Michael Rosenthal

(9/2015) It’s easy to make the assumption that because a medical drug is available on the market and your physician recommends it, that it will be effective and safe. As this story shows, it’s isn’t always that simple!

Thalidomide was developed by a German pharmaceutical company, Chemie Grunenthal, and a twenty-year patent was obtained in 1954. It was marketed for the treatment of respiratory infections under the name Grippex, a combination drug in which a chemical named thalidomide was combined with other chemicals. Upon finding that thalidomide was effective for having an inhibitory effect on morning sickness, it was marketed aggressively as an over-the-counter drug in 1957 under the name Contergan. At this time, the use of medications in pregnant women was not strictly controlled. Drugs were not routinely tested for safety to the fetus, because it was not thought that such drugs could cross the placental barrier and damage the fetus.

This drug became very popular in Europe, Australia, New Zealand, and the United Kingdom, marketed under the name Distaval as a remedy for morning sickness. It was advertised as being completely safe. More and more pharmaceutical companies around the world obtained licenses from Grunenthal, and by the mid-1950s, 14 companies were marketing the thalidomide-containing drug under many different trade names. Smith, Kline, and French was approached by Grunenthal, and they conducted animal tests and ran a clinical trial involving 875 people, including pregnant women in 1956-57. They declined to distribute the drug in North America, feeling that it was not as effective as claimed by Grunenthal. Safety was not an issue at this time.

In 1958, Grunenthal reached an agreement with the Cincinnati-based William S. Merrell Company, and they licensed the drug and began to distribute it to 1200 physicians for testing purposes, expecting rapid approval from the Food and Drug Administration. It has been estimated that more than 2.5 million tablets were distributed to some 20,000 patients, several hundred of whom were pregnant.

About that time in 1960, Dr. Frances Oldham Kelsey was hired as a medical officer at the FDA, along with six other scientists, to review the 300 human drug applications that appeared annually. Dr. Kelsey raised serious concerns about thalidomide, feeling that Merrill had not produced adequate test results. Merrill refused to produce the test results that Dr. Kelsey demanded multiple times, and she blocked the approval of this drug for 19 months in the United States, worrying about its possible side effects. Not surprisingly, the pharmaceutical industry was not pleased, but her caution prevented an American tragedy from occurring.

Dr. Kelsey felt that the absorption and toxicity studies submitted by Merrell were incomplete, and thus she rejected the application and repeatedly requested more data. By February of 1961, Kelsey found that there were side effects and potential adverse reactions that had not been brought to the FDA’s attention. No research had been done on pregnant animals, so there was no indication of potential danger to pregnant women. The drug had been used in Canada, but was banned in March 1962 due to worry about birth defects, which turned out to be the drug’s prominent danger.

A particular physical deformity, the development of seal-like flippers, known as phocomelia, as well as infant deaths, were appearing abroad where thalidomide was being sold, including some 17 cases of phocomelia reported in the United States that apparently stemmed from the early distribution. Investigators were beginning to suspect thalidomide was the culprit. Due to the concerns raised by Dr. Kelsey, approval of the drug was stalled.

Faced with the inevitable likelihood thalidomide was a dangerous drug to pregnant women, Merrell withdrew its application for the drug’s approval. The seventeen United States cases of infant deformity were conclusively linked to the trial distributions of the drug by American physicians.

Further research indicated that thalidomide did indeed cross the placental barrier and retarded development of the fetus. It has been estimated that tens of thousands of babies had been affected by this drug in Europe! Many babies were born with no limbs or with withered appendages protruding directly from the trunk. Some babies had other deformities as well, and many babies died in the womb.

An important secondary benefit came from Dr. Kelsey’s work. The Kefauver-Harris amendments, approved by Congress and signed into law by President Kennedy in 1962, created the clinical trial system which makes extensive drug testing mandatory.

In 1998, thalidomide was approved by the FDA for treatment of leprosy lesions, and in 2006 was approved for treatment of certain cases of multiple myeloma. Along with this approval, however, came strict safeguards for use including pregnancy testing. An apology was made to thalidomide victims by the German distributor of the drug, Grunenthal, in 2012.

Another aspect of this story is the success in this period of a woman scientist. It will be a surprise to younger readers how hard it was for a woman during this period to be successful in science. Women were expected to stay home, cook and clean, and have babies. I’m not kidding! Yes, there were women who overcame these biases, but it wasn’t easy.

There were very few women chemistry majors in my undergraduate school. The only woman on the chemistry faculty at the University of Illinois during my graduate study, 1961-1965, was the chemistry librarian. I struggled for many years as a chemistry professor and health professions advisor in the 1960s and 1970s to get my women students into medical school and veterinary school. It is ironic how the veterinary profession is now dominated by women.

Dr. Kelsey, Canadian-born, was once a family doctor and professor, with both a doctorate in pharmacology and a medical degree from the University of Chicago. She became director of the FDA Office of Scientific Investigations, spending 45 years with the FDA. She was a scientific hero and was a great role model for women aspiring to careers in science and medicine, retiring at age 90. She passed away recently at age 101.

Here’s a pseudo-science quickie. For a period of time, there were advertisements (including a full page ad in USA Today) for Vitamin O. It was advertised as a dietary supplement, utilized by adding 15-20 drops two or three times a day in water. It was said to "maximize your nutrients, purify your bloodstream, and eliminate toxins and poisons". It was said to "stabilize oxygen molecules in a solution of distilled water and sodium chloride". It’s salt water! It’s entirely safe at that concentration, but it is of no use whatsoever. At its peak, they were selling 60,000 vials per month! It is still purchasable, among other sources, at Amazon! As P.T. Barnum said, "There’s a sucker born every minute", or as Mel Brooks says, "Everything is Showbiz".

Michael is former chemistry professor at Mount. St. Marys

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