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.
Jessica Fitzjohn, a postdoctoral fellow at the University of Canterbury, demonstrates the novel breast cancer screening device.
Researchers at the University of Canterbury and startup Tiro Medical in Christchurch, New Zealand are hoping their new device—which doesn’t involve any radiation or compression of the breasts—could increase the accuracy of breast cancer screening, broaden access and encourage more women to get checked. They’re digging into clues from the way buildings move in an earthquake to help detect more cases of this disease.
Earthquake engineering inspires new breast cancer screening tech
What’s underneath a surface affects how it vibrates. Earthquake engineers look at the vibrations of swaying buildings to identify the underlying soil and tissue properties. “As the vibration wave travels, it reflects the stiffness of the material between that wave and the surface,” says Geoff Chase, professor of engineering at the University of Canterbury in Christchurch, New Zealand.
Chase is applying this same concept to breasts. Analyzing the surface motion of the breast as it vibrates could reveal the stiffness of the tissues underneath. Regions of high stiffness could point to cancer, given that cancerous breast tissue can be up to 20 times stiffer than normal tissue. “If in essence every woman’s breast is soft soil, then if you have some granite rocks in there, we’re going to see that on the surface,” explains Chase.
The earthquake-inspired device exceeds the 87 percent sensitivity of a 3D mammogram.
That notion underpins a new breast screening device, the brainchild of Chase. Women lie face down, with their breast being screened inside a circular hole and the nipple resting on a small disc called an actuator. The actuator moves up and down, between one and two millimeters, so there’s a small vibration, “almost like having your phone vibrate on your nipple,” says Jessica Fitzjohn, a postdoctoral fellow at the University of Canterbury who collaborated on the device design with Chase.
Cameras surrounding the device take photos of the breast surface motion as it vibrates. The photos are fed into image processing algorithms that convert them into data points. Then, diagnostic algorithms analyze those data points to find any differences in the breast tissue. “We’re looking for that stiffness contrast which could indicate a tumor,” Fitzjohn says.
A nascent yet promising technology
The device has been tested in a clinical trial of 14 women: one with healthy breasts and 13 with a tumor in one breast. The cohort was small but diverse, varying in age, breast volume and tumor size.
Results from the trial yielded a sensitivity rate, or the likelihood of correctly detecting breast cancer, of 85 percent. Meanwhile, the device’s specificity rate, or the probability of diagnosing healthy breasts, was 77 percent. By combining and optimizing certain diagnostic algorithms, the device reached between 92 and 100 percent sensitivity and between 80 and 86 percent specificity, which is comparable to the latest 3D mammogram technology. Called tomosynthesis, these 3D mammograms take a number of sharper, clearer and more detailed 3D images compared to the single 2D image of a conventional mammogram, and have a specificity score of 92 percent. Although the earthquake-inspired device’s specificity is lower, it exceeds the 87 percent sensitivity of a 3D mammogram.
The team hopes that cameras with better resolution can help improve the numbers. And with a limited amount of data in the first trial, the researchers are looking into funding for another clinical trial to validate their results on a larger cohort size.
Additionally, during the trial, the device correctly identified one woman’s breast as healthy, while her prior mammogram gave a false positive. The device correctly identified it as being healthy tissue. It was also able to capture the tiniest tumor at 7 millimeters—around a third of an inch or half as long as an aspirin tablet.
Diagnostic findings from the device are immediate.
When using the earthquake-inspired device, women lie face down, with their breast being screened inside circular holes.
University of Canterbury.
But more testing is needed to “prove the device’s ability to pick up small breast cancers less than 10 to 15 millimeters in size, as we know that finding cancers when they are small is the best way of improving outcomes,” says Richard Annand, a radiologist at Pacific Radiology in New Zealand. He explains that mammography already detects most precancerous lesions, so if the device will only be able to find large masses or lumps it won’t be particularly useful. While not directly involved in administering the clinical trial for the device, Annand was a director at the time for Canterbury Breastcare, where the trial occurred.
Meanwhile, Monique Gary, a breast surgical oncologist and medical director of the Grand View Health Cancer program in Pennsylvania, U.S., is excited to see new technologies advancing breast cancer screening and early detection. But she notes that the device may be challenging for “patients who are unable to lay prone, such as pregnant women as well as those who are differently abled, and this machine might exclude them.” She adds that it would also be interesting to explore how breast implants would impact the device’s vibrational frequency.
Diagnostic findings from the device are immediate, with the results available “before you put your clothes back on,” Chase says. The absence of any radiation is another benefit, though Annand considers it a minor edge “as we know the radiation dose used in mammography is minimal, and the advantages of having a mammogram far outweigh the potential risk of radiation.”
The researchers also conducted a separate ergonomic trial with 40 women to assess the device’s comfort, safety and ease of use. Angela was part of that trial and described the experience as “easy, quick, painless and required no manual intervention from an operator.” And if a person is uncomfortable being topless or having their breasts touched by someone else, “this type of device would make them more comfortable and less exposed,” she says.
While mammograms remain “the ‘gold standard’ in breast imaging, particularly screening, physicians need an option that can be used in combination with mammography.
Fitzjohn acknowledges that “at the moment, it’s quite a crude prototype—it’s just a block that you lie on.” The team prioritized function over form initially, but they’re now planning a few design improvements, including more cushioning for the breasts and the surface where the women lie on.
While mammograms remains “the ‘gold standard’ in breast imaging, particularly screening, physicians need an option that is good at excluding breast cancer when used in combination with mammography, has good availability, is easy to use and is affordable. There is the possibility that the device could fill this role,” Annand says.
Indeed, the researchers envision their new breast screening device as complementary to mammograms—a prescreening tool that could make breast cancer checks widely available. As the device is portable and doesn’t require specialized knowledge to operate, it can be used in clinics, pop-up screening facilities and rural communities. “If it was easily accessible, particularly as part of a checkup with a [general practitioner] or done in a practice the patient is familiar with, it may encourage more women to access this service,” Angela says. For those who find regular mammograms uncomfortable or can’t afford them, the earthquake-inspired device may be an option—and an even better one.
Broadening access could prompt more women to go for screenings, particularly younger women at higher risk of getting breast cancer because of a family history of the disease or specific gene mutations. “If we can provide an option for them then we can catch those cancers earlier,” Fitzjohn syas. “By taking screening to people, we’re increasing patient-centric care.”
With the team aiming to lower the device’s cost to somewhere between five and eight times less than mammography equipment, it would also be valuable for low-to-middle-income nations that are challenged to afford the infrastructure for mammograms or may not have enough skilled radiologists.
For Fitzjohn, the ultimate goal is to “increase equity in breast screening and catch cancer early so we have better outcomes for women who are diagnosed with breast cancer.”