by Beverly Merz
Neurosurgeon Liliana Goumnerova, MD, is preparing to remove a brain tumor from a 2-year-old boy. He's the smallest patient yet to be treated in Children's Hospital Boston's new MR-OR—an operating suite where surgeons can use magnetic resonance imaging (MRI) mid-operation to ensure they've removed as much diseased tissue as possible before closing the incision. Children's is the first pediatric hospital in the nation to have this new technology.
After the child is anesthetized, Goumnerova and colleagues fix his head in the position specified by the MRI manufacturer and activate the 15,000-pound mobile magnet. The enormous white tube emerges from behind its protective wall, moves down the table on an overhead track and pauses over the child to take the image. The team scrutinizes the MRI, but the tumor isn't visible. In fact, the child's brain is nowhere to be seen on the scan.
A check of the MRI settings determines that they are correct—for an adult patient. "The computer makes an assumption based on a standard head size and distance from the head to the shoulders, and that determines where the patient is placed on the table," Goumnerova explains. Because the boy's neck is much shorter than an adult's, the magnet went past the toddler's head before taking the image.
The team recalculates where the child's head should be placed and repositions him. This time, the tumor appears clearly on the MRI, and they remove it completely.
The challenges Goumnerova and others face are more the rule than the exception in caring for small children. Beyond a few widely used instruments like stethoscopes, most medical equipment is designed with a 200-pound adult in mind. The reason is economic: Adults constitute the major market for medical devices simply because they are far more likely to get sick. Heart disease is a typical example. Approximately 1.4 million adults undergo cardiac catheterizations annually, compared with about 14,000 children. With a 100-fold smaller market, manufacturers have little incentive to design products scaled to fit children.
The small pediatric market also makes it more difficult to recruit children for clinical trials, complicating the process of gaining marketing approval from the Food and Drug Administration (FDA). Filling trials with children often requires the involvement of a large number of medical centers. Another difficulty is that pediatric medical research faces special ethical concerns. In a trial of a feeding tube, for example, recruiting healthy children for a control group would be prohibited because inserting the tube presents more than a minimal risk. Recruiting adults wouldn't pose this problem because they are deemed capable of evaluating the risk and choosing to accept it.
"Pediatrics is an orphan market," Goumnerova says. Her assessment sounds flip but is literally true: the FDA defines an orphan product as one with an annual market of no more than 200,000 people in the United States. With fewer than 500 children in the country developing brain tumors annually, and the difficulty of mounting clinical trials, it's unlikely that large medical device companies will choose to develop products exclusively for children. This numbers game often requires finding an adult use for a pediatric product—if one exists.
Working with colleagues James Lock, MD, and Wayne Tworetzky, MD, to build Children's Fetal Cardiac Intervention Program, cardiologist Audrey Marshall, MD, knows about the need to find an adult market when developing products for children. She recalls how the team prepared for the first fetal surgery to avert hypoplastic left heart syndrome (HLHS)—in which the left ventricle, the heart's main pumping chamber, is underdeveloped and can't provide enough blood to the body.
Although a series of three operations in early childhood has greatly reduced deaths from HLHS, the Children's cardiologists felt they could prevent the defect from developing by treating the baby in the womb.
The team planned to thread a catheter through the mother's abdomen into her uterus and guide it into the fetal heart. There, they would inflate a balloon to widen the outlet from the left ventricle, increasing blood flow through the left ventricle and enabling the chamber to grow to full size.
But first they had to collect the proper instruments. "We used what we had available—catheters that were the right size and could work together," Marshall recalls. In September 2001, the team performed the first successful fetal procedure in a 24-week fetus, collaborating with physicians at Brigham and Women's Hospital. The boy was born 10 weeks later with no evidence of HLHS.
Despite their success, the team felt their instruments were less than ideal. "If we were working from scratch, we wouldn't make any of the catheters the way they are," Marshall says. The problem is that the catheter must enter through the mother's abdomen, then must often change directions once inside the fetal circulation. Unfortunately, all the catheters, though as narrow as a pencil lead, are equally straight. When the catheter won't enter the fetal heart at the correct angle, surgeons must open the mother's abdomen and insert it directly through the uterus. Curved catheters are available for laparoscopic surgery, but are much too large for fetal procedures.
So Marshall and Lock designed a catheter with a flexible end that would bend inside the fetal heart. But finding a manufacturer was a problem because the market for such a device is infinitesimal; the team has performed only 63 fetal procedures over the past five years. "One company thought the fetal catheter was great, but couldn't justify it economically," Marshall says. To sweeten their case, Marshall and Lock polled colleagues in adult medicine for potential uses for the catheter. They aroused interest from anesthesiologists, who envisioned using it to deliver nerve blocks to hard-to-reach areas of the body, and urologists, who thought it could help open obstructed bladder valves. Lock convinced the manufacturer of the catheter's expanded market potential, and it should roll off the production line this spring.
Anesthesiologist and perioperative physician Stephen B. Corn, MD, is also used to innovating when he sees an unmet clinical need.
One need was a reliable way to detect respiratory depression and apnea (temporary respiratory arrest) in surgical patients receiving epidural or spinal narcotics. While still in training, Corn learned of a child who had died from an unwitnessed respiratory arrest after surgery. He was concerned that lapses in the boy's breathing hadn't been detected early enough, and felt there should be a way to monitor respiration in hospitalized patients, even those thought to be at low risk.
Apnea monitors do exist, and are used in high-risk patients, but they tend to generate false alarms: the electrical leads sometimes fall off, or alarms can be triggered by something as simple as the patient turning over. As a result, patients and nurses often turn the alarm volume down, defeating the monitor's purpose. Corn visualized a new kind of monitor that wouldn't need to be tethered to the patient. "When we bring patients from the OR to the recovery room, they're not connected to monitoring devices," Corn says, "so instead, I advise residents to monitor patients' respiration by watching for the periodic rise and fall of the blanket. And I thought, 'What if we automate this, and make the measurement continuous'?"
So Corn designed a device that employs ultrasound imaging to monitor breathing by detecting and analyzing chest and abdominal motions in real time. He took his plan to a pair of engineers, and together they produced a sleek prototype the size of a TV remote control, mountable above a patient's bed. Like the fetal cardiac team's catheter, it will be tested initially in adults, but Corn foresees a huge market as a home monitor for infants to prevent Sudden Infant Death Syndrome, and as a way of screening children for sleep apnea.
Corn's long experience designing clinical devices—he holds 29 patents, many for medical devices that are now being manufactured—is now being tapped to help get more pediatric products to market. As Chief of Clinical Innovation at Children's and neighboring Brigham and Women's Hospital, he assists colleagues who have good ideas but need help implementing them—especially in a market that is tough on pediatric products.
Corn first helps clinician-inventors document their device on paper and file for a provisional patent to safeguard their property rights during the early stages of development. Provisional patents, which cost only about $100 to file, allow inventors to label their product "patent pending," while postponing the need to spend $10,000 or more on a formal patent application. "Not all clinicians realize how important it is to protect their idea early on," says Corn. "If you don't, no company or investor will risk the time and money to develop the invention, regardless of its clinical merits."
Corn next directs inventors to Children's Intellectual Property Office (IPO), where product ideas are evaluated and guided to market. The IPO manages the patenting process, finds companies that might be interested in licensing the ideas and negotiates agreements with the companies. It also offers guidance on navigating regulatory hurdles.
Most pediatric devices qualify as either a Humanitarian Use Device (HUD), which benefits fewer than 4,000 patients annually, or a 510(k) submission, which covers products that are substantially equivalent to other devices on the market. The FDA can approve products in both categories for marketing without the need for new clinical trials. Lock's catheter qualified for a 510(k) submission because it is comparable to catheters used in laparoscopic procedures. Corn's apnea monitor qualified as well.
The IPO feels the need for pediatric products is so great that it began the Pediatric Product Initiative (PPI) to help clinicians overcome barriers to commercialization. The PPI team meets weekly to consider potential products and determine what's needed to guide them to market, how to make the best case to potential investors and how to find licensees for each patent.
Recently, the IPO has begun to evaluate alternative paths to market. "Instead of taking an invention or idea as is, filing a patent and trying to interest a company in licensing it, we're getting outside input earlier, during the first stages of development," explains Donald Lombardi, Children's chief intellectual property officer.
To that end, Lombardi has been working with Children's Angels—a group of entrepreneurs, business consultants, venture capitalists, product development specialists, scientists and physicians. While angels traditionally provide financial backing for very early-stage businesses, the Children's Angels instead act as volunteer advisors and strategists.
"The IPO is asking for our intellect, not our money," says Children's Angel Keith Batchelder, MD, CEO of Genomic Healthcare Strategies. "The program is unique in the field of tech transfer as I know it."
He and his Angel colleagues often see product suggestions that are little more than intriguing ideas, and they like it that way. "From my perspective, it's important to look at a technology early rather than later," says Batchelder.
That's exactly what the Angel team did in a February session with neurosurgeon Joseph Madsen, MD. An inveterate inventor with six issued patents, Madsen has several products in various stages of development, ranging from a pillow to reduce plagiocephaly—a flattening of the skull that often results from infants sleeping on their backs—to a device to improve the safety of epilepsy monitoring.
At the session, the Angels considered how best to advance each of these products and brainstormed ways of meeting more general needs that Madsen sees in pediatric neurosurgery. One such need is better shunts for hydrocephalus, a condition affecting 1 in 500 newborns in which excess cerebrospinal fluid accumulates in the brain. Madsen and collaborators envision "smart shunts" that would not only drain the fluid but measure fluid pulsations inside the brain. They are seeking grants to develop this idea and better understand the physiologic importance of fluid pulsation. In a lively exchange, the Angels considered the feasibility of applying knowledge gained from this research to broader markets, such as migraine patients.
Another neurosurgery need is to reach deep areas of the brain without having to cut through large amounts of brain tissue. The Angels were fascinated with Madsen's proposal—using tiny, minimally invasive, remotely guided robots—and suggested finding a solution that would be applicable to a larger market, perhaps one outside neurosurgery. Madsen will soon attend a follow-up brainstorming session with engineers, business people and surgeons from different specialties.
When a device does show economic potential, the IPO and the Angels can remove some of the stumbling blocks on the road to market. An Angel might act as matchmaker between an inventor and a like-minded manufacturer, or suggest financial instruments for sustaining a device through clinical trials, while the IPO provides legal assistance.
With so many unmet needs in pediatrics, Madsen, Corn, Marshall and many other clinicians at Children's have decided that they need to take matters into their own hands rather than wait for the private sector to create better fits for medicine's smallest patients.
"When the device that helps you best take care of your patients doesn't exist," says Corn, "sometimes you just have to develop it yourself."
For more information on Children's Hospital Boston's Intellectual
Property Office, visit www.childrenshospital.org/ipo.