernize it. It took years to come up with a compromise, which did happen by 1937, but Congress was going nowhere in passing a new law. Then disaster struck, the 1937 Elixir Sulfanilamide Incident, which killed over 100 people in 15 states:
Sulfanilamide, a drug used to treat streptococcal infections, had been shown to have dramatic curative effects and had been used safely for some time in tablet and powder form. In June 1937, however, a salesman for the S.E. Massengill Co., in Bristol, Tenn., reported a demand in the southern states for the drug in liquid form. The company’s chief chemist and pharmacist, Harold Cole Watkins, experimented and found that sulfanilamide would dissolve in diethylene glycol. The company control lab tested the mixture for flavor, appearance, and fragrance and found it satisfactory. Immediately, the company compounded a quantity of the elixir and sent shipments–633 of them–all over the country.
The new formulation had not been tested for toxicity. At the time the food and drugs law did not require that safety studies be done on new drugs. Selling toxic drugs was, undoubtedly, bad for business and could damage a firm’s reputation, but it was not illegal.
Because no pharmacological studies had been done on the new sulfanilamide preparation, Watkins failed to note one characteristic of the solution. Diethylene glycol, a chemical normally used as an antifreeze, is a deadly poison.
From the perspective of 2015, it’s hard to believe that any chemist could do something so completely boneheaded. Even back then, it was known that diethylene glycol was toxic, as even just a review of the medical literature would have revealed. After all, the first case of fatality from diethylene glycol poisoning had only been reported in 1930, and the studies showing that it could cause kidney failure had been published. Even in the absence of a literature review, animal testing would have revealed the extreme toxicity, but, for whatever reason, S. E. Massengill Company didn’t do a literature search or animal testing. It just marketed the its new formulation of its drug.
This incident is worth remembering 80 years later, because the claim that the free market will guarantee drug safety because companies cannot bear the hit to their reputations that selling unsafe drugs would cause has not died, even though an incident like the Elixir Sulfanilamide incident should have put a stake in its heart. Indeed, I’ve documented such claims right here on this very blog as representing magical thinking.
It is also worth remembering how the victims died:
Victims of Elixir Sulfanilamide poisoning–many of them children being treated for sore throats–were ill about 7 to 21 days. All exhibited similar symptoms, characteristic of kidney failure: stoppage of urine, severe abdominal pain, nausea, vomiting, stupor, and convulsions. They suffered intense and unrelenting pain. At the time there was no known antidote or treatment for diethylene glycol poisoning.
Nor was there dialysis or kidney transplantation. The first dialysis machine was not developed until 1943.
Spurred on by the outrage caused by the Sulfanilamide incident, Congress passed the Food, Drug, and Cosmetic (FD&C) Act of 1938. For the first time, drug manufacturers had to demonstrate that their drugs were safe before they could market them. Manufacturers had to submit an application to the FDA before marketing a drug, but if the FDA didn’t act on it within a certain time period the drug would be automatically approved. Further amendments allowed for factory inspections and the designation of certain drugs to be designated for sale by prescription only. That was the state of regulation at the time Dr. Kelsey received that fateful application for thalidomide.
Then this is what happened:
The company made glowing claims for Kevadon’s safety and effectiveness. It had been developed in West Germany, and since 1957 had been widely sold in Europe and elsewhere as an excellent sedative, Merrell said, giving prompt, deep, natural sleep without hangovers. Moreover, doctors had recently been prescribing it to women to suppress nausea in pregnancy.
Laws governing new drugs had been on the books for decades but were not always rigorously enforced, and F.D.A. approval was often routine. But Dr. Kelsey, working with a chemist and a pharmacologist, found the evidence for Merrell’s claims about Kevadon to be insufficient. She withheld approval and asked Merrell for more data on toxicity, strength and purity.
Merrell stood to make millions and was anxious to get moving. It had tons of Kevadon in warehouses, ready for marketing, and 1,000 American doctors had already been given samples for “investigational” research. The company supplied more data, but also mounted a campaign to pressure Dr. Kelsey. Letters, calls and visits from Merrell executives ensued. She was called a fussy, stubborn, unreasonable bureaucrat.
It wasn’t just her, either. Dr. Kelsey and the other two FDA officials responsible for reviewing the application quickly developed questions about the drug. For example, the pharmacologist, Oyam Jiro, questioned whether the company’s toxicity tests were adequate, while the chemist, Lee Geismar, was skeptical about the company’s manufacturing controls. Dr. Kelsey thought that the safety data were inconclusive.
In pushing for more data, Dr. Kelsey was also prescient, with a very keen eye for spotting bullshit. As a result, she was subjected to intense pressure from Merrell executives. As described by Dr. Kelsey in the August 10, 1962 issue of LIFE, they “came to Washington in droves.” They wrote letters, and they called her superiors as often as three times a week. They complained bitterly that Dr. Kelsey was being “unreasonable and irresponsible.” Dr. Kelsey noted that, “Most of the things the called me, you couldn’t print.” To his credit, Dr. Kelsey’s division chief, Julius Hauser, decided to back his young pharmacologist, joking, “When they would get too thick around Dr. Kelsey, I would just come in with my little hatchet and clear them out.”
By February 1961, reports of thalidomide toxicity were filtering in from Europe, in particular a report in the British Medical Journal linking thalidomide to peripheral neuropathy. More cases were reported, and there were indications that the drug could cause numbness, shaking, and tingling of the hands and other disturbances. These reports lead Dr. Kelsey to wonder whether thalidomide could damage nerves in a developing fetus. By November 1961, the first report of phocomela linked to thalidomide was reported. Phocomelia is a severe birth defect in which the fetal limbs are horrendously malformed resulting from use of thalidomide in the first trimester, when the fetal limb buds are forming. Further clinical development of thalidomide ceased, at least until it was found to be effective against multiple myeloma decades later.
Alternative medicine quacks often like to attack the FDA by pointing out the thalidomide tragedy. Most of them seem not to know that thalidomide was never approved for use in the US, and that was almost entirely due to the vigilance and, yes, outright stubbornness of one brave woman, who could sniff out spin and misinformation in a drug company application and would not be swayed by unrelenting pressure. Thankfully, her superiors backed her up, something that wouldn’t have happened if the FDA regime at the time didn’t take drug safety seriously.
Dr. Kelsey’s battle was unknown to the public until Washington Post reporter Morton Mintz broke the story in July 1962. The story led to public pressure for Congress to do something. As a result, Congress passed the Kefauver-Harris Drug Amendments to the Federal Food, Drug, and Cosmetic Act. These amendments required that drug companies not just show safety, as had been the case prior to the amendments, before their drugs could be FDA-approved, but also to provide substantial evidence of effectiveness for the product’s intended use. That evidence had to be in the form of adequate and well-controlled clinical trials, which at the time was considered a revolutionary requirement. (Believe it or not, no requirement for high quality clinical trials existed before 1962.) This led to the current system of phase I, II, III, and IV clinical trials in force today. The amendments also included a requirement for informed consent of study subjects and codified good manufacturing processes, as well as the requirement that adverse events be reported. This has been, with some tweaking over the years, the law of the land regarding how the FDA approves drugs for specific indications. In 1962, President John F. Kennedy awarded Dr. Kelsey the Distinguished Civilian Service Medal, the nation’s highest federal civilian service award, saying she had “prevented a major tragedy of birth deformities, which she undoubtedly had.
That is the legacy of this remarkable woman, who will long be remembered for her achievement, as well as her decades of service to the FDA. Indeed, she didn’t retire until 2005, and in 2010 the FDA she was the first recipient of an FDA award named after her and continues to be awarded annually.