FDA approval of any drug is no small matter. The process is rigorous and often lengthy — and that's by design. But it wasn't always that way. Back in the day, "drugs were not developed on target," says Katherine Donovan, a senior scientist at the Dana-Farber Cancer Institute in Boston, Massachusetts, "it was more like trial and error."
So what changed? Today's FDA drug approval standards, developed 60 years ago, were largely the product of a single drug and a woman who refused to give it FDA authorization.
We're talking about Frances O. Kelsey. She was born Frances Oldham on Vancouver Island, British Columbia, in 1914. She developed an interest in science early in life. She earned a master's degree from McGill University in Montreal at age 20, and would go on to complete both an M.D. and Ph.D. in pharmacology at the University of Chicago.
Like many women in science at the time, Kelsey faced opposition from the overwhelmingly male scientific establishment. In fact, she suspected that her gender-neutral first name helped launch her career: The letter of acceptance for her Ph.D. program was even addressed to 'Mr. Oldham.'
"I knew that men were the preferred commodity in those days," she later wrote, "I do not know if my name had been Elizabeth or Mary Jane, whether I would have gotten that first big step up."
Nevertheless, Kelsey eventually joined the University of Chicago as a full-fledged faculty member in 1942. It was there that she met and married fellow staff member Dr. Fremont Kelsey. In 1960, the couple moved with their two daughters to Washington, D.C., where Frances accepted a position as a drug reviewer for the FDA. Little did she know, she was about to alter the course of history.
Dodging a Bullet
Just as Frances Kelsey was stepping into her new role at the FDA, a new drug was making the rounds in Europe, Africa and Asia.
Known as thalidomide, the drug was originally developed in the early 1950s as a sedative. "Back then, it was post-wartime and things were a little bit crazy," says Donovan, "so the world was in need of a decent sedative to help people sleep."
Patients taking thalidomide for anxiety quickly realized that it also worked wonders on an upset stomach, and it soon caught on as a cure for morning sickness. A few people reported tingling in their hands and feet — also called neuropathy — after prolonged thalidomide use. However, these negative effects wore off as soon as they stopped taking it, and so the drug was generally considered safe. By 1957, it was approved for over-the-counter sale in Germany, and available by prescription in dozens of other countries.
The FDA application for thalidomide crossed Kelsey's desk in September 1960, just seven months after she began working there. At the time, the FDA's approval process for new drugs lasted just 60 days, during which the reviewer would wade through a hodgepodge of assorted mouse trial data and other material submitted by the applicants. Given thalidomide's popularity, it seemed destined to sail through with ease.
But Kelsey had some concerns. An English study, which included some reports of neuropathy and similar nerve-related symptoms, gave her pause. She was also wary of the lack of data regarding the drug's effect on pregnancy. Without further research, she refused to approve the drug.
It was a bold move. "There was a lot of pressure from around the world to approve it," Donovan says. Still, Kelsey stayed firm. One year later, her caution was vindicated.
The Rise and Fall of Thalidomide
Around the same time thalidomide was under scrutiny for approval in the United States, Dr. William McBride of Australia and Dr. Widukund Lenz of Germany both noticed a strange pattern: an unusual number of children born with strikingly similar congenital limb anomalies, all within a relatively small geographic area. The common denominator, they discovered, was that their mothers had all taken thalidomide for morning sickness early in their pregnancies.
McBride raised the alarm with a bombshell piece published in the Lancet in 1961, sending shock waves through the medical community. Thalidomide was pulled from shelves in Germany almost immediately; other countries followed suit shortly thereafter.
Kelsey's contribution in keeping thalidomide largely out of U.S. pharmacies might have gone unnoticed by the public if not for a Washington Post article published in 1962. That same year, President John F. Kennedy awarded Kelsey the President's Award for Distinguished Federal Civilian Service and signed the Kefauver-Harris amendments into law. This key bit of legislation is the reason that drugs in the U.S. must meet strict clinical trial standards in order to be approved by the FDA.
Kelsey would go on to serve the FDA for 45 years, helping hone the organization's drug approval process all the while.
Curiously, that's not where the story of thalidomide ends. In the wake of its disastrous legacy, scientists began looking deeper into the mechanism of the drug itself to discover why it caused such unexpected side effects. They found that, unlike most drugs, which simply bind to one receptor in the body, thalidomide "actually recruits other things to bind. And that leads to those proteins being removed from the body completely," Donovan says. This can be either good or very bad, depending on which proteins get removed. But by fine-tuning thalidomide's molecular structure, researchers believed it might be possible to target specific "bad" proteins for removal.
In 2006, this research revealed the drug's potential for treating leprosy and plasma cell myeloma, an uncommon type of bone marrow cancer. Since then, two different drugs based on the structure of thalidomide have been approved for cancer treatment by the FDA.
Now That's Interesting
Part of the reason for thalidomide's wide range of effects is because it is a chiral molecule — a type of molecule that exhibits "handedness." The left-handed version is an effective painkiller, while the right-handed version is toxic.
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