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The FDA for the Average SBM Consumer

How the Food and Drug Administration came to be is a story that is filled with death, intrigue and dubious characters. It also, like most stories, has its share of heroes and vindications. The list of those who have died to bring us the agency we know today is long, but even today, the death-toll continues. Now this is not the horrible thing it may at first seem. People are all born with a terminal disease known as life, and they will die. The goal of Medicine is to forestall that death as long as possible and to give people good, long, healthy and safe lives. This is where the Food and Drug Administration comes into play. They help guide the pharmaceutical world in the safest manner possible.

The legal quagmire that is the Food and Drug Administration (FDA) is a result of a series of laws which it behooves the Science-Based Medical community, to understand. Many of these laws were a result of deaths, which were themselves the result of either poor safeguards, or, as we will see in one case, lack of information on the part of a company. It began with the Division of Chemistry inside the U.S. Department of Agriculture. The original concern of this group was the misbranding and adulteration of both food and drugs. The first of the laws which came into effect, to give the Bureau of Chemistry as it became known, was the Biologics Control Act of 1902. As is so often the case with FDA regulations, this was a result of deaths in the populous.

The Biologics Control Act of 1902 came about after children had died from vaccines for both diphtheria and smallpox. In the first case, a horse named Jim, who had been used to produce some 30 quarts of diphtheria antitoxin, was found to have contracted tetanus. This was after additional diphtheria antitoxin had been produced, packaged and shipped and resulted in the death of 13 children in St. Louis, Missouri. The second case, which involved a contaminated smallpox vaccine, claimed the lives of nine children in Camden, New Jersey. The BCA of 1902 directly led to the creation of the Center for Biologics Evaluation and Research or CBER. This act set the precedent for regulating drug products, specifically Biologics. 

This was followed, in 1906 by the “Wiley Act” which is also known as the Pure Food and Drug Act of 1906 which prohibited the “manufacture, sale, or transportation of adulterated or misbranded or poisonous or deleterious foods, drugs, medicines, and liquors, and for regulating traffic therein, and for other purposes.”1 During this time, the enforcement for this act was given to Harvey Washington Wiley (Yes, the same Wiley the Act was named after) and the USDA Bureau of Chemistry. Slowly, the Food & Drug Administration is being born. One of the first major legal tests to this was United States v. Johnson2in which the Supreme Court held that “misbranding” did not attach to the therapeutic claims of the drug product but only to the ingredients. The case involved containers of medicinal product bearing labels that stated or implied that the contents were effective in curing cancer, when the creator knew that such representations were false. To quote Justice Holmes, “One may say with some confidence that, in idiomatic English, this half at least, is confined to identity, and means a false statement as to what the ingredients are.” This ruling was a serious blow for the fledgling agency and Congress responded with the Sherley Amendment in 1912 which clarified the authority to enforce the Wiley Act based on fraud in the therapeutic claim. In 1927, the government underwent a reorganization and the Bureau of Chemistry was folded into the Food, Drug and Insecticide organization within the USDA. Three years later, this became the Food & Drug Administration.

In the 1930’s we had another major event which influenced the laws surrounding the FDA. One of the important things to understand is that the Pure Food and Drug Act of 1906 did not regulate, in any way, the safety of new drugs, and was mainly concerned with those drugs already on the market. This is where the story of Elixir Sulfanilamide enters the picture. Created in 1937 by the S. E. Massengill Company, this sulfanilamide concoction was prepared with diethylene glycol (DEG) as a solvent. DEG was at this point known to be toxic, although the exact extent of its toxicity was not known.3In September of 1937, Elixir Sulfanilamide was being sold in the U.S. Markets and by October the American Medical Association had begun receiving complaints about possible deaths resulting from it. An important name for later appears here for the first time. Frances Oldham Kelsey, during her Ph.D. in Pharmacology studies at the University of Chicago, assisted in the research project which showed that the 100 deaths from Elixir Sulfanilamide were due to the DEG which was used as a solvent.4These deaths were classified as fatal adverse events. The FDA at this time was hampered in its authority as to what action it could take. Under the Pure Food and Drug Act of 1906, the ability of the FDA to regulate this “medication” was reduced to labeling. According to the regulations, an “Elixir” was required to contain some percentage of alcohol to be permitted to be labeled as such. Elixir Sulfanilamide contained none. The end result of this was that the S. E. Massengill Company paid a small fine and their chief Chemist, Harold Watkins, committed suicide5. But, as with most regulations, it didn’t end there. Congress now passed the Food, Drug and Cosmetic Act of 1938.

The Food, Drug and Cosmetic Act of 1938 was a major leap forward for the FDA. Now, for the first time, the Agency had an ability to regulate a drug before it came onto the markets. A key part of the Act mandated that safety data had to be collected and reviewed prior to marketing of a New Chemical Entity (NCE). Additionally the FDA no longer needed to prove fraudulent intent before intervening with false or misleading labeling. These were major steps forward for the FDA and with the additional inspection authorities that the FDA gained, the Agency that we know today was basically formed. This Act also saw Homeopathic Nostrums classified as a “drug” by the FDA. They are protected under Section 201(g) and 201(j) of the act and this was the FDA’s first serious attempt at regulating these products.

In 1951 we see the next major step in the process with the Durham-Humphrey Amendment. This Amendment had the effect of basically creating a class of drug which must be taken under the supervision of a medical practitioner, the so called “prescription only” drugs. In addition, the 1940’s had seen two Amendments, the Insulin and Penicillin Amendments added a requirement for potency testing. During this time the Public Health Services Act of 1944 expanded the Agency’s scope to cover biological products as well.

This brings us to 1959 and to a tragedy on a global scale which was, through decisive action on the part of one FDA reviewer, greatly minimized in the United States. Although the tragedy would take a few years to manifest itself, 1959 saw the US Senate try to put in place regulations to have pharmaceutical companies demonstrate the efficacy of their product. There was a great deal of push back from both the public and the pharma industry, but this stopped in 1962 when thalidomide appeared.

As this is one of the true pivotal moment in the history of the FDA, we will examine it in a bit more detail. Thalidomide came on to the European Markets in 1957 and was used as a pain killer and tranquilizer6. Another key reason for its use was that it was found to combat morning sickness in pregnant women. That was to be Thalidomide’s ultimate downfall. During the 1950’s and 1960’s, after Thalidomide made it onto the Market, more than 10,000 children in 46 countries were born with deformities. This alarmed two European Doctors who began investigating the reasons7. Now we meet Frances Oldham Kelsey again. Remember her from earlier? By this time she had completed both her PhD and her M.D. and was working as a reviewer at the FDA. When Thalidomide, also known as Kevadon, came across her desk she decided that the safety documentation was not sufficient to support the requested indication of relief from morning sickness. The Application was rejected8. Richardson Merrell (Now Marion Merrell Dow), the manufacturer, then attempted to apply pressure to have their drug approved, but Dr. Kelsey remained firm in her desire for safety studies. What Richardson Merrell did manage to do was distribute 2.5 million pills to approximately 1,200 doctors in the US with the understanding that this product was not approved and still “under investigation”. As Dr. Kelsey dug deeper into the product, the 10,000 birth defects became publically known and Richardson Merrell rescinded their Application. Seventeen (17) children in the US were born with birth defects as a result of Thalidomide. Currently it is marketed in the United States by Celgene under the name Thalomid and is part of a RiskMAP known as S.T.E.P.S.

The Thalidomide incident led directly to the Kefauver-Harris Amendment of 1962. This is also known as the “Drug Efficacy Amendment”9. The main effect of this Amendment on the FDA was that they now had the authority to mandate clinical studies to show that a Drug is both safe and effective. 

As we draw to the close of the establishment of the FDA, a few more milestones should be noted. In 1976 the Medical Device Amendments expanded the FDA’s reach to cover medical devices. 1983 saw the Orphan Drug Act which makes it easier to conduct studies and research drugs for rare diseases. The Food and Drug Administration Act of 1988 makes the FDA part of the Department of Health and Human Services. Finally, in 2007, the Food and Drug Administration Amendments Act (FDAAA) put in place the ability for the FDA to being mandating Risk Management and Evaluation Strategies (R.E.M.S.) for products which have a high risk to patient populations, which was brought about, in part by the death related to Class II Extended Release Opioid Products.

This is how the FDA grew out of a few small offices to the true Agency that it is today. It has, through trial and error, learned to deal with death, unscrupulous marketing and outright contempt. The FDA will not be going anywhere soon, and with the recent appointment of Dr. Hamburg as the Commissioner the focus on Safety will once again be brought to the forefront as we are already seeing in some of the more recent enforcement actions the Agency has undertaken. 

Martin A. Lessem is a Regulatory Attorney with eight years of working in the Pharmaceutical Industry. Although currently working for a Generic manufacturer, Martin has worked for Innovator companies as well. His current area of expertise is Risk Management, specifically the new R.E.M.S. guidelines, Promotional Compliance and the Regulatory aspects of Clinical Trials. The views that he expresses in his posts are his own and do not necessarily reflect those of his current or previous companies.

Posted in: History, Medical devices, Politics and Regulation

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