This is an installment for the 'How regulation came to be' series I planned to write someday, just not this week. I had it envisioned for some weeks off -- maybe months -- with time to immerse myself in the subject, mine the internet sources, mull over options, ponder my approach. But current events have conspired to make this subject suddenly topical, so I hope the reader will forgive a rather rushed entry with perhaps, and ironically, some compromising of whatever quality standards we fancy ourselves trying to maintain for our little series, as we explore -- with some very graphic reinforcement -- the impact a single committed person can have, just by doing her job, and not compromising standards.
Frances Oldham was born in British Columbia, Canada in 1914. After graduating high school at the age of 15, she attended McGill University in Montreal where she studied pharmacology, earning a B.Sc. in 1934 and a M.Sc. the following year. (By my calculation, that's a master's degree by 21, for those of you keeping track.)
After graduation from McGill, Ms. Oldham applied to and was accepted into a new graduate program in pharmacology at the University of Chicago under a noted researcher, E. M. K. Geiling. (The story goes that Dr. Geiling assumed 'Frances' was a male, and she was content to let him continue to believe that until all the t's were crossed and i's dotted on her admission. This was 1935, after all.)
It was at the University of Chicago that Ms. Kelsey crossed paths with the subject of our very first "How regulation came to be"
post, when the FDA enlisted Dr. Geiling and the University to help investigate a string of mysterious deaths that they were encountering nationwide. She was thus part of the University of Chicago team that helped trace the cause to a liquid sulfa product, "Elixir Sulfanilamide", produced by the S. E. Massengill Company of Bristol, Tennessee, which was discovered to consist of a suspension of sulfa drug in, essentially, anti-freeze. The tragedy, which claimed over a hundred victims, predominantly children, led to the passage of the 1938 Food, Drug, and Cosmetic Act which, ironically, would play a pivotal role in the events that were to transpire two decades later.
Frances Oldham earned per PhD in pharmacology at Chicago, joined the faculty after graduation, and later earned her MD at the school. She married a fellow faculty member, Dr. Fremont Ellis Kelsey in 1943 and remained at Chicago until 1954, when she left for a position at the University of South Dakota.
In 1960 she left teaching and research to join the Food and Drug Administration in Washington, D.C. At the time, she was one of only seven full-time staff members at the FDA who, with the help of four part-time employees, were responsible for reviewing all the drug applications coming in to the FDA.
(Summarized from Wikipedia, and from sources cited below.)
Dr. Kelsey had barely settled in at the FDA when her first drug review assignment landed on her desk in September, 1960, only a month into her tenure. The application, from a Cincinnati, Ohio company named Richardson-Merrell, was a request to approve a drug already being marketed extensively in Europe for sale in the United States. The drug, which they hoped to have on the market in time for the holiday season, had been approved in European countries beginning in 1957 and was being widely used as a sedative, a sleep aid, and for relief of morning sickness. The drug, touted as a completely safe sedative and sleeping pill with no lethal overdose and no long-term side effects, was to carry the brand name "Kevadon ", certainly much easier to pronounce than its tongue-tying chemical name, phthalimidoglutarimide .
Kelsey had concerns about the drug from the beginning. So did the pharmacologist and chemist who assisted Kelsey in the drug review. The chronic toxicity studies were not long enough, the absorption and excretion data were inadequate, and the manufacturing controls had shortcomings. "We were concerned about the non-absorption," says Kelsey. "That you could give enormous amounts, both to animals and humans, without toxicity. We felt that there might be conditions, illnesses, or other drugs that might change the absorption, and toxic effects might appear." After Kelsey detailed these deficiencies in a letter to Richardson-Merrell, the company sent in additional information -- but not enough to satisfy Kelsey.
FDA Consumer: Frances Oldham Kelsey
The law governing drug sales in the United States at the time, the Food, Drug, and Cosmetic Act of 1938, required only that the drug be proven safe. The company wasn't obligated to prove that it actually cured any disease or helped alleviate any condition, so it was a rather low bar. Still, it gave the FDA a degree of authority. Under FDA rules, the agency had 60 days to review and rule on an application. Dr. Kelsey's request for additional data constituted a rejection of the application, requiring the company to re-start the application process, and re-setting the 60-day clock. Richardson-Merrell's plans to have Kevadon on the market in time to sedate stressed-out holiday shoppers were being seriously impacted.
Richardson-Merrell re-submitted the application, but with no new information, and Kelsey again rejected it, again re-starting the 60-day clock. The company again re-submitted the application, and Kelsey again rejected it, requesting still more data. Richardson-Merrell, its plans to cash in on the lucrative holiday business being upset by this recalcitrant hireling, sent executives and scientists to personally lobby Kelsey, appealed to Kelsey's superiors and cranked up the pressure. Kelsey, and her superiors, held their ground.
Then the first small crack appeared. A December, 1960 article by a physician in the British Medical Journal related cases of patients who had taken the drug for long periods now experiencing pain in their extremities, one of Kelsey's concerns in her initial rejection. Kelsey again rejected the application and requested studies on the potential problem. As 1960 rolled into 1961 and 1961 dragged on, more reports of problems with the drug, albeit unofficial and anecdotal, cropped up, and Kelsey requested more information, and rejected more applications, and restarted more 60-day clocks.
And then, beginning in November, 1961, the reports started to cascade in from Europe, official and alarming.
This past week in London, Great Britain officially apologized. The apology by health minister Mike O'Brien went out to the 466 surviving victims, and the families of victims, who suffered birth defects and deformities as a result of mothers taking the drug thalidomide during pregnancy -- which astute readers deduced long ago was the generic name of the drug Kevadon that Frances Kelsey was being pressured to approve.
"The government wishes to express its sincere regret and deep sympathy for the injury and suffering endured by all those affected when expectant mothers took the drug thalidomide between 1958 and 1961," health minister Mike O'Brien told a hushed parliament.
"We acknowledge both the physical hardship and the emotional difficulties that have faced both the children affected and their families as a result of this drug, and the challenges that many continue to endure, often on a daily basis," he said.
The thalidomide scandal triggered a worldwide overhaul of drug-testing regimes and boosted the reputation of the U.S. Food and Drug Administration, which proved a lone voice in refusing to approve the drug.
Reuters: Britain apologizes 50 years after Thalidomide scandal
(Link to Thalidomide UK, the website of the British thalidomide survivors' organization.)
Thalidomide had been developed by a West German pharmaceutical company, Chemie Grünenthal, in 1953, which immediately started looking for something it would cure.
The Grünenthal scientists could not find any antibiotic activity, or any other encouraging effects, in mice and rats. However, they saw that the new chemical seemed to be harmless; outrageously high doses did not kill rodents, rabbits, cats, or dogs. In addition, the animals showed no other side effects. The research team began to describe thalidomide as "nontoxic," and Grünenthal began to consider the lucrative prospects of their new find. Notably, although no sedative or tranquilizing effects were observed in animals, Grünenthal management considered "a nonlethal sedative would have enormous market potential."
With only these animal tests, no clinical trial plans, and no scientific rationale, Grünenthal began distributing free samples of thalidomide to doctors in Switzerland and West Germany in 1955. It was first recommended for the prevention of seizures in patients with epilepsy; although no anticonvulsant effect was found, patients reported experiencing a deep sleep. Other patients said they felt calming and soothing effects. Some reported side effects, but they were not believed to be serious. One author later said that "Thalidomide was introduced by the method of Russian Roulette. Practically nothing was known about the drug at the time of its marketing."
With no more testing than this, the drug began to be marketed in 1957 under the name of Contergan. It would appear under various names in different countries. Among its claims, that it would be impossible to take a lethal overdose, that accidental overdoses by children would be unheard of, both of which turned out not to be true, thalidomide did its most appalling damage when, at its manufacturer's encouragement, it became "the drug of choice for morning sickness".
When the terrible toll of thalidomide was finally researched and documented, the findings revealed a very narrow window with a very gruesome outcome:
A stunning statistic was that 50 percent of the mothers with deformed children had taken thalidomide during the first trimester of pregnancy. The limits of danger were amazingly narrow: women who took even one tablet of thalidomide between the 20th and 36th day after conception were at risk for delivering malformed infants - beyond that time, the drug caused no deformities at all. Lenz notified Chemie Grünenthal about the dangers of its flagship product; ten days later, German authorities removed thalidomide from the market against Grünenthal's wishes.
(other articles, for instance here, give a slightly different time window in which malformations occur)
Thalidomide was ultimately marketed in 46 different countries under no less than 37 different names. An estimated 8,000 to 12,000 babies were born with severe deformities, including missing or deformed limbs, absence of ears, deformities of internal organs and skeletal structure, and other problems. The most severely deformed typically died in their first year. About 5,000 survived beyond childhood, including the 466 in Great Britain to whom Mr. O'Brien issued the country's official apology and announced the institution of a fund of £20 million to pay medical expenses of the "Thalidomiders" -- many of whom now suffer chronic conditions such as arthritis and joint deterioration from a lifetime of physically compensating for their handicaps. The fund will augment the approximately £20,000 (approximately US $32,000) they receive annually from the Thalidomide Trust, compensation extracted from the manufacturer of the drug.
Even the one major country that refused to approve thalidomide for sale did not escape unscathed.
The medication never received approval for sale in the United States, but 2.5 million tablets had been given to more than 1,200 American doctors during Richardson-Merrell's "investigation," and nearly 20,000 patients received thalidomide tablets, including several hundred pregnant women. In the end, 17 American children were born with thalidomide-related deformities. An estimated 40,000 people developed drug-induced peripheral neuropathy. Exact numbers will never be known because the companies and doctors kept incomplete and inaccurate records.
Dr. Kelsey is presented the award for Distinguished Federal Civilian Service by President Kennedy in 1962
For her role in keeping thalidomide off the market, Dr. Frances Oldham Kelsey became a hero. The story of her role in protecting the public was written up in first the Washington Post and then newspapers and magazines across the country. In 1962 she was presented the President's Award for Distinguished Federal Civilian Service by President John F. Kennedy at a ceremony in Washington, D.C. She was inducted into the National Women's Hall of Fame in 2000. There is even a secondary school
named for her 'back home' in Mill Bay, British Columbia.
Frances Oldham Kelsey insisted Richardson-Merrell follow the regulations in place at the time, and in doing so, insured that the United States largely escaped the tragedy that befell Europe. The regulations we, the people through our representatives, put in place in 1938 did their job and protected us in 1960.
But this series is about how regulation came to be, not how regulation already was. In the wake of the thalidomide scandal, countries world-wide impacted by the tragedy over-hauled drug approval and testing regulations. But even in the one country that largely escaped the consequences of the disaster the incident had its effect.
More importantly, a controversial bill by U.S. Senator Estes Kefauver, of Tennessee, was resurrected and rewritten, passed by Congress, and signed by President John F. Kennedy on October 10, 1962. The Kefauver Harris Amendment strengthened the FDA's control of experimentation on humans and changed the way new drugs were approved and regulated. Before the thalidomide scandal, U.S. drug companies only had to show their new products were safe; for the first time, they would have to show their new drugs were safe and effective. Informed consent was required of patients participating in clinical trials, and adverse drug reactions were required to be reported to the FDA.
So the next time you're sitting on the sofa watching TV and a drug commercial comes on telling you how their product "has been proven safe and effective..." remember that they' really don't have much choice -- they have to be able to say that because we won't let them sell that drug unless they can.
And that, dear Kossacks, is where regulation comes from -- not from bored bureaucrats sitting in an office in Washington trying to think up ways to make life miserable and expensive for some innocent and unsuspecting businessman, but from real human suffering and tragedy brought about, all too often, by people who shirk what should be obvious responsibilities, who neglect basic diligence, who sacrifice safety for profit. They bring suffering on those who trust them and their products, and society adopts measures to make sure it never happens again. We have to force them, through regulation, to behave as they should have been behaving all along. That's how regulation came to be.
Hat tip to Mulkum, who provided quotes from and a link to the Medic8.com article on Thalidomide quoted above in a comment thread in our very first 'How regulation came to be' installment. The article gives a very detailed account of the development, marketing, and consequences of thalidomide, as well as the narrative of Dr. Kelsey's efforts to make the company follow the rules. It provides much greater detail than I was able to fit into this diary. Well worth taking the time to read. Many thanks.
Previous installments of How Regulation came to be: