Professionalism/Frances Oldham Kelsey and Thalidomide

Biography and Background
Frances Oldham Kelsey was born in 1914 in Cobble Hill, British Columbia. In 1934 and 1935, she earned a bachelor’s degree in science and a master degree in science from McGill University in Montreal. Eventually, she accepted a scholarship, where she earned her Ph.D. from the University of Chicago, and went on to teach there from 1938 to 1950 .In 1960 she moved to Washington, D.C., and began her long and distinguished career at the Food and Drug Administration (FDA), where she later became chief of the Division of New Drugs, director of the Division of Scientific Investigations. Dr. Frances Kelsey took her stand against thalidomide during her first month at the FDA, on her first assignment. The application was for thalidomide, a drug then popular in Europe to aid sleep and alleviate nausea during pregnancy. Kelsey and her FDA colleagues found the safety and toxicity data submitted by the company to be lacking supportive evidence, and she insisted that the company provide better data. Those concerns proved to be well-founded: about a year later a European outbreak of phocomelia, a severe birth defect in which infants are born without limbs or with severely deformed limbs, was associated to the use of thalidomide during pregnancy. Kelsey’s refusal to approve the application is credited with saving thousands of US children from such a fate. It also helped prompt massive changes in the regulation of drugs in the United States and abroad, changes she helped to shape during her 45-year career at the FDA.

Accutane
Accutane (clinically known as isotretinoin) was invented in the late 1950s to treat acne, though in its earliest trials it proved to have teratogenic effects in animals, causing birth defects when mothers are exposed to the drug. Accutane is a human teratogen that can cause multiple major malformations; the embryopathy associated with exposure during the first trimester of pregnancy includes craniofacial, cardiac, thymic, and central nervous system malformations. The drug was released in 1982 by Roche Pharmaceuticals under FDA pregnancy category X which states that “the risks involved in use of the drug in pregnant women clearly outweigh potential benefits” but says nothing about women who may become pregnant. The drug was approved for the treatment of severe recalcitrant cystic acne, but within the first year became the drug of choice for treating all types of acne, prescribed by nearly 90% of dermatologists nationwide until the first reports of malformed babies came in. Babies of accutane users were born with heart and central nervous system problems, malformed or absent ears, wide-set eyes and sometimes a cleft palate. Each successive year, as more reports came in, Roche Pharmaceuticals issued further warnings and increased labels, but the rate of birth defects continued to grow.

FDA
In February 1988 the Office of Epidemiology and Biostatistics at the FDA recommended that the drug be withdrawn from the market, but at Roche’s request, the FDA merely appointed a committee to review the drug. A follow up report was issued later that year stating that a woman exposed to Accutane in her first trimester had a 40% chance of miscarrying and a 25% chance of delivering a malformed baby. At the end of 1988, the manufacturer began a Pregnancy Prevention Program (PPP) that includes educational materials for both prescribers and patients and offers women reimbursement for contraceptive counseling by a physician. The PPP protocol states that women of reproductive potential must either abstain from sexual intercourse or use two methods of effective contraception simultaneously, have a negative pregnancy test before starting Accutane, and wait until the second or third day of their next menstrual period before beginning to take Accutane. The PPP also asks women of childbearing age being treated with Accutane to voluntarily enroll in the Boston University Accutane Survey (BUAS). Although Accutane is contraindicated in pregnancy, and its package explicitly warns users to avoid pregnancy while taking the product, exposed pregnancies continue to occur. Approximately 85 cases of congenital anomalies after exposure to Accutane have been reported to the FDA since 1989. Sixty of these reports have at least one of the features of retinoid embryopathy.

Accutane is known to be a very harsh drug with a long list of side effects including pink eye, chronically dry and sensitive skin, chapped lips, nosebleeds and joint pain, and possibly chest pain, depression, fatigue, headache, nausea, vomiting, rashes and skin infections and decreased night vision. In addition to the medical side effects, women who wanted to take accutane now also had to take birth control, monthly pregnancy tests and drive back and forth to renew prescriptions. Alternatively, a waiver was available that said you were not sexually active and would not become pregnant.

Sloan Survey
In conjunction with the PPP, the FDA conducted what was called the Sloan Survey, a voluntary program that surveyed women treated with accutane since 1989, totalling about 35% of the total female users. The study sought to determine how effective the PPP was and what the continued risk was among women of childbearing age.

Between 1992 and 1999 the number of women taking accutane went up 200%, and 80% of its users were between 15 and 30 years old, the age group considered by the FDA to be the prime child bearing population. Results of the Sloan Survey discovered major issues of non-compliance although 40% of female users in the high risk age group were sexually active. Between 1982 and 2000 there were 1,995 exposed pregnancies of which only only 383 were carried to full term and 42% of those babies with available medical records were born with major malformations. 1,446 of these pregnancies were terminated either electively or spontaneously and the outcome of the remaining 166 is unknown.

The FDA concluded that pregnancies are still occurring, there is substantial non-compliance with regulations, and that the survey only captured about 40% of all users and does not likely represent the actual number of problems.

Ethics
To get out of the strict qualifications, including added costs, additional drugs and inconvenient logistics, women can sign a waiver that says they are not sexually active and will not become pregnant. It seems that this an indication that the FDA is more concerned with liability than actually preventing birth defects.

The pregnancy classification X under which Accutane was first released and continues to be distributed stipulates that it cannot be prescribed to pregnant women because the risks outweigh the benefits. This stipulation should probably be expanded to include women who might get pregnant because they are at just as much a risk of passing on defects to their potential unborn children.

Accutane is a very expensive drug that is very attractive to a large portion of the population who can afford it. This could be a factor in its continued distribution. Those who have money are willing to pay for it to treat their acne and seem to be willing to take the risks of either signing the waiver or giving birth to a child with birth defects.