Kathleen Z. Rooney
Beginning in the 19th century, the practice of medicine was licensed. The American Medical Association formed in 1847 and the US Pharmacopoeia was founded in 1820
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to create a formulary and official record of drugs. However, medical practice and drug production and distribution regulations varied from state to state. Many "quacks" existed who marketed ineffective and sometimes unsafe medicines. It is equally true that many fine remedies existed, remedies often culturally based: Native American, African American, British, Amish, and Chinese. Many medical practitioners used these remedies to great healing effect.
As the economy and infrastructure of the United States expanded in the late 19th and early 20th century, the FDA grew from a single chemist in 1862 who worked at the Department of Agriculture, to a full agency with a large mission. Charged with regulating the safety of foods and drugs produced and imported into the United States, the FDA took food as its primary focus at its beginning. Coming on the heels of revelations in Upton Sinclair's The Jungle
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, The 1906 Pure Food and Drug Act charged the FDA to regulate interstate transport and sale of unlawfully adulterated or inaccurately labeled foods and drugs. The act, however, was extremely vague and lacked enforceable language. Author of Inside the FDA, Fran Hawthorne writes: "… the law applied primarily to what was said on the label, not what was actually in the bottle. Government regulators were given no authority to look inside the container, let alone test the ingredients, to ensure the contents would not harm the public."
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The first regulations to require pre-market testing for safety came with the passage of the Food, Drug, and Cosmetic Act of 1938. President Roosevelt signed the law that required all drug manufacturers to show scientific proof that a drug was safe prior to being sold in the United States. This law followed the Sulfanilamide crisis of 1937, when a remedy laced with a toxic solvent killed 100 people, mostly children. The FDA was now charged with the evaluation of data related to the safety of products being developed.
The regulation that is responsible for the modern clinical trial model was the 1962 amendments to the Food and Drug act following the Thalidomide crisis. This story is proudly retold on the FDA website with the hero of the story, Frances Kelsey, as the human face for the critically important role that the government plays in protecting consumers. In September 1960, the drug company Richardson Merrill applied to the U.S. and Canada for the rights to market Thalidomide, a sleeping aid popular in Europe. Frances Kelsey's very first assignment at the FDA was to review the sedative that was also being marketed as a remedy for morning sickness in pregnant women. Frances Kelsey did not like the company's application, especially its lack of unbiased evidence. In a recent interview with the CBC, she said the "Claims were so obviously outrageous, I mean it was supposed to be perfect. It didn't have any ill effects" But she was also under " great pressure to approve it."
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Since this was to be her very first approval, no one expected her to do very much with the application. In fact, she was given the file of a popular drug approved overseas as a way to learn the ropes.
Frances Kelsey used bureaucratic rules to delay approval. It is documented that drug representatives visited her no less than 50 times. Despite the pressure, she continued to delay, and her hunch paid off the following year. Articles began appearing in British journals reporting tingling and neuropathy, and then followed the reports of deformed babies. Eventually, over 10,000 thalidomide-affected births have been documented worldwide. These were horrifying, debilitating birth defects causing the limbs of these children to be truncated or missing completely.
In 1962 President Kennedy awarded Francis Kelsey the civilian Medal of Honor and the Kefauver-Harris amendments to the 1938 act were passed unanimously by Congress. The FDA now required scientific proof through well-controlled studies that drugs sold and manufactured in the United States be proven not only safe but also effective. This was evidence that Thalidomide lacked and Kelsey was so tenaciously demanding. This formalized, evidence-based approval process is why " the FDA today is considered the gold standard for approval. Again, Hawthorne: What the 1962 amendments essentially did was to codify Kelsey's courage and careful attention into law."
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The regulation requiring pre-marketing studies for safety and efficacy have directly resulted in the formation of standards for clinical trials in the United States. The first clinical trials guidance documents came out in 1970, with additional changes in 1985
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. These guidance documents have largely been adopted as worldwide standards in the International Conference on Harmonization.
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