Wednesday, August 8, 2012

The heroine of the FDA: a Stranger than Fiction true thriller


This blog is about fiction, but I am a firm believer in authenticity.  A thriller that incorporates slices of truth can enthrall me, as I race through the plot while marveling at or wondering about the non-fictional elements.  If the story is good enough, it can drive me to research the non-fiction laced within.  And I hope to motivate my readers to do the same.  The below is the first in my "Stranger than Fiction" series - a collection of true stories that, like a good thriller, can have us on the edge of our seats.  This is the story of thalidomide, and the one brave woman who narrowly averted a national epidemic in the United States.

In 1953, German pharmaceutical company Chemie Grünenthal first synthesized the drug that was to be termed thalidomide.  They were searching for antibiotics, but thalidomide showed no antibiotic activity.  However, it appeared to be safe.  Extremely high doses did not kill lab animals nor show any obvious side effects.  They began to consider it as a sedative, although no sedative or tranquilizing effects were observed.

In 1955, Grünenthal began distributing free samples of thalidomide to doctors in Switzerland and West Germany.  They recommended it for the prevention of seizures.  Although no anti-seizure activity was found, some patients reported experiencing a deep sleep or a noticeable sense of calm.  Grünenthal began to advertise thalidomide as a perfectly safe, powerful hypnotic drug.

An employee of Chemie Grünenthal brought home samples of the new drug for his pregnant wife, ten months before thalidomide was approved for market in Germany.  On Christmas Day in 1956, their child was born without ears.

Chemie Grünenthal began selling the drug over the counter in Germany in October 1957, under the brand name Contergan.  By 1960, the drug was being sold in 46 countries under at least 37 names, without any additional independent testing.  There had never been any teratogenicity tests (tests on pregnant females); yet, thalidomide became the drug of choice worldwide for morning sickness.

The United States was the exception.

In September, 1960, Richardson-Merrell applied for Food and Drug Administration (FDA) approval to sell thalidomide in the United States under the brand name Kevadon.  The approval was not expected to be controversial, and the case was given to the agency's newest reviewer, Frances Oldham Kelsey, who had joined the FDA just one month prior.

At the time, the prevailing US law was the 1938 Federal Food, Drug, and Cosmetic Act, which required proof of safety be sent to the FDA before a medication could be approved for sale in the United States.  The law did not require demonstration of efficacy.  It also allowed "investigational" or "experimental" use of a drug while approval for its sale was being sought, allowing a medication to be widely distributed prior to approval.  The law gave the FDA 60 days to review a drug application.  If the FDA reviewer told a drug company that its application for a medication was incomplete, it was considered withdrawn and the company would have to submit more data when it resubmitted the application.  With each resubmission, the 60 days started anew.

Francis Kelsey had studied the effects of another drug on pregnancy, and was unconvinced that thalidomide was safe for pregnant women, their fetuses, or children.  In addition to the lack of teratogenicity data, Kelsey wanted to know about the drug's mechanism of action – its effects on human metabolism, its chemistry and pharmacology and its stability.   None of this data had been provided by Richardson-Merrell.  Kelsey rejected the application and requested additional data.

Richardson-Merrell resubmitted the application with no further data.  Richardson-Merrell employees began a campaign of harassing Francis Kelsey, rather than providing the data she requested, even complaining to her superiors that she was being unreasonable in her requests for additional data.  Kelsey continued to reject their proposals.  In total, she rejected the application six times.

Then the birth defects began.  As women worldwide who had been taking thalidomide for morning sickness began giving birth, it became clear that thalidomide was a horrible, horrible teratogen.  Children were born with abnormally short limbs, toes sprouting from the hips, flipper-like arms, eye and ear defects, or malformed internal organs.  Chemie Grünenthal encouraged doctors to withhold reporting of the abnormalities, as they continued to vehemently insist that they could not have been caused by the drug.

On November 18, 1961, the German paper Welt am Sonntag published a letter by German pediatrician Widukind Lenz.  Lenz described more than 150 infants with thalidomide-induced malformations.  The data showed that 50 percent of the mothers with deformed children had taken thalidomide during the first trimester of pregnancy.  Grünenthal finally withdrew thalidomide from the market.

Worldwide, an estimated 8,000 to 12,000 infants were born with deformities caused by thalidomide, and of those only about 5,000 survived beyond childhood.  Due entirely to the intelligence and will of Francis Kelsey, the medication never received approval for sale in the United States.  Nonetheless, 2.5 million tablets had been given to more than 1,200 American doctors during Richardson-Merrell's "investigation" and nearly 20,000 patients received thalidomide, including several hundred pregnant women.  Seventeen American children were born with thalidomide-related deformities.

The actions of Francis Kelsey led to a major change in U.S. law for drug approval.  Prior to the thalidomide scandal, US drug companies only had to show their new products were safe.  Afterward, they would have to show that new drugs were safe and effective.  To this day, informed consent is now required of patients participating in clinical trials, and adverse drug reactions were required to be reported to the FDA.

But thalidomide has been revived.
 
In 1964, Israeli physician Jacob Sheskin was trying to help a critically ill French patient with erythema nodosum leprosum (ENL), a painful complication of leprosy.  Sheskin searched his small hospital for anything to help his patient sleep.  He administered two tablets of thalidomide, and the patient slept for hours, and was able to get out of bed without aid upon awakening.  Dr. Sheskin's drug of last resort revolutionized the care of leprosy, and led to the closing of most leprosy hospitals.  

Thalidomide has potent anti-inflammatory effects that may help ENL patients. In July 1998, the FDA approved the application of Celgene to distribute thalidomide under the brand name Thalomid for treatment of ENL.  

The very mechanism of action that led to the wave of thalidomide-induced birth defects is also responsible for its efficacy in treating cancer.  Thalidomide inhibits the growth of new blood vessels (angiogenesis).  Angiogenesis is a critical process for cancer growth, and also, for the development of a fetus.  Pharmion Corporation, who licensed the rights to market Thalidomide in Europe, Australia and various other territories from Celgene, received approval for its use against multiple myeloma in Australia and New Zealand in 2003.  Thalomid, in conjunction with dexamethasone, is now standard-of-care therapy for multiple myeloma.

Now that its anti-angiogenic and anti-inflammatory effects are understood, thalidomide is under investigation for prostate cancer, glioblastoma, lymphoma, arachnoiditis, Behçet's disease, and Crohn's disease as well as several AIDS-related conditions.  It is approved to treat leprosy and multiple myeloma.

It carries a black box warning and is not for use in pregnant women or in children.

2 comments:

  1. Wow, what a fascinating story. Thanks for sharing.

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    1. Thanks Sara. Yes, it's one of those moments in history that few people outside of the drug discovery community know about today. But it was huge!

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