President John F. Kennedy gave Dr. Frances Oldham Kelsey the nation's highest federal civilian service award in 1962, saying she had "prevented a major tragedy of birth deformities."
By 1960, Thalidomide was being sold in countries throughout the world, and the United States was expected to soon follow suit. Dr. Frances Oldham Kelsey, a pharmacologist and physician, was hired by the Food and Drug Administration (FDA) in September of that year to review and approve drugs for the administration. Immediately, Kelsey was tasked with approving thalidomide for commercial use in the United States under the name Kevadon. Kelsey's approval was supposed to be a formality, since the drug was so widely used in other countries.
But Kelsey did something that few people expected – she paused. Rather than approving the drug offhand as she was expected to do, Kelsey asked the manufacturer – William S. Merrell Co., who was manufacturing thalidomide under license from Chemie Grünenthal – to supply her with more safety data, noting that Merrell's application for approval relied mostly on anecdotal testimony. Kelsey – along with her husband who worked as a pharmacologist at the National Institutes of Health (NIH) — was highly suspicious of a drug that had no lethal dose and no side effects. "It was just too positive," Kelsey said later. "This couldn't be the perfect drug with no risk."
At the same time, rumors were starting to swirl across Europe that thalidomide was not as safe as everyone had initially thought: Physicians were starting to notice an "unusual increase" in the birth of severely deformed babies, and they were beginning to suspect thalidomide as the cause. The babies, whose mothers had all taken thalidomide during pregnancy, were born with conditions like deafness, blindness, congenital heart problems, and even phocomelia, a malformation of the arms and legs. Doctors and midwives were also starting to notice a sharp rise in miscarriages and stillbirths among their patients as well.
Kelsey's skepticism was rewarded in November 1961 when thalidomide was yanked abruptly off the market, following a growing outcry that it was responsible for hundreds of stillbirths and deformities.
Kelsey had heard none of these rumors, but she did know from her post-doctoral research that adults could metabolize drugs differently than fetuses – in other words, a drug that was perfectly safe for adults could be detrimental to a patient's unborn child. Noting that thalidomide could cross the placental barrier, she asked for safety data, such as clinical trials, that showed specifically the drug was non-toxic for fetuses. Merrell supplied Kelsey with anecdotal data – in other words, accounts from patients who attested to the fact that they took thalidomide with no adverse effects – but she rejected it, needing stronger data: clinical studies with pregnant women included.
The drug company was annoyed at what they considered Kelsey's needless bureaucracy. After all, Germans were consuming around 1 million doses of thalidomide every day in 1960, with lots of anecdotal evidence that it was safe, even among pregnant women. As the holidays approached – the most lucrative time of year for sedative sales – Merrell executives started hounding Kelsey to approve thalidomide, even phoning her superior and paying her visits at work. But Kelsey was unmovable. Kelsey's skepticism was solidified in December 1960, when she read a letter published in the British Medical Journal from a physician. In the letter, the author warned that his long-term thalidomide patients were starting to report pain in their arms and legs.
"The burden of proof that the drug is safe … lies with the applicant," Kelsey wrote in a letter to Merrell executive Joseph F. Murray in May of 1961. Despite increasing pressure, Kelsey held fast to her insistence that more safety data – particularly for fetuses – was needed.
Kelsey's skepticism was rewarded in November 1961 when Chemie Grünenthal yanked thalidomide off the market overseas, following a growing outcry that it was responsible for hundreds of stillbirths and deformities. In early 1962, Merrell conceded that the drug's safety was unproven in fetuses and formally withdrew its application at the FDA.
Thanks to Kelsey, the United States was spared the effects of thalidomide – although countries like Europe and Canada were not so lucky. Thalidomide remained in people's homes under different names long after it was pulled from the market, and so women unfortunately continued to take thalidomide during their pregnancies, unaware of its effects. All told, thalidomide is thought to have caused around 10,000 birth defects and anywhere from 5,000 to 7,000 miscarriages. Many so-called "thalidomide babies" are now adults living with disabilities.
Niko von Glasow, born in 1960, is a German film director and producer who was born disabled due to the side effects of thalidomide.
Wikimedia Commons
Just two years after joining the FDA, Kelsey was presented with the President's Award for Distinguished Federal Civilian Service and was appointed as the head of the Investigational Drug Branch at the FDA. Not only did Kelsey save the U.S. public from the horrific effects of thalidomide, but she forever changed the way drugs were developed and approved for use in the United States: Drugs now need to not only be proven safe and effective, but adverse drug reactions need to be reported to the FDA and informed consent must be obtained by all participants before they volunteer for clinical trials. Today, the United States is safer because of Frances Kelsey's bravery.
Peanut allergies affect about a million children in the U.S., and most never outgrow them. Luckily, some promising remedies are in the works.
Typically, people with peanut allergies try to completely avoid them and carry an adrenaline autoinjector like an EpiPen in case of emergencies. This constant vigilance is very stressful, particularly for parents with young children.
“The search for a peanut allergy ‘cure’ has been a vigorous one,” says Claudia Gray, a pediatrician and allergist at Vincent Pallotti Hospital in Cape Town, South Africa. The closest thing to a solution so far, she says, is the process of desensitization, which exposes the patient to gradually increasing doses of peanut allergen to build up a tolerance. The most common type of desensitization is oral immunotherapy, where patients ingest small quantities of peanut powder. It has been effective but there is a risk of anaphylaxis since it involves swallowing the allergen.
"By the end of the trial, my son tolerated approximately 1.5 peanuts," Sharon Wong says.
DBV Technologies, a company based in Montrouge, France has created a skin patch to address this problem. The Viaskin Patch contains a much lower amount of peanut allergen than oral immunotherapy and delivers it through the skin to slowly increase tolerance. This decreases the risk of anaphylaxis.
Wong heard about the peanut patch and wanted her son to take part in an early phase 2 trial for 4-to-11-year-olds.
“We felt that participating in DBV’s peanut patch trial would give him the best chance at desensitization or at least increase his tolerance from a speck of peanut to a peanut,” Wong says. “The daily routine was quite simple, remove the old patch and then apply a new one. By the end of the trial, he tolerated approximately 1.5 peanuts.”
How it works
For DBV Technologies, it all began when pediatric gastroenterologist Pierre-Henri Benhamou teamed up with fellow professor of gastroenterology Christopher Dupont and his brother, engineer Bertrand Dupont. Together they created a more effective skin patch to detect when babies have allergies to cow's milk. Then they realized that the patch could actually be used to treat allergies by promoting tolerance. They decided to focus on peanut allergies first as the more dangerous.
The Viaskin patch utilizes the fact that the skin can promote tolerance to external stimuli. The skin is the body’s first defense. Controlling the extent of the immune response is crucial for the skin. So it has defense mechanisms against external stimuli and can promote tolerance.
The patch consists of an adhesive foam ring with a plastic film on top. A small amount of peanut protein is placed in the center. The adhesive ring is attached to the back of the patient's body. The peanut protein sits above the skin but does not directly touch it. As the patient sweats, water droplets on the inside of the film dissolve the peanut protein, which is then absorbed into the skin.
The peanut protein is then captured by skin cells called Langerhans cells. They play an important role in getting the immune system to tolerate certain external stimuli. Langerhans cells take the peanut protein to lymph nodes which activate T regulatory cells. T regulatory cells suppress the allergic response.
A different patch is applied to the skin every day to increase tolerance. It’s both easy to use and convenient.
“The DBV approach uses much smaller amounts than oral immunotherapy and works through the skin significantly reducing the risk of allergic reactions,” says Edwin H. Kim, the division chief of Pediatric Allergy and Immunology at the University of North Carolina, U.S., and one of the principal investigators of Viaskin’s clinical trials. “By not going through the mouth, the patch also avoids the taste and texture issues. Finally, the ability to apply a patch and immediately go about your day may be very attractive to very busy patients and families.”
Brandon Wong displaying origami figures he folded at an Origami Convention in 2022
Sharon Wong
Clinical trials
Results from DBV's phase 3 trial in children ages 1 to 3 show its potential. For a positive result, patients who could not tolerate 10 milligrams or less of peanut protein had to be able to manage 300 mg or more after 12 months. Toddlers who could already tolerate more than 10 mg needed to be able to manage 1000 mg or more. In the end, 67 percent of subjects using the Viaskin patch met the target as compared to 33 percent of patients taking the placebo dose.
“The Viaskin peanut patch has been studied in several clinical trials to date with promising results,” says Suzanne M. Barshow, assistant professor of medicine in allergy and asthma research at Stanford University School of Medicine in the U.S. “The data shows that it is safe and well-tolerated. Compared to oral immunotherapy, treatment with the patch results in fewer side effects but appears to be less effective in achieving desensitization.”
The primary reason the patch is less potent is that oral immunotherapy uses a larger amount of the allergen. Additionally, absorption of the peanut protein into the skin could be erratic.
Gray also highlights that there is some tradeoff between risk and efficacy.
“The peanut patch is an exciting advance but not as effective as the oral route,” Gray says. “For those patients who are very sensitive to orally ingested peanut in oral immunotherapy or have an aversion to oral peanut, it has a use. So, essentially, the form of immunotherapy will have to be tailored to each patient.” Having different forms such as the Viaskin patch which is applied to the skin or pills that patients can swallow or dissolve under the tongue is helpful.
The hope is that the patch’s efficacy will increase over time. The team is currently running a follow-up trial, where the same patients continue using the patch.
“It is a very important study to show whether the benefit achieved after 12 months on the patch stays stable or hopefully continues to grow with longer duration,” says Kim, who is an investigator in this follow-up trial.
"My son now attends university in Massachusetts, lives on-campus, and eats dorm food. He has so much more freedom," Wong says.
The team is further ahead in the phase 3 follow-up trial for 4-to-11-year-olds. The initial phase 3 trial was not as successful as the trial for kids between one and three. The patch enabled patients to tolerate more peanuts but there was not a significant enough difference compared to the placebo group to be definitive. The follow-up trial showed greater potency. It suggests that the longer patients are on the patch, the stronger its effects.
They’re also testing if making the patch bigger, changing the shape and extending the minimum time it’s worn can improve its benefits in a trial for a new group of 4-to-11 year-olds.
The future
DBV Technologies is using the skin patch to treat cow’s milk allergies in children ages 1 to 17. They’re currently in phase 2 trials.
As for the peanut allergy trials in toddlers, the hope is to see more efficacy soon.
For Wong’s son who took part in the earlier phase 2 trial for 4-to-11-year-olds, the patch has transformed his life.
“My son continues to maintain his peanut tolerance and is not affected by peanut dust in the air or cross-contact,” Wong says. ”He attends university in Massachusetts, lives on-campus, and eats dorm food. He still carries an EpiPen but has so much more freedom than before his clinical trial. We will always be grateful.”