Food and Drug Legislation - The Story Behind the Law

Introduction
The Early Days of Our Nation
The Industrial Revolution
The 1937 Elixir Sulfanilamide Incident
U.S. vs. Dotterweich
The Thalidomide Incident
Medical Device Amendments of 1976
GMP's
Conclusion

Introduction

Food and drug laws are significant considerations for all manufacturers regulated by The Food and Drug Administration. But did you ever wonder how these regulations came about or why these requirements exist? They are not arbitrary rules created simply to aggravate manufacturers, but rather they are responses to consumer concerns and documented tragedies in our history. Understanding the story out of which these regulatory requirements were born is the first step in truly complying with the spirit of the laws.

The Early Days of Our Nation

In the early days of our nation, society was based on agriculture, and most food was bought in bulk from farmers in the area in which people lived. People made their own food, and they knew the people who grew the ingredients for the food they made. Food laws were mostly unnecessary, as people checked for quality themselves, and grievances were effectively handled between individuals. During the colonial era, there was no federal government, so the few laws that did exist varied from state to state. As bread was one of the few "pre-made" foods available, the Massachusetts Bay Colony passed a law in 1646 standardizing the weight of loaves of bread in relation to the price of wheat and flour. This effectively fixed prices so that the baker’s profit was regulated. Other laws followed which forbade the substitution of grains, created a standard weight, and outlawed adulteration in bread. However, the overwhelming majority of the food supply remained unregulated at this time.

Drugs were also unregulated during this era, even though many ineffective drugs were on the market. The practice of medicine at this time relied more on tradition and superstition than on science. Additionally, people in rural areas often did not have access to doctors who would recommend medicines. Therefore, no real standards existed against which drugs could be measured.

The Industrial Revolution

The real push for food and drug laws began as a result of the Industrial Revolution. In the late 19th century, people began leaving their farms and moving to the cities to work in factories. People no longer knew the people who grew and prepared their food, and conditions in urban food factories and warehouses were notoriously unsanitary. The development of railroads made it possible for food manufacturers to ship their products over long distances and into different states, thereby engaging in interstate commerce. It became harder and harder for people to check their own food for quality, as they had no knowledge of where it was manufactured and held. Additionally, food technology was changing rapidly with the new use of preservatives, coloring materials, and other additives which amounted to adulteration of the product.

The main crusader of standards for food quality at this time in history was Harvey Washington Wiley. He was the chief chemist at the U.S. Department of Agriculture, and he had a very prestigious academic and career background in the U.S. and in Germany. He was so concerned about the effects of food additives that he headed up the famous "Poison Squad," which tested the safety of preservatives by eating them. Wiley’s quest for food standards did not become a national issue, however, until the publication of a novel detailing the horrific conditions in which some food was processed. In 1906 Upton Sinclair, a muckraking journalist, published the novel The Jungle. This novel detailed the true to life filthy conditions of a Chicago meat packing plant.

The publishing of this novel caused an uproar among the American public. People were appalled to learn that the food they ate was produced under such unsanitary conditions. A women’s movement was forming at this time in history, and pure food became an issue that the women took on. Women’s magazines, such as Ladies Home Journal and Colliers published articles calling for consumer protection. Congress was flooded with correspondence demanding that action be taken. The government turned to Wiley, who was clearly the expert in this field. That same year the Food and Drug Act of 1906 was passed. This, along with the Meat Inspection Act, which was passed on the same day, constituted the first federal regulation of food and drugs. The Food and Drug Act prohibited interstate commerce in misbranded and adulterated foods, drinks, and drugs. While this was a strong law for the time, it had many shortcomings. False therapeutic claims for patent medicines were basically unregulated, as the manufacturer had only to show that he personally believed that his remedy worked to avoid prosecution, and standards for food purity and content were nonexistent. Attempts to make changes to the law were unsuccessful until a major tragedy occurred in 1937.

The 1937 Elixir Sulfanilamide Incident

The glaring need to revise the 1906 Food and Drug Act arose in 1937 with a tragic incident involving the drug Sulfanilamide. Sulfanilamide was a drug commonly used to treat streptococcal infections. It was produced in tablet and powder forms, but not in a liquid form that would have been easier for children to take. The S.E. Massengill company decided to develop a liquid form of Sulfanilamide. Massengill’s chief chemist and pharmacist, Harold Cole Watkins, found that diethylene glycol was a good medium for the elixir Sulfanilamide. The new substance had a nice appearance and a pleasant taste. What Watkins did not realize was that diethylene glycol, which is more commonly known as antifreeze, is a deadly poison. Unfortunately, the existing law did not require any kind of pharmacological studies proving that a drug is safe, and 240 gallons of Elixir Sulfanilamide went on the market.

The people who took this drug, many of them children being treated for sore throats, suffered tremendously before they eventually died. They were ill between one and three weeks, and experienced stoppage of urine, severe abdominal pain, nausea, vomiting, stupor, and convulsions. The pain was severe and unrelenting, and eventually 107 people died.

The American Medical Association began receiving complaints from physicians a few weeks after it was sold, and quickly isolated diethylene glycol as the offending ingredient. Warnings were issued not to use the drug. Once FDA was notified of the problem, it insisted on more severe letters be sent to distributors warning of the lethal nature of the product. FDA dispatched nearly its entire force of 239 investigators to the task of tracking down the remaining unused portions of the medicine. This was a very difficult task, as pharmacies often kept very poor records of who had purchased various types of medicines. But the FDA investigators were tireless in their pursuit of the dangerous medicine, and eventually tracked down 234 gallons and 1 pint of the 240 gallons. The remaining amount had been consumed.

Massengill denied any responsibility for the tragic outcome of its quest for a liquid form of Sulfanilamide. Watkins, the chemist who developed it, however, committed suicide. Massengill was charged on a misbranding technicality in the incident. Unfortunately, the fact that they had produced an unsafe pharmaceutical product did not violate any existing law. Therefore, the 1906 Food and Drug Act was quickly replaced by the Federal Food, Drug, and Cosmetic Act of 1938. The legislation had been enforced by the Bureau of Chemistry until 1927, when the Food, Drug, and Insecticide Administration was created. In 1931 it was renamed the Food and Drug Administration. In 1940, FDA was transferred from the U.S. Department of Agriculture, to the Federal Security Agency, which later became the Department of Health, Education, and Welfare, and later the Department of Health and Human Services. This law, after many revisions, is still in effect today. In 1938, this law introduced the following improvements to the existing legislation: cosmetics and therapeutic devices were regulated for the first time, fraud no longer needed to be proved to prevent false claims for drugs, scientific proof of safety for new drugs was required before they could be marketed, addition of poisonous substances to food was outlawed in most cases, and tightly regulated in others, authority was created for factory inspections, food standards were required to be created, and federal court injunctions against violations were made legal.

Future amendments to the 1938 law ensured that no substance could be introduced into the food supply without a prior determination that it was safe. These amendments were a result of the work of a committee sanctioned by Congress to investigate chemicals in food. They are: the Pesticide Amendment (1954), the Food Additives Amendment (1958), and the Color Additive Amendment (1960).

U.S. vs. Dotterweich

In 1941, the court case U.S. vs. Dotterweich established the fact that FDA can hold individuals as well as companies responsible for violations of the Federal Food, Drug, and Cosmetic Act. Joseph H. Dotterweich was an executive at Buffalo Pharmacal Company, a pharmaceutical distributing company, and it was clear that nothing happened at that company without his approval. Dotterweich and Buffalo Pharmacal Company were both charged with shipping adulterated and misbranded cascara compound tablets, digitalis tablets, and posterior pituitary solution across state lines.

As the evidence clearly demonstrated that the charges were justified, the company agreed to plead guilty if the government dropped the charges against Dotterweich. FDA refused to drop the charges, and the case went to court. The prosecution showed that Dotterweich was responsible for all actions which occurred at the plant, and made a case that the accountability extended to him personally as well as to the company. The defense countered with the fact that if Dotterweich and the company were convicted, the company would go out of business, and many good jobs would be lost. As this happened at the end of the Great Depression, loss of jobs was a serious concern, which impacted the jury. They ruled that Dotterweich was guilty, but they were unable to decide on the guilt or innocence of the company. The ruling was appealed all the way to the Supreme Court, which convicted Dotterweich and maintained that distributors of pharmaceuticals are responsible for the quality of their products, even if they were manufactured elsewhere.

This litigation was very significant in the history of food and drug law, as it established that responsible individuals can be held personally accountable for the quality of the products manufactured by their company. This is true regardless of whether or not the individual has direct knowledge of the wrongdoing. A later case, U.S. vs. Park, further strengthened this interpretation. It established that responsible individuals can be held personally accountable for the quality and compliance status of products manufactured by their company even if they have delegated the job to another capable person on staff.

The Thalidomide Incident

When the drug thalidomide was submitted to FDA for approval, Frances Kelsey, a new FDA employee, reviewed the application very carefully, and kept it off the market until it was determined that it caused birth defects when used by pregnant women. This near catastrophe highlighted the need for more stringent drug laws.

Thalidomide was a drug commonly used in Europe to treat sleep disorders and morning sickness in pregnant women. It was available starting in 1958 in West Germany, and did not even require a prescription. The William S. Merrill Company submitted an application to market thalidomide in the U.S, and Frances Kelsey, a new FDA employee, was given the job to process the approval. As it was so widely used in Europe, it was viewed as an easy task. Kelsey, however, was a first class scientist. She had helped with the collection of Elixir Sulfanilamide in 1937 and 1938, and knew the impact that her job had on millions of people. As she was reviewing the material submitted by Merrill, she noticed that it acted differently on animals than on humans. This was her first inkling that thalidomide required a closer investigation than Merrill and many others thought necessary. She returned the application and requested more information.

Meanwhile, in Europe, several developments had occurred relating to the use of thalidomide. In 1960, 83 children were born with birth defects, even though there were no cases of this in the previous 5 years. These defects were attributed to several causes, but no one noticed the link to the use of thalidomide during pregnancy. In February of 1961, a letter in a British medical journal reporting a tingling nerve inflammation in the fingers of long-time thalidomide users. As this side effect was confirmed, Germany made it a prescription drug. During this time thousands of babies were born with birth defects.

Kelsey started exploring the idea that the tingling could affect the fetus as well as the mother. She wanted to require that a warning be placed on all bottles telling users not to take it during pregnancy. However, she received much criticism regarding this, as it was so widely used during pregnancy. When a German scientist finally began to make the connection between thalidomide and birth defects in November of 1961, it was withdrawn in Germany, and Merrill withdrew its drug application. Some 5,000 German babies were born with birth defects resulting from use of thalidomide, and there were many more in other countries. FDA discovered that it had been distributed to over 3,000 women in the U.S. as a clinical test which also worked as a marketing promotion. This was not illegal at the time. Through the diligent efforts of Kelsey to make sure that the drug was safe and effective, thousands of birth defects were prevented in this country.

This near tragedy and the need for tougher food and drug laws did not come to public attention until the Washington Post ran a story on it on July 15, 1962, stating that thalidomide could have passed the current laws in this country. This aroused concern, and Congress passed the Drug Amendments of 1962 which addressed safety requirements for testing on human subjects. It also required that patients be informed if they are taking a drug that is experimental, that drug companies must report to FDA any adverse effects of drugs found during clinical trials, that new drugs be proven effective as well as safe, that the drug label carry the common or generic name of the product as well as the brand name, and that prescription drug advertising to doctors list the side effects of a drug as well as its benefits.

Medical Device Amendments of 1976

Many other amendments to the Food, Drug, and Cosmetic Act have been enacted. One of the most significant is the Medical Device Amendments of 1976. This amendment gave FDA authority to regulate medical devices, so that now all medical devices on the market are proven to be safe and effective.

Medical device technology changed rapidly during the 1960’s and 1970’s. As more devices were created, their safety and effectiveness became more of an issue. Diagnostic devices, which aided in the detection of diseases and other conditions such as pregnancy, were regulated as drugs prior to these amendments. This involved some legal manipulations of the definition of drugs, but the courts upheld it, as it believed that the regulation of these devices was necessary. However, FDA pressed Congress to allow for the regulation of diagnostic devices as devices rather than drugs. In 1969, the President issued a message calling for the study of the medical device field. This was delegated to the Department of Health, Education, and Welfare, which created the Cooper Committee Report of 1970. The Cooper Report recommended the system of regulation that was eventually adopted in 1976. However, while this was being debated in Congress during 1972 and 1973, a pacemaker failure occurred. And in 1973, problems with Dalkon Shield intrauterine devices were reported, and injuries resulted. These two incidents underscored the need for medical device legislation requiring that devices be safe.

The Medical Device Amendments were passed in 1976, and FDA was then able to regulate all medical devices. The amendments defined devices similarly to drugs, but noted the difference that drugs cause a chemical reaction in the body, whereas devices do not. They called for all devices to be divided into three classifications, with varying amounts of control required in each classification.

GMP’s

GMP’s or Good Manufacturing Practice Regulations were promulgated by FDA to assist in their enforcement of the Food, Drug, and Cosmetic Act. They are a set of controls which assure that manufacturers operate in a state of control, and therefore create products which are safe, pure and effective.

Efforts to produce regulatory documents to list a proper set of manufacturing conditions go back to 1948, when the vague quality of the Food Drug and Cosmetic Act on the topic of food adulteration caused some people to want more detail. This effort was unsuccessful at this time, but later it would be formalized. In 1962, the Drug Amendments gave explicit statutory power to GMP Regulations, but it wasn’t until 1976 that the Medical Device Amendments gave GMP’s full detailed authority over medical devices that they were first promulgated. We now have GMP regulations for the drugs, medical devices, food, blood, medicated feeds, and type A medical products. The medical device GMP was revised in October of 1996 to reflect a harmonization with international standards, and it is now known by the title Quality System Regulation. These regulations carry the full force of law, as they are expounding on the Food, Drug, and Cosmetic Act.

Good Manufacturing Practice Regulations are often called cGMP’s as well as just GMP’s. The "c" stands for current, meaning that the regulation allows for changing technology, and requires that manufacturers use current technology to minimize contamination, mix-ups, and errors. Therefore, the regulations are not specific "how to" documents, as each manufacturer must decide the appropriate level of controls and technology to ensure that their products are safe, pure and effective.

Conclusion

Food and drug law in this country has evolved since the Colonial days. The consistent goal of all the legislation in this area has been consumer protection. While it is unfortunate that much of this legislation has come as a result of tragedy or near tragedy, these situations help to keep the importance of food and drug laws in perspective.