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Dr. Frances Kelsey - one of my heroes- died this month at the age of 101. Every year I discuss her work at the FDA with my students during an introduction to Evidence Based Medicine lecture. In class we all find it amazing that only a very few have heard of Dr. Kelsey, or of thalidomide. At any rate- It seemed to me that it would be an injustice if I didn't submit a blog about her impact to ASHP Connect. A little bit of background is in order:

In 1954 a German company Chemie Grunenthal developed a new compound thalidomide having hypnotic and tranquilizing properties. Of course in 1954 the only sedatives on the market were barbiturates, and a safer alternative to barbiturates could find a huge market. Since studies in rodents found thalidomide to have a wide safety margin a decision was made to promote the use of thalidomide to pregnant women, possibly as a non prescription product. Grunenthal had little success entering the market in the United States and approached several pharmaceutical companies including Smith, Kline, and French and also Lederle. These experienced pharmaceutical companies reviewed the data and were dissatisfied with the studies of safety and efficacy and turned Grunenthal down. Grunenthal later granted the license for US sales to Richardson-Merrell. Thalidomide would be marketed by Richardson-Merrell as Kevadon-tm as a treatment for nausea and vomiting in pregnancy.

Frances Kelsey a Canadian by birth earned her M.D. and Ph.D. in Pharmacology at the University of Chicago. She had previous experience studying toxic effects on the fetus during studies of quinine conducted during World War II. After the war she and her husband worked at the University of South Dakota and she later became a family physician for a time. Her husband Ellis was appointed a special assistant to the Surgeon General and both were relocated to Washington DC and Dr. Kelsey became a medical officer for the FDA.

She was assigned the thalidomide file, thought to be an easy first assignment as the drug was already on the market in Europe, and South America. She noted the submitted file contained mostly anecdotes, and testimonials of company employed physicians. She also noted (as did scientists at SKF, and Lederle) there were gaps in the data supporting safety and efficacy. Although the submitted rodent data showed a wide safety margin she noted there were no tests conducted to determine if the rats were able to absorb thalidomide. Another FDA scientist also expressed concerns about evidence to support safety.

Dr. Kelsey decided to declare the application as incomplete (rather than rejecting the application) proving herself to be an expert at working under the Washington Bureaucracy. Richardson-Merrell put great pressure on Dr. Kelsey to approve Kevadon, calling in prominent physicians including another pharmacologist Louis Lasagna M.D. as well as other scientists demanding the approval of the drug. She was referred to as a petty bureaucrat! Her delaying tactics went on for over a year.

In December 1961 Dr. William McBride published a letter to the editor in the Lancet observing a relationship between phocomelia (absent or severely malformed limbs) and maternal use of thalidomide. A second physician Dr. Widukind Lenz completed a systematic canvasing of cases in the area of Hamburg Germany identifying 14 cases. Although attempts were made to discredit Dr. Lenz he held his ground. In the final analysis it was determined that 40,000 Germans had suffered from peripheral neuritis attributed to thalidomide and between 8,000 and 12,000 babies were born deformed.

Fortunately Dr. Kelsey's superiors backed her up and resisted pressures for approval. What if they didn't back her up? What if Dr. Kelsey backed down from her position in the face of expert testimony and relentless pressure? What would we think of her if thousands of infants were born with phocomelia, and many thousands of adults were crippled with irreversible peripheral neuritis? Hopefully none of us will end up in her situation, but if that happens what would we do? Something to think about isn't it?

Of course there are many unnecessary, frivolous, and probably useless government regulations. However every time I listen to a politician rant against federal regulations I think of Dr. Kelsey, and how fortunate so many parents and children are that we had this regulation, and that we had the right person in the job at the right time. President John Kennedy awarded her the Distinguished Federal Civilian Service Medal for her work on thalidomide. In 2010 the annual Drug Safety Excellence Award was established in her honor. Oh and its not a coincidence that her guidelines for FDA approval require at least two adequately powered randomized placebo controlled trials which of course we now consider as the minimum requirement for Level 1 Evidence.