There is an old adage, “women and children first.” In orthopedics, the women are covered…the children, however, don’t always make it into the lifeboat.
In an effort to address the needs of children, in fall 2009 the FDA held the Pediatric Clinical Trial Workshop in Washington, D.C. Dr. Robert Campbell, who attended the event and is an orthopedic surgeon at Children’s Hospital of Philadelphia, said of the event: “This was the FDA’s first such conference and it offered attendees an assessment of unmet needs, study design, safety and effectiveness, and outcomes. In part this workshop grew out of a 2005 survey by the American Academy of Orthopaedic Surgeons (AAOS) which found that 33% of respondents had used adult-sized devices on children.”
The musculoskeletal panel set about detailing the unique needs of pediatric patients and how those special requirements translate into pediatric medical devices. Dr. Campbell:
“There are two broad categories of need in pediatric surgery, namely, spinal deformity and trauma care. Pediatric surgeons need minimally invasive (MI) growth modulation devices and we are currently considering staples, MI tethers of the spine, and even animal work on magnet technology. This is timely because Axial Biotech has recently released a genetic test for adolescent idiopathic scoliosis, which will determine the genetic likelihood that early mild scoliosis will progress to surgical levels.”
Many of the trials and tribulations that come from using pediatric devices can be found in the literature and clinical trials. “Pediatric surgeons need to have growth modulation for scoliosis cases that are expected to progress, but this is not yet a reality. While there are promising initiatives, it is a substantial challenge for researchers and the FDA. One of the points made at the workshop was that the FDA and researchers must work together to find affordable regulatory pathways. It is tough to determine ways to have a device be both safe and effective, yet not be prohibitively expensive to develop and bring through the FDA approval process. The cost of a pediatric device may range from $3, 000 to $ 10, 000 per patient during a clinical trial, and can increase further if an issue arises during the trial—if, for example, the FDA wants the study investigator or company to repeat something. And the reality is that the companies involved are often startups and must answer to their investors.”
But Washington has begun to shift its thinking in a way that should benefit children. Dr. Campbell: “Laws were passed in 2007 that should ensure a more common sense approach. It is becoming clear that requiring perfection in device trials for safety and effectiveness is impossible for anyone. If we can let this ‘make it as safe and effective as possible, but make affordable’ philosophy sink into our work, then we can reign in the expenses. One of the biggest cost issues is trial design. In the past we would get halfway into the trial and the regulations would change, which plays havoc with timelines and budgets. At the workshop Donald Berry, Ph.D., made a point of saying that the classic clinical trial with its large patient populations and extreme statistical power and controls may not be necessary in many instances of small pediatric patient populations, since other statistical approaches can support conclusions from smaller sample sizes. All of us have, in the past, been stymied by the thought that we needed matched controls for pediatric device trials. Actually, robust clinical trials can still be designed for children with other types of controls.”
Dr. Campbell, inventor of the Vertical Expandable Prosthetic Titanium Rib (VEPTR), adds,
There are several companies working on developing devices with self expansion capability to power both growing rods and VEPTRs. At present, growing rod and VEPTR patients require surgery twice a year to lengthen their devices until skeletal maturity, with a significant cost and morbidity because of the limitations of the technology. But this can change once self-expansion is clinically proven. Self expanding devices are primarily magnet-based devices that a surgeon activates with an external fixed magnet or battery powered rotating magnets. The future is brighter because of these advancements.
On the trauma front, says Dr. Campbell, “We have metal screws and plates to stabilize fractures, items which remain in the patient after healing and may be a problem later in life. Straightening and lengthening limbs with external fixation is also an area with a high rate of complication. There are plates and screws made of bioabsorbable materials which may be able to address these issues; the trick, however, is to make them strong enough to resorb without any adverse reaction. Also, we need more internally expandable implants that can lengthen limbs or correct angular deformities near the joint and with fewer complications than our current methods. The most important consideration here is reliability; these devices need to get the job done with a low amount of force although there can also be problems with excessive reactive force from scarring. I would like to see a mechanical growth plate developed that would mimic gradual physiological lengthening of the long bone to normally lengthen the limb with time.”
Benjamin Spock, American pediatrician (with his first granddaughter, Susannah)
LOOK Magazine, February 20, 1968
Those in the pediatric device world know that to get on target you’ve sometimes got to go off label. “Physician directed (off label) devices are a reality in pediatric orthopedics. Pedicle screws are off label as are growing rods; we need to figure out how to get them officially FDA approved as safe and effective. A major catch 22 is as follows: you may want to compare growing rods to another treatment, but the Institutional Review Boards [IRB] won’t let you perform a device trial because the rods are not FDA approved.”
More focus and funds are now flowing to pediatric device development. Dr. Campbell: “Three nonprofit pediatric device development consortia have just been established: one at Boston Children’s Hospital, one at the University of California, San Francisco, and one at the University of Michigan. These facilities have the resources in place to make a substantial impact in a relatively short amount of time.”
Dr. Michael Vitale, Chief of pediatric spine at Morgan Stanley Children’s Hospital Columbia University Medical Center, was the moderator for the orthopedic panel at the workshop in October. He notes, “The event was successful in that it opened lines of communication on issues and highlighted challenges in innovation. One of the things we covered was how to deal with the fact that it’s hard to spend prohibitive amounts of money on research and development on items that have such a small market. On the regulatory side of things, doing a premarket Investigational Device Exemption (IDE) requires a large multicenter study with very strict outcomes. You need tremendous participation by a large number of people around the country, something which can cost between 20 and 30 million dollars.”
Dr. Richard E. McCarthy, President of the Scoliosis Research Society, adds,
It is imperative that the FDA approve the use of pedicle screws and growing rods in children soon or further advances in this area will be thwarted. In its present status, the regulation does not allow us to prospectively study our patients to determine how effective these treatments are.
The conference was eye opening for Dr. Brian Snyder, a pediatric orthopedist with Children’s Hospital Boston. “The single biggest thing that I was hoping to come away with was that the NIH and FDA think about the IRB problem. I propose that we develop universal IRB regulations specific to FDA studies…that would allow us to systematically investigate the ‘off label’ uses of a device. Also, we should establish requirements that allow the use of previously published high quality studies that establish the safety and efficacy of an adult medical device used in children.”
The visionary behind this multifaceted event was Dr. Barbara Buch of the FDA. Dr. Buch, a Deputy Director of the Division of Surgical Orthopaedic and Restorative Devices, at the Center for Devices and Radiological Health, states, “The meeting’s purpose was to gather information related to collecting sound scientific information in clinical trials for pediatric devices, and solicit information about various aspects of device clinical trials involving pediatric diseases and patients.”
As for the most important issues facing pediatric orthopedic devices, Dr. Buch notes, “Understanding the unmet needs, understanding the regulatory requirements to get pediatric devices to market, communication between professionals, and FDA and industry support of good clinical data collection for pediatric diseases and devices. Physician-directed use of devices engineered for adult populations has been a problem for a long time. We would like to have future interactions and discussions such as this one to keep the lines of communication open and transparent as pediatric specific devices are being developed.”
And, says Dr. Buch, it is time for some creative—yet logical—approaches. “Pediatrics is largely a new area for devices. Since most children are well, the populations needing devices may be relatively small and so traditional ways of thinking about clinical trials may need to be reexamined and tailored to the specific populations or subpopulations involved. Traditionally pediatric patients have been excluded from clinical trials for a variety of reasons and the scientific community has to think of ways to overcome the multiple barriers inherent in this population.”
And the prospects for little limbs? Dr. Buch:
“The FDA is in an exciting period now with lots of changes in the works. Even more emphasis on good science and evidence-based decision making will benefit the development of safe devices for pediatric patients. The orthopedic review branches have always been proactive with current technologies so it comes as no surprise that the agency is anticipating medical device development in the area of pediatric orthopedics and wants to be prepared for the future in this area.”
“The audience was diverse, ” states Dr. Buch, “and included clinicians, representatives of research societies, members of industry, members of various government agencies, venture capitalists, epidemiologists and researchers. The meeting drew interest from international stakeholders including participants from Australia, the United Kingdom and Canada. All told there were approximately 200 participants talking and sharing ideas in a ‘think tank’ atmosphere. It was really terrific, and I have received a lot of complimentary feedback about the FDA staff who participated in the event. We look forward to going forward with a team approach to helping children.”
