Federal Vigilance Saves Lives

For centuries, products consumed by humans for nutritional and health purposes were debased by merchants seeking economic gains. During the last 120 years, the U.S. has taken numerous steps to arrest food adulteration and to ensure the safety and efficacy of medical and other products. Advances in science combined with the fundamental determination for protection against fraudulent harmful goods have led to a vibrant interdisciplinary system in which consumers, investigators, regulatory and research scientists, legislators, and adjudicators collaborate for the public good.

Numerous events led to legislation and related actions for the protection of humans. This article focuses on several tragedies that highlight problems requiring solution.

Research in Europe demonstrated that diphtheria toxin injected in pigs, dogs, and horses produced a substance in their blood that could be used as an antitoxin to treat diphtheria in other species. By the start of the 20th century in the U.S., the use of antitoxin for treating diphtheria was successful. The Health Commission in St. Louis, MO had been developing the antitoxin in a factory with a horse farm. Serum extracted from one horse on September 30, 1901 was used to produce the antitoxin, although the horse was executed two days later when it was diagnosed with tetanus. By November 7th, 13 children treated for diphtheria died from tetanus (lockjaw), and the city discontinued production of the antitoxin.

In early October 1901, a father and his eight children died of smallpox in Camden, NJ. This led to the enforcement of an 1897 law requiring that all schoolchildren be vaccinated. Based on European studies, the smallpox vaccine was produced by collecting fluid leaking from lesions on the udders of cows infected with cowpox. The school contracted with the H.K. Mulford Company for the vaccine, which led to the deaths of nine students from tetanus. A hospital in Pennsylvania using this product had five deaths. Nothing against the company was proven.

In 1902, Congress passed the Biologics Control Act (also known as the Virus-Toxin Law), giving the federal government’s Hygienic Laboratory of the Public Health and Marine Hospital Service control over biological products processing and responsibility to protect public health. Manufacturers of antitoxins, vaccines, and serums were required to undergo inspections, have licenses approved annually, and have a qualified scientist supervising production.

Four years later, Congress passed the Pure Food and Drug Act, which prohibited adulterated foods, drugs, and drinks in interstate commerce. Enforcement of the Act was the responsibility of the Department of Agriculture’s Bureau of Chemistry, where Dr. Harvey W. Wiley, “Crusading Chemist,” had performed studies on food adulteration, preservatives, and colors. On the same day in 1906, Congress passed the Meat Inspection Act.

From 1920 to 1933, the U.S. Treasury Department administered alcohol prohibition laws and issued limitations on the amount of ethanol permitted in patent medicines. One analgesic medicine, containing 70% alcohol by weight, was Jamaica ginger, which became popular as a beverage. In order to develop a version of “Jake” (the colloquial name of the product) that could falsely pass alcohol tests, bootleggers adulterated the product with a plasticizer, tri-ortho cresyl phosphate. Numerous adulterated Jake users developed a form of paralysis that affected their hands and feet. In 1930, the product was seized. On April 2, 1932, The Washington Post reported that Harry Gross, who produced adulterated Jake, was sentenced to two years in prison.

The number of victims of organophosphate-induced delayed neuropathy was never established, but it is estimated to be between 30,000 and 50,000. In 1933, the FDA recommended that the obsolete 1906 Food and Drugs Act be revised. On December 5, 1933, the National Prohibition Act was repealed, and control of alcohol use was transferred to the states.

Results of scientific research in Europe demonstrating that sulfanilamide could be used to fight streptococcal infections gained attention of the pharmaceutical industry, and Merck, Eli Lilly, and Squibb began to produce tablets and capsules. In Bristol, TN, the chief chemist at the S.E. Massengill Company was requested to develop a liquid form of treatment involving sulfanilamide. Based on solubility, a solution with 16% water, 72% diethylene glycol, and 10% sulfanilamide was prepared. After taste testing, for the remaining 2% a mix consisting of raspberry extract, caramel, saccharin, and other ingredients was added, resulting in elixir sulfanilamide. In October 1937, one month after 240 gallons of the “elixir” were distributed, reports of six deaths of patients in Tulsa, OK, due to renal failure prompted Commissioner Walter Campbell of the newly formed FDA to order the Agency’s chemists and investigators to examine the problem. Once diethylene glycol (antifreeze) was implicated as the cause of the deaths, without legal authority the Agency tracked and seized bottles of elixir sulfanilamide.

Unfortunately, over 100 other deaths occurred, but thousands of deaths were averted. Because the existing law didn’t require Massengill to prove the safety of its product, the only legal complaint was that the term “elixir” was reserved for drugs containing ethanol. Following the disaster, Congress passed the 1938 Food, Drug, and Cosmetic Act, which included the requirement that new drugs be shown to be safe before marketing and authorized inspections of manufacturing facilities.

The requirement for proof of safety before a drug is marketed in the United States is the main reason the country was practically spared from the severe physical disabilities impacting thousands of children worldwide due to treatment of pregnant women with a product initially marketed as a sleeping pill and then as an effective treatment of morning sickness. Thalidomide was developed by German company Chemie Grünenthal in the 1950s. It was found that after the pregnant wife of a Grünenthal employee used the product, she gave birth to a baby girl without ears on December 25, 1956, now thought to be the first known victim of thalidomide. Although the drug was sold in 46 other countries, when a request for thalidomide marketing approval was submitted to the FDA in September 1960, the pharmacologist reviewing the file requested safety research results. Little information was provided, causing Dr. Frances O. Kelsey to keep asking the company for more data. By the end of November 1961, evidence became public in Germany linking thalidomide to birth defects, and by 1962 use of the drug by pregnant women was banned worldwide. In 1962, Congress passed the Kefauver Harris Drug Amendment to the Federal Food, Drug, and Cosmetic Act, stating a specific approval from FDA must be received before a drug may be marketed. FDA was requested to develop rules defining the scientific investigations that should be done to prove safety and efficacy before approval is sought. Research on thalidomide continued, and three decades later it was approved for the treatment of medical disorders such as leprosy and cancerous tumors like multiple myeloma.

In 1960, a year before Johnson & Johnson purchased it, and 23 years before it would become the first western pharmaceutical company to open a factory in China, Janssen Pharmaceutica developed fentanyl at its headquarters in Belgium. The synthetic opioid branded as Sublimaze began being used as an intravenous analgesic in Western Europe and soon was combined with other drugs to create analgesic anesthesia.

In 1968, Innovar, an anesthetic that was a mix of 2% fentanyl with 98% droperidol, was approved for use in the U.S. A decade later, cardiac anesthesiologists began trials substituting fentanyl for morphine. Other uses for fentanyl as a painkiller resulted in a transdermal drug delivery patch for cancer patients and lozenges or lollipops as premedication before surgery, nasal, and sublingual sprays. Although initially products were approved only for hospital use, it wasn’t long before there were adverse events associated with misuse by clinicians and others. After fentanyl products designed to treat cancer patients with high opioid tolerance were approved in 1998, it became obvious that prescriptions were provided for other pain-related problems. The CDC noted a wave of deaths due to overdose associated with increased fentanyl use, then, in 2010 a rapid increase in deaths due to heroin (later determined to involve the mixing of fentanyl with heroin), and in 2013 a significant increase of overdose deaths associated with synthetic opioids mainly illicitly manufactured fentanyl.

During that period, the Kingpin Act, enacted in December 1999, gave the Department of the Treasury authority to deny foreign narcotics traffickers access to the U.S. financial system and to prohibit their trade and transactions with U.S. companies and individuals. Federal and state law enforcement and health agencies developed an interactive system that led to indictments of drug trafficking organizations. The problem persists due to counterfeiters producing fentanyl disguised as legitimate drugs such as Xanax or as candies and selling products through the dark web. FDA news releases from June 5 and August 28, 2018 report 74 websites marketing unapproved opioids.

The Department of Justice Drug Enforcement Authority July 2016 Intelligence Brief on “Counterfeit Prescription Pills Containing Fentanyls: A Global Threat” presents the current situation. It is time for all hands on deck.

Lois Ann Beaver is with LAB Enterprises.

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