The Historical Rise of Pharmaceutical Regulation

The first rumblings for US drug legislation began after the Civil War, which had spurred the separation of drug manufacturers from drug prescribers and drug dispensers. This was the time of the traveling medicine shows selling dangerous, addictive or just non-sense patent medicines. Today's pharmaceutical companies got their start in the apothecary shops of that time, but still, most drugs were imported from Europe. In fact the U.S was a dumping ground for substandard and contaminated drugs.

Adulteration and Misbranding

Harvey Wiley of the US Department of Agriculture first began testing food products for adulteration about 1870. He became chief chemist of the Department of Agriculture in 1883. In 1890, Congress enacted a law to prevent importation of dangerously adulterated food or drink. The President could simply issue a proclamation prohibiting such articles from entering the country.

In 1906, Harvey Wiley wrote the Pure Food and Drug Act with the blessings and promotion of President Teddy Roosevelt. The act was prompted by shameful practices in the food and drug industries described in Upton Sinclair's book, The Jungle. One of the most nauseating references in this book is to the lard industry, where if workers fell into a lard vat ..." sometimes they would be overlooked for days, until all but the bones of them had gone out to the world as Durham's Pure Leaf Lard."

The 1906 Pure Food and Drug Act applied tough penalties for certain acts of misbranding and adulteration. It required the identification of narcotics. It set up quality standards based on monographs published in the US Pharmacopoeia, and it drove scores of secret nostrums off the market. Unfortunately, the US Supreme Court significantly weakened the act in a ruling saying it did not prevent false health claims, only false labeling.

The 1912 Shirley Amendment attempted to rectify this loophole, but left another. It required a prosecutor to prove a deliberate intent to defraud the public.

Drug Product Safety

The Shirley Amendment did not control the marketing of new drugs, devices or cosmetics. Yet, it lasted for thirty-two years until the drug industry once again drew public indignation and a new bunch of consumer advocates rose to document the industry's disgrace. Two writers, Kallet and Schlik, wrote a book called 100,000 Guinea Pigs, and went on to found Consumers Research. Ruth Lamb wrote American Chamber of Horrors, which also captured the public's attention. Ruth Lamb, it turns out, had been secretly hired by the Department of Agriculture to write a book that would stimulate the passage of legislation. These books documented examples of poisonous cosmetics, contaminated foods, and false drug advertising.

The Shirley Amendment did not control the marketing of new drugs, devices or cosmetics. Yet, it lasted for thirty-two years until the drug industry once again drew public indignation and a new bunch of consumer advocates rose to document the industry's disgrace. Two writers, Kallet and Schlik, wrote a book called , and went on to found Consumers Research. Ruth Lamb wrote , which also captured the public's attention. Ruth Lamb, it turns out, had been secretly hired by the Department of Agriculture to write a book that would stimulate the passage of legislation. These books documented examples of poisonous cosmetics, contaminated foods, and false drug advertising.

Still, it took a national tragedy to spur legislative action. In 1937, the Massengil Company started to market a new product, sulfanilamide elixir. Sulfanilamide is an antibiotic that is insoluble in water. Massengil chemists therefore dissolved the drug in ethylene glycol instead. No toxicity testing of the product, containing what we now call automotive antifreeze, was done and little was generally known about its deadly toxicity. Over a hundred people were killed before the US government pulled the product from the market. Even then, the only power the government had to do so was in a technical labeling violation: the drug product was a solution, not an elixir (e.g., it did not contain alcohol).

The resulting Food Drug and Cosmetic Act of 1938 required that proof, in the form of a New Drug Application (commonly called an NDA) be submitted to a new department called the US Food and Drug Administration. Anyone wishing to market a "New Drug" had to show safety for intended use in the form of an NDA.

Efficacy

Congressional hearings in the 1950's and 1960's by legislators such as Senator Kefauver focused public attention on excessive drug costs, inadequate competition, price controls and patent protection. In this period of tremendous industry growth and the rapid introduction of many important drugs (such as penicillin, the sulfonamide antibiotics and tetracycline, the first antihistamines, cortisone, and major tranquilizers), the Food and Drug Administration and many clinical investigators were publicly criticized for ineptitude and dishonesty. Once again, however, it took a national tragedy to bring about legislation.

Thalidomide was discovered in West Germany and sold over-the-counter as a tranquilizer/sedative until April 1961, when it was recognized as causing a type of polyneuritis in adults. By November of that year, the drug become associated with an outbreak of phocomelia, more commonly called "seal limbs." By that time, over a thousand "flipper babies" had been born with grossly disfigured appendages. The drug was distributed worldwide, with the notable exception of the United States. The Merrell Company had been conducting US. experiments since 1960 but had not yet gained marketing approval. An FDA Medical Officer had insisted on further proof of safety before granting marketing approval to Merrell. In so doing, the FDA limited the number of phocomelia babies in the US. to only a few cases.

The 1962 Kefauver-Harris Amendments (to the 1938 Food Drug and Cosmetic Act) required that pharmaceutical companies submit evidence of safety, and now, efficacy. A number of lesser acts have been passed since 1962, but the Kefauver-Harris amendments, and the FDA regulations promulgated from them, chiefly govern drug research and development to this day.

The 1962 amendments made a significant impact on drug development. On the plus side, the act required that the FDA be notified before a company begins human testing (e.g., the pharmaceutical company must obtain an Investigational Drug Exemption or IND), thus eliminating the previous method of starting clinical trials on the basis of skimpy animal toxicity tests. This legislation allowed the FDA to license and inspect drug manufacturers. It also prevented the use of generic names that were obscure and difficult to remember, a practice the manufacturers used to diminish generic substitution. On the negative side, it could be argued that this legislation has significantly increased the time it takes for a new drug to reach the marketplace, has substantially increased research expenditures and thereby the retail cost, and has limited the breadth of drugs as companies target their R&D investment only at the most promising, e.g., potentially profitable, candidates.

Photos were taken by the author at the New Orleans Pharmacy Museum (prior to Hurricane Katrina).

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