A Brief FDA History Lesson
Just before a presentation I gave on Monday concerning Virtual Reality and its use in medicine, the group that had assembled was discussing a variety of current topics in the pharmaceutical and biotechnology industries. One of the attendees, Peter Castellano, caught my interest when he described an article he found in the October 2007 issue of Scientific American about Abigail Burroughs, a cancer patient. After he sent me the article today, I read about her dilemma with great interest; her doctor recommended the use of an experimental drug in treatment of the disease, which could have potentially saved her life, or at least prolonged it.
But she never got the medicine. Because of the US Food and Drug Administration’s (FDA’s) requirements to test both the safety and efficacy of the medication, and the lengthy clinical trial process that follows, Abigail succumbed to her cancer in 2001. The experimental drugs that had been identified as potentially helpful did end up being approved between 2003 and 2004 and are used to treat cancer today.
The article does a good job of summarizing the issue currently in debate now at the FDA: should experimental drugs be made more readily available to patients for whom they may help, or should the gold standard of testing safety and efficacy dictate the course by which patients are allowed to test the drug? I was given some unique insight into this when I further researched a couple of historical events highlighted by the article: the first is the Food, Drug and Cosmetics act of 1938 that deemed it necessary to prove a drug’s safety before it could be sold in the United States, and the second is the Kefauver Harris Amendment of 1962, which set up the framework for modern clinical trials and required that drugs be tested for safety and efficacy.
In 1937 and for several years prior, the drug sulfanilamide was widely used by doctors to treat streptococcal infections in both a pill and powder form. In June of that year, a pharmaceutical salesman for the S.E. Massengill Company in Bristol, Tennessee, had indicated that there was heavy demand for the drug in liquid form in southern states, presumably to dose children more easily. Up for the challenge, the company’s lead chemist and pharmacist, Harold Cole Watkins, developed a formulation using diethylene glycol into which the sulfanilamide would easily dissolve. The mixture was tested for flavor, appearance and fragrance before it was mass produced and shipped all over the country.
The shipments were headed for their destinations, but one critical characteristic that the company had neglected to test was the compound’s toxicity. Pharmacological studies had not been done and Watkins’ failure to test it would lead to disaster. Diethylene glycol is a deadly poison, something used in certain formulations of antifreeze. Interestingly, lack of this test was not an illegal move at the time. The US did not require a drug be proven safe; it was simply assumed that a company wouldn’t risk bad business by sending out a drug that was unhealthy.
Well, this drug was most certainly not safe. The American Medical Association (AMA) started receiving reports in October that the drug had been used in several cases, and there was a high incidence of death and extreme pain in the patients taking the medication. Upon confirmation of the reports, the FDA dispatched a significant number of inspectors to track down and recover every trace of the drug that had been distributed by unwitting doctors. Though most of it was recovered shortly after the first reports were made available, over 100 patients died from poisoning. In one letter sent to then-president Franklin D. Roosevelt, one woman said:
“The first time I ever had occasion to call in a doctor for [Joan] and she was given Elixir of Sulfanilamide. All that is left to us is the caring for her little grave. Even the memory of her is mixed with sorrow for we can see her little body tossing to and fro and hear that little voice screaming with pain and it seems as though it would drive me insane. … It is my plea that you will take steps to prevent such sales of drugs that will take little lives and leave such suffering behind and such a bleak outlook on the future as I have tonight.” (1)
Because no laws existed preventing the sale of toxic substances, no legal action was ever taken against the company for its negligence in reviewing the toxic substance it had used in its drug. The only reason the FDA was able to seize distributed doses of the drug was because it had been mislabeled an “Elixir,” which by the FDA’s official definition, required an alcoholic component in its formulation. Without this mistake, the FDA would have had no legal recourse and it would have likely lead to more deaths as a result of poisoning.
This incident lead to the passage of the aforementioned 1938 Federal Food, Drug, and Cosmetic Act, which contained an added section covering new drugs to be sold in the United States. It outlined a drug testing protocol to provide better protection for the general public and was intended to prevent such a tragedy from occurring again. You can get the full FDA article here.
The new system was put a difficult test in 1961 when a Cincinnati, Ohio company named Richardson-Merrell attempted to bring a new drug, called thalidomide, to the United States from the German company that created it, Chemie Grünenthal at Stolberg. The company had synthesized the compound in 1953 while searching for an inexpensive method for manufacturing antibiotics from peptides. The drug was a failure at the original intent; it showed no appreciable effect as an antibiotic. In tests on animals, however, it showed no ill effect even at high doses. On that basis alone, the company decided that the best use for this new compound was to market it as a nonlethal sedative, even though no such effect had ever been observed in its studies on animals.
In a step to begin popularizing the drug, the company distributed free samples to doctors in Switzerland and Germany in 1955, and it was promoted as a treatment for seizures in patients with epilepsy. Though patients did not report improvement in the frequency of their seizures, they did report having a deeper sleep at night and a calmer mood during the day. The anecdotal evidence lead to Grünenthal performing experiments on mice to test its validity, and though the documented results were questionable, they were accepted by most European authorities. The drug was prescribed across the continent as a “safe” sedative, and it quickly became the drug of choice for helping pregnant women with morning sickness.
By 1960, Grünenthal enjoyed success with its drug throughout the world, but the United States was still an untapped market. As the sales team at Richardson-Merrell began preparing their documents for submission to the FDA, Frances Oldham Kelsey joined the agency and would be assigned as the agent responsible for reviewing the drug’s documentation and providing approval for the drug in the US market. The case was not expected to be lengthy or controversial. In advance of its approval, the FDA rules established by the 1938 Food, Drug and Cosmetic Act allowed Richardson-Merrell to distribute the drug on an “investigational” or “experimental” basis, which it did.
Kelsey, however, would prove to be the drug’s downfall. She was specifically interested in the fetal safety of the drug because she had studied quinine in the 1940s and its effects on pregnant women as part of a team of researchers trying to discover a synthetic cure for malaria. In one revealing study done on rabbits, she discovered that the substance was metabolized differently by pregnant rabbits versus their non-pregnant counterparts, and not metabolized at all by the embryos. She suspected that thalidomide may act in the same way, and therefore could cause serious side effects to the embryos of pregnant women, the very women who were taking the drug for their morning sickness in other countries.
Kelsey was additionally concerned that there was no acceptable “proof” that the drug behaved as a sedative; she needed to understand more about how the drug worked in humans. Several studies had been bypassed that might have shown the level of the drug’s toxicity over time, its effects on human metabolism, and its absorption rate, and a lack of manufacturing controls could not satisfactorily ensure the quality of the final product. Despite pressure from the Richardson-Merrell sales and marketing team to approve the drug, Kelsey refused the drug’s application 6 times over the second half of 1960.
In December 1960, the first reports emerged from Europe indicating there were possible toxicity effects from use of thalidomide among pregnant women. A most stunning letter published in the German paper “Welt am Sonntag” on November 18, 1961 by the German pediatrician Widukind Lenz. According to the letter:
Lenz described more than 150 infants with malformations, including phocomelia, and associated them with thalidomide given to their mothers. 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. (2)
The negative publicity eventually caused Chemie Grünenthal to withdraw the drug from most markets, and inform Richardson-Merrell of its decision. Kelsey’s persistence paid off, and most of the US public was spared from the side effects brought on by taking thalidomide, however, those pregnant women who participated in the “experimental” or “investigational” use of the drug suffered, so the rules needed to be changed.
In 1962, the Kefauver Harris Amendment was passed and gave the FDA better control over the experimentation of new drug substances on humans, and forced drug companies to prove both safety and efficacy of drugs. It lead to the birth of the 4-phase clinical trial structure that we enjoy today, and proves to be a more effective method in keeping potentially devastating drugs out of the market. You can read more about the fascinating history of thalidomide here, on Wikipedia (it is, incidentally, approved for use in the US today, though certainly not for the same effects for which it was advertised back in the 1950s and 1960s).
So, two major incidents in our drug history brings us to where we are today (with some other changes over time, of course). The clinical trial framework has been arguably the most beneficial development for keeping unsafe and ineffective drugs off of our drugstore shelves. However, one can see how it can be a hindrance to those whose life is threatened and who may not have many alternatives that will result in living longer. Should our structure be changed? Is the lengthy period associated with approvals a detriment to someone who might only have a few weeks, or even days, to contemplate their next steps? Do we release experimental drugs for use by terminally ill patients? What about people in perpetual pain? Where do we draw the line?
Please, share your thoughts!
(1) See “Taste of Raspberries, Taste of Death: The 1937 Elixir Sulfanilamide Incident,” written by Carol Ballentine for the June 1981 issue of the FDA Consumer Magazine.
(2) See “Thalidomide,” written collaboratively in Wikipedia
