Adolescent idiopathic scoliosis: Current concepts, treatment advances and regulatory barriers

Orthopedics Today last convened a Round Table on idiopathic scoliosis 3 years ago. Since that time, posterior spinal fusion with segmental pedicle screw instrumentation and some form of derotation maneuver have become the norm for the usual case. In certain cases, more complete 3-D correction has allowed orthopedic surgeons to be more selective about the choice of fusion levels (Figure 1). There continue to be proponents of hybrid constructs who achieve good results. Selectivity with fewer levels fused should minimize the potential of subsequent degenerative adjacent segment disease as the patient ages. The management of spinal deformities in adolescents has been and will continue to be dynamic.

As the treatment of adolescent idiopathic scoliosis has evolved, there has been a concomitant recognition of the importance of early detection among primary care physicians and general orthopedists. We are able to diagnose and identify deformities much earlier. At the same time, considerable controversy remains about the appropriate role and efficacy of almost any non-interventional treatment. The National Institutes of Health-sponsored Braist study seeks to definitely answer the question as to whether braces work. This dilemma continues to challenge spine surgeons, and the results of the study are not expected for a number of years.

Enter a return of the Mehta cast expertise.

The child with infantile onset scoliosis (birth to age 3 years) with progressive deformity presents with especially difficult treatment decisions. The use of innovative casting techniques has regained popularity among many centers to buy time for many challenging young patients. Still, the thought of a very young child being intermittently partially immobile until puberty could have consequences on patients’ psyche.

There is a paucity of effective and efficient, reliable implant devices to modulate the abnormal growth of the spine, even though there are many types with varying degrees of success and failures. This area is ripe for the development of an implant that would allow for a minimally invasive approach to modulate the abnormal spinal growth in young children. However, the regulatory obstacles to the development of this device can be daunting.

Our patient population has been and will continue to be exposed to considerable informational input from media — some scientific and other social. I’ve been fortunate to convene a diverse panel of active spine surgeons to discuss frequently asked and unanswered questions regarding genetic testing, growth modulation, stapling, tethers and the regulatory obstacles to innovation. We consider these issues to be timely and would love to hear your comments.

— Alvin Howell Crawford, MD
Moderator

Round Table Participants Moderator Alvin Howell Crawford, MD Crawford Spine Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio Robert M. Campbell Jr., MD The Center for Thoracic Insufficiency Syndrome, The Children’s Hospital of Philadelphia, The University of Pennsylvania School of Medicine, Philadelphia, Penn. Daniel J. Sucato, MD, MS Sarah M. and Charles E. Seay/Martha and Pat Beard Center for Excellence in Spine Research, Texas Scottish Rite Hospital, Dallas, TX Lawrence G. Lenke, MD Washington University School of Medicine, St. Louis, Mo. Michael Vitale, MD, MPH Pediatric Spine and Scoliosis Service, Morgan Stanley Children’s Hospital of New York – Presbyterian, Columbia University Medical Center, New York, N.Y.

Alvin Howell Crawford: Is genetic testing adequate and reliable to determine the potential for curve progression in all patients?

Michael Vitale MD, MPH: Genetic prognostic testing is the first foray into the era of customized medicine in our field. While other diseases are treated differently depending on a patient’s genetic makeup (eg, chemotherapy for breast cancer), to date we have lacked the ability to customize treatment to patient. While I fully recognize that we do not completely understand how to optimally interpret the results of the ScoliScore (Axial Biotech, Salt Lake City), I use this routinely in my practice as one further piece of information that informs the discussion and decision making. For example, I have tended not to brace patients with very low ScoliScores.

Robert M. Campbell Jr., MD: The Scoli Score genetic test for progressive scoliosis is an exciting development, but at this point it is difficult to say how it will be integrated into our scoliosis treatment thought process. Although not clearly evidence-based, we currently choose our approach to scoliosis treatment based on the degree of curve at presentation or the projected degree of curve in the future based on serial radiographs over time. The tough part is that first visit when we have a newly diagnosed scoliosis, and we are asked the prognosis for progression, and we can only offer gross estimates from past natural history studies.

A genetic test for “progressive” scoliosis is something new. In this Internet age, we should be prepared for parents who will want to know how we use such a test in our scoliosis care or why we do not. There has been criticism that many ScoliScore patients are in the “gray area,” where the risk of progression is equivocal. There is also concern about third-party payer reimbursement. I personally think this test has potential to complement our current approach, possibly enabling us to cut back on radiographs in patients who genetically are at low risk for progression, but it probably is not suitable as a screening tool. I would counsel parents about these issues and prescribe the test if requested.

A 15-year-old with adolescent idiopathic scoliosis was treated with selective fusion and followed for 2 years. Preoperative standing AP x-ray showing 55° right dorsal scoliosis (a). The preoperative standing lateral X-ray (b) is shown. Standing AP X-ray of thoracolumbar spine at 2 years following posterior spinal fusion (c) is seen here with the standing lateral X-ray of thoracolumbar spine at 2 years following surgery (d). Images: Crawford AH

I think that at some point in the future, genetic testing for progressive scoliosis will provide a much needed trigger for yet to be developed minimally invasive growth guidance surgical approaches for curves that are relatively mild, but have the potential to advance genetically to current surgical fusion levels, but that will require a major shift in paradigm.

Lawrence G. Lenke, MD: Genetic testing for assessing the risk for curve progression in patients between the ages of 9 years and 13 years with less than a 25° curve has been available for the last several years on a research basis and for the last year and a half on a commercial basis. Although there has been and still quite a bit of active genetic research on the topic of scoliosis initiation and progression, the ScoliScore test is currently the only available genetic test to provide information on the risk of curve progression in select Caucasian patients.

Currently, if the results demonstrate a very low score, this portends a very low risk of progression. Conversely, a very high score between 181 and 200 is classified as having a high progression risk. Unfortunately, there remains a very large middle group wherein the score does not provide much assistance regarding the risk of progression. We utilize this genetic test as another piece of clinical information along with the family history, markers of skeletal and clinical maturity, Cobb magnitude, growth history, menarchal status, etc. as factors, which all play a role in determining the relative risk of radiographic curve progression.

In its current form, I do not feel that pediatricians or other health care providers with a lesser understanding of the complexities of scoliosis patients should utilize this test unless they are working closely with scoliosis clinicians who can help to interpret not only the test results, but also how they should be viewed in the context of the entire clinical picture.

Daniel J. Sucato, MD, MS: Genetic testing seems promising in that it appears to have some ability to predict those patients with adolescent idiopathic scoliosis who will progress. There has been a lot of marketing by the company to promote this product, and it has been useful to hear the information. The two issues that are most important to me are: first, the scientific merits of the genetic testing are still being reported and the dataset is not complete. This has left me with some question as to its utility in predicting those patients who will progress. Second, the patients who were tested to develop this genetic test are a small subset of the patients we evaluate with very small curves in a specific demographic and ethnic population. This cannot be extrapolated to the general population and, in general, they are the patients who are less likely to progress since the vast majority of them have very small curves.

The most challenging questions we have today are related to the patients who are young, have larger curves, and require a decision on whether to brace. Certainly any patient who is <20º is not considered for bracing, and this is the vast majority of the patients in the cohort that has been studied. There are many well-accepted clinical exam features and radiographic features that allow the experienced clinician to adequately assess the risk of curve progression.

In the end, this test should be used by the experienced clinician who fully evaluates the patient with a good history, physical examination and thorough evaluation of their radiographs, and is the individual treating the patient if or when necessary. In this context, the test, in my opinion, has little utility today since it adds useful information to the evaluation and treatment only in a small subset of patients.

Crawford: What is the current status of stapling and tethers to modulate abnormal growth? What are your indications and/or contraindications vis-à-vis early onset idiopathic scoliosis?

Vitale: There is little doubt in my mind that it is possible to modulate growth of the spine. I have seen this in a handful of patients who I have treated with stapling. Larry Lenke’s case report in the Journal of Bone and Joint Surgery provides a powerful proof of this concept. What we don’t know is: Who are the ideal patients? What are the full gamut of risks and long-term outcomes? What the optimum implant will look like? Nevertheless, I think this is a reasonable procedure for the “right” patient/family. To me, “right” means that the child will almost certainly progress to a fusion – strong family history, skeletal immaturity, perhaps high ScoliScore and documented consistent progression despite use of a brace. Importantly, the family is usually the one seeking vertebral stapling. It is a relative pre-requisite that the family has a deep understanding of the options and trade-offs.

Campbell: Stapling and tethers for growth modulation in spinal deformity have great promise, but it is early in the game for both approaches. While we hope long term they will gradually correct deformity while preserving motion without causing spine fusin, that remains to be proven. I think it is somewhat paradoxical to make the assumption that we can reliably depend on the poorly growing concave side of a curve to overpower the relatively healthy growth of the convex side, even though it is inhibited by a tethering device. I also think we are attempting to address a poorly understood problem of spinal growth.

Scoliosis is a dynamic 3-D deformity that appears to be part mechanical and part secondary growth inhibition, with ill-defined contributions of disc deformity, vertebral body wedging, and posterior column malformation once significant rotation is present. Will convex tethers reverse all this deformity, derotate the spine sufficiently for long-term stability, and restore disk health and normal spine mobility? We don’t know at this point. Do the tethers need to be permanent or can they be removed at skeletal maturity? There is not enough experience or long-term follow-up to say. We don’t even know how much “mobility” of the spine is needed for normal function or how we measure it. Bending films measure maximum coronal plane angular deformation of the spine, but is dependent on technique and cannot measure rotational or other planes of mobility that are probably important for normal function.

This child presented at age 3 years with cervicothoracic congenital deformity and underwent Vertical Expandable Prosthetic Titanium Rib (VEPTR) management. At age 9 years, she has obtained maximal length from this unit and is doing well. AP radiograph at presentation shows congenital cervicothoracic congenital deformity (a), and 1 month following VEPTR insertion (b). Six years following insertion the device, there is improvement of the space available for the lung and the child is doing well (c).

Extension of the thoracic spine is important for full inspiration to obtain total lung capacity. But how is this affected by scoliosis and is this important mobility of the spine restored by tethers? There is no agreement on the definition of a “fused spine” beyond gross inspection at surgical exploration. Image averaging on CT scans may overcall “fusion,” and facet fibrosis may go on to bony fusion long term. I don’t think we know any of these answers, and this needs to be explained to parents who are considering treatment of their children by these techniques. I think early scoliosis intervention by growth modulation techniques is preferable to late fusion intervention, but considerable work remains to validate these approaches.

Lenke: Older juveniles and adolescents who are highly skeletally immature (premenarchal, Risser 0 or 1) are offered observation, bracing or stapling based on a multitude of factors that ultimately lead to informed patient and family decision-making. Our goal is to educate the patient and their parents/caregivers regarding these treatment options, and allow them to make a well-informed decision based on what is best for their child.

We do not consider observation or bracing absolute. It is common to initially start with observation possibly followed by bracing or stapling, or to begin with a brace and end up with stapling or even observation based on the patient’s brace tolerance and the clinical and radiographic response to the provided treatment. Currently, we limit the indications for stapling to the immature idiopathic patient who is brace-averse or brace noncompliant with a 20° to 30° curve.

We have limited experience with spinal tethers. However, in a recent publication on our first tethered patient at 4 years follow-up, he demonstrated dramatic spontaneous correction of the curve with coexistent clinical correction of the deformity as well and an overall excellent result. We are very excited about this technique for future applications.

Sucato: Growth modulation has been extremely effective primarily in the lower extremities where we have a clear understanding of the physes or growth plates with respect to their direction and the rate of growth. We know that the distal femoral physis grows at a rate of approximately 9 mm/year while the proximal tibia grows at approximately 6 mm/year. However, spine growth is much more sophisticated since there are growth plates at the ends of the vertebrae as well as growth plates at the base of the pedicles (neurocentral synchondroses).

Despite this, tethering devices have been utilized and have shown promising results in the spine, especially in animal models. The clinical results to date have been equivocal when compared to bracing, which is a controversial subject in and of itself. There are institutions, such as ours, that strongly believe in bracing and have studied it well, while there are others who feel it has no or little effect on the natural history of curve progression. I continue to utilize the brace which, in our experience, has been very effective to prevent curve progression when prescribed for the right patient. Bracing is especially useful for patients who are compliant with the brace as was recently published from our institution.

The disadvantages of the brace must be weighed against the disadvantages of growth modulation. Growth modulation requires a surgical procedure and carries some risk for complications, especially because they are placed through an anterior surgical approach. There is also an unknown long-term outcome of the implants. Unlike any other implant in the spine utilized for spine deformity, these implants will always be between motion segments that are not fused and the possibility for migration is prsent. We continue to study the concepts of growth modulation at our institution and are excited to continue to investigate this technique to the point of utilizing it clinically.

Crawford: With the new emphasis on spine/rib cage/lung growth in treatment of early onset scoliosis, what surgical strategies do you consider? What outcomes do you measure beyond Cobb angle correction?

Campbell: With this new focus, growth sparing spine instrumentation in lieu of classic fusion treatment is now more actively considered. Goldberg et al have suggested adverse pulmonary outcome associated with early fusion, and recent landmark study by Karol et al of pulmonary outcome at skeletal maturity following early fusion of EOS showed a significant relationship between the height of the thoracic spine (normal height is 26 cm to 28 cm) and presence of severe, restrictive lung disease. Thoracic spines shorter than 18 cm were associated with a 63% incidence of restrictive lung disease. Thoracic spine height between 18 cm to 22 cm had a 25% incidence, and patients with more than 22 cm (the normal thoracic spine height of a 10-year-old) had no severe restrictive lung disease. Likely, thoracic spinal height was contributing to thoracic volume and indirectly to lung volume. This suggests that surgical techniques should be considered for the patients which control deformity without the additive growth inhibition effects of a spinal fusion superimposed on a thoracic spine already shortened by deformity and congenital anomalies.

Current growth sparing options available include physician-directed approaches, such as the time-honored growing rods and lately the FDA-approved Vertical Expandable Prosthetic Titanium Rib (VEPTR) device (Figure 2), with the former championed by the members of the Growing Spine Foundation Study Group and the latter by the members of the Chest Wall and Spine Deformity Foundation. Either approach can be used in a growing small child with spine deformity, but the specific indications that direct one technique over the other are controversial. The indications for VEPTR use include patients with thoracic insufficiency syndrome, defined as the inability of the thorax to support normal respiration or lung growth, and patients with several types of anatomic diagnosis, including constrictive chest wall syndrome, such as fused ribs and scoliosis, absent rib syndrome, hypoplastic thorax, and scoliosis of neuromuscular or congenital origin without rib anomaly.

Traditionally, growing rods have been used in young children who have a spinal deformity, are scoliosis-resistant to brace or cast treatment, or have scoliosis most often due to idiopathic origin – neuromuscular or syndromic. Published outcomes of both techniques have depended heavily on standard Cobb angle correction on AP radiographs, along with clinical complication rates. Pulmonary outcomes are difficult to measure in EOS patients since routine pulmonary function tests (PFTs) are difficult to perform under the age of 6 years. Follow-up PFTs post-VEPTR surgery suggest a stable percent normal vital capacity with the best results in children younger than 2 years old at time of surgery. Recent studies using infant PFTs suggest similar results.

Although vital capacity decreases normally with age, the probable decrease in vital capacity in untreated EOS patients over time remains undefined. No apparent published pulmonary outcome data is available for growing rod treatment.

Other outcome measurements that can be considered include the “space available for lung” – the ratio of concave lung height to the convex lung height on AP radiograph – which has more correlation to vital capacity than the Cobb angle. CT scan lung volumes also can be performed on any age patient and values compared to normative data. However, concerns about radiation exposure and difficulty in breath holding in younger patients limit the usefulness of the technique. Dynamic lung MRI has promise in defining both static lung volumes and thoracic performance based on lung expansion by diaphragm and rib cage, but validated data for normal children and EOS patients is not yet available. A gold standard for outcome measurement in EOS treatment that assesses development of the spine, rib cage and the lungs is probably obtainable, but currently a goal for the future.

Growth-sparing surgical approaches to EOS, in my opinion, should be considered for patients with a projected thoracic spinal height at skeletal maturity less than 22 cm, based on the Karol data, with age 10 years probably an appropriate age to consider definitive fusion unless the thoracic spine is shorter than 22 cm at that point and additional growth is needed. Surgeon preference should guide the choice of VEPTR vs. growing rod in the absence of comparative studies, but signs and symptoms of thoracic insufficiency syndrome or respiratory insufficiency should suggest consideration of VEPTR.

Temporizing measures, such as bracing or casting, should always be considered first if curves are not too severe. But if further curve progression occurs despite conservative care, then a surgical approach is the next option. Despite the considerable complication rate of these current techniques, what we know now is that growth is good for both the spine and the lungs. Many people are working to refine growth sparing techniques to reduce morbidity and to pioneer new surgical approaches to address these complex problems, such as tethers, shape-memory staples or other devices.

Lenke: The field of early onset scoliosis owes a huge debt of gratitude to Dr. Robert Campbell for his groundbreaking work not only for the development of an innovative chest wall device, but more importantly, for the education of all spinal deformity surgeons to the nuances of chest wall and lung development, patient evaluation, as well as novel treatments for these highly complex patients.

Because of his efforts, all scoliosis physicians evaluating and treating these patients are much more attuned to their clinical situation and the benefits and challenges of various surgical procedures, which are used to treat complex spine and chest wall deformities in the early-onset patient. The radiographic outcomes that we measure include not only the Cobb measurements, but also the space available for the lung. It is important to utilize a measurement ruler on films for evaluating the growth of the spine and chest wall over time as this will take into account that radiographic magnifications can vary with the techniques used for film acquisition.

Pictured is the growing rod treatment in an 8-year-old girl with 35° thoracic curve with negative MRI. She started with Milwaukee brace treatment and had compliance issues. Her parents elected to pursue growing rod treatment. She was converted to posterior spinal fusion at age 12 years (a). Standing AP thoracolumbar X-ray with 35° right dorsal scoliosis and standing lateral thoracolumbar X-ray demonstrating mild thoracic lordosis (b) are shown. Standing AP X-ray showing curve progression in Milwaukee brace (c). Initial AP X-ray 1 year following growing rod insertion (d) is shown. Standing AP thoracolumbar scoliosis X-ray 1 year following conversion to posterior spinal fusion (e) and standing lateral thoracolumbar scoliosis 1 year following posterior spinal fusion (f) are pictured.

We also measure thoracic (T1-T12) height, thoracic AP depth on the lateral as well as T1 to S1 height and length as well. Some form of pulmonary system assessment is also mandatory including formal PFTs if the child is old enough and cooperative versus CT generated lung volumes. Dynamic MRI imaging of the chest wall can also be utilized and quantified as a noninvasive means of assessing regional lung ventilation perfusion and V/Q ratios. This is still primarily a research tool, but we look forward to clinical applications in the near future.

Our current surgical strategies revolve around rib-to-rib or rib-to-spine/pelvis implants when the main pathology appears to be rib or chest wall-based, and growing spine implants when the main pathology is primarily spine-based. Obviously, there are situations where there is overlap and surgical decisions will be made based on a host of additional factors.

Crawford: How do you counsel parents regarding motion, activity and ability to participate in sports following non-fusion growth modulation and stabilization?

Lenke: For patients having either stapling or tethering, after a few weeks of recovery and performing activities of daily living, they are released to full activities, including active sports participation. For our growth modulation techniques, such as chest wall implants, growing rods and Shilla constructs, postoperative activities are somewhat individually based on the time from initial implantation, type of deformity treated, size of the patient, and any issues related to thoracic hyperkyphosis, which tend to be one of the main issues causing implant problems with any type of growing device. However, the majority of patients can participate in non-contact athletic activities.

Crawford: What is your current experience with growing rods?

Vitale: Growing rods don’t grow. They are expandable if one is willing to undergo multiple repetitive surgeries. We have shown that a subset of patients develop a post-traumatic stress-like disorder from the repetitive return to the operating room. Given all the issues with coverage of implants and infection, cutting through the same incision would seem to be the last thing we would want to do. While I firmly believe that all the complications inherent in growing rod surgery are justified by averting fusion in young children, it is frustrating that we don’t have other options in this country. The technology exists.

Campbell: Growing rod systems have gained in popularity during the past 20 years with the increasing use of dual-rod systems and multicenter publications from the Growing Spine Study Group led by Dr. Behrooz Akbarnia (Figure 3). While growth sparing instrumentation for early onset scoliosis resistant to bracing or casting is beneficial for gains in height and probably for pulmonary function compared to early fusion, the inherent complications of infection, skin slough, dislodgement and instrumentation breakage remain a problem. The cost and morbidity of repetitive surgeries currently necessary for growing rod expansion to accommodate patient growth also remains an issue.

While true self-lengthening rod mechanisms currently do not exist, magnet-based implantable expansion aids for these systems are being developed that could enable either physician or parent to schedule rod lengthening without surgery. However, long-term durability, safety and replacement cost await ongoing clinical trial results.

Although somewhat controversial, the VEPTR device for the treatment of thoracic insufficiency syndrome associated with chest wall abnormalities, including the FDA-approved indications of congenital or neuromuscular scoliosis without rib anomaly, also has been used for treatment of early onset idiopathic scoliosis with similar Cobb angle correction and complication rates. The relative merits of growing rods vs. VEPTR for EOS await a prospective matched clinical trial. Implantable expansion assist mechanisms are also being developed for this device.

Lenke: We have a vast experience at our institution in the past decade with the use of growing rods (n > 50 patients) for the early onset scoliosis population. We tend to favor dual-rod constructs with four to six pedicle screws as upper anchors, and typically four screws as lower anchors. We tend to undersize the rod diameter utilized such that we use a smaller 3.5-mm rod-based system for the very young and small infantile patients, and a 4.5-mm-based system for the middle-aged and older juvenile patients.

The theory behind this is that we do not want to place an excessively large and strong implant against the unfused spine for fear of over-stiffening and autofusion, which are definite known risks of these types of procedures. In that realm, we tend to experience more rod fractures over time, which are easily replaced during subsequent lengthenings with the underlying spine staying mobile.

We are inclined to lengthen every 6 months for the first several years and then yearly thereafter. We have some patients almost 10 years postoperative from this type of procedure and still being lengthened with this specific pedicle screw/dual rod construct.

Sucato: The growing rod technique, like any other procedure, has specific indications where it is very effective. For me to utilize growing rods, three conditions need to be met – a very young patient less than 8 years of age with spinal deformity; demonstrated curve progression; and all non-operative treatments have been exhausted including very effective methods such as traction, casting and bracing. The challenge with growing rods today is the need for planned reoperations for lengthening using conventional growing rod systems, as well as unplanned operations for such events as infection, rod breakage and anchor pullout. The promise of self-lengthening growing rods is exciting but we must be cautious since medium- andlong-term follow-up data are lacking.

The advantages, however, are promising in that the child is allowed full or near-full activities without the need for growth promoting procedures every 6 months to 8 months.

There are two types of self-promoting growth rods – those that have an internal mechanism to promote growth and those that rely on the growth of the child to promote spine growth. The latter will be interesting to see whether the same amount of growth occurs when compared with the devices that promote growth as we do today.

Crawford: Given the success and failures of growing rods and the need for multiple interventions, is there a possibility of a rod with intrinsic capability for extension similar to extremity implants in pediatric tumor patients?

Lenke: One of the major drawbacks of any type of growing rod or chest wall expanding device is the need for routine lengthenings. It seems logical that a device with the potential for externally controlled internal lengthening would be an ideal solution in order to avoid the multiple surgical procedures currently required. The Shilla technique of short apical pedicle screw correction and fusion with proximal and distal screw anchorage allowing rod elongation during growth is a novel concept that provides a similar benefit.

We are certainly aware of the European experience with a magnetically controlled growing device, as well as a recently introduced device utilized in Asia for the same purpose. Intuitively, this would seem to be of great benefit to these patients. We currently await further clinical data and follow-up of these devices with the hope that our North American patients may benefit from this technology when available.

Crawford: Given the current regulatory climate towards implant development, describe your experiences and strategies toward overcoming these barriers.

Vitale: This is largely an orphan market. For the most part, the market really doesn’t support the major investment that industry would need to make to push through an investigational device exemption on a new technology, like an externally controlled growth rod. No 510(k) pathways exist for the majority of devices needed to treat children with spinal deformity. The FDA is well aware of the many barriers to innovation in this area which leads to unmet needs for children with scoliosis.

A novel regulatory mechanism, akin to the Orphan Drug Act could provide incentives to industry (tax, patent protection, liability protection and otherwise) to develop devices for smaller populations. Diseases were cured by the Orphan Drug Act. Our patients deserve more than they are getting.

Campbell: The regulatory climate is only one of many recurring obstacles to spinal deformity treatment innovation. The prime restraint is economic. Relatively small market potential for pediatric spinal devices, compared to more robust markets like coronary artery stents for adult, make development funding risky for investors. Adverse economic times seem to dampen enthusiasm of venture capitalists for small market opportunities, leaving innovators to depend on angel investors, grants and occasionally commercial company largess to fund development of promising technology.

The constant wild card is “how much is all of this going to cost?” This is a difficult question to answer even for the experts, but the people with the checkbooks need to know to justify the risk exposure to their own investors. Defining potential market is the first major task for inventors.

The next hurdle is finding the right manufacturing partner. Like marriage, it depends on common sense, getting to know the other party as well as possible, basic intuition and ultimately a leap of faith. Sometimes it just doesn’t work out and one has to start over. Each innovator has to choose between self-financed efforts, early partnerships with large, medium or small companies, start-ups, institutional relationships or other entities that can provide sustainable support for successful market entry of a new device.

Once a manufacturing partner is chosen, then a regulatory approval pathway must be negotiated with the FDA – an extremely important complex task that requires skill, patience and regulatory expertise. The major cost of device development is decided by the final design of that pathway, ranging in cost from a 510(k) application to a premarket approval application requiring a costly clinical trial, or a humanitarian device exemption (HDE) application for rare indications. The latter has become more attractive for potential pediatric spinal device developers with enactment of the 2007 Pediatric Device Safety and Improvement Act that authorizes profit for sales of a humanitarian use device.

A constant danger in clinical device trials is an unexpected increase in cost of the regulatory pathway that may threaten completion of the trial. Some reasons that may trigger this are the surfacing of new safety or efficacy concerns by FDA during a device trial that may require additional subject recruitment or extension of trial length. While the ideal is to define early a common sense, transparent, affordable regulatory pathway for device approval clinical trials, there will always be the need to work out equitable agreements with the FDA for resolution of problems mid-trial that both address their safety and efficacy concerns as well as the financial constraints of protocol support by manufacturers. The FDA recently emphasized the use of science in the regulatory approval of devices, so manufacturers need to appreciate the need for validated scientific outcome measures and defined treatment goals in device protocol design.

Both FDA and National Institutes of Health are mandated by the 2007 Pediatric Device Act to provide support for pediatric device development, so assistance in the pre-IDE (Investigational Device Exemption) protocol design is commonly available from FDA. The common problems of financial support, prototype design, available manufacturing partners and clinical trial protocol formulation can also be assisted by new non-profit pediatric device development consortia supported by grants from the FDA Office of Orphan Product Development as authorized by the 2007 Pediatric Device Act. The road to successful pediatric device innovation has improved, but innovators still must appreciate the long-term commitment needed to survive the many uncertainties of pediatric device development to successfully bring their dream to market.

Lenke: With the basic premise of heightened concern for any device applied to young children, it is not surprising that the regulatory climate toward spinal implant development in children has been highly challenging. However during the last decade, we have seen progress in the understanding of the unique challenges inherent to these patients and their various spinal and chest wall deformities, with the HDE given to the VEPTR device (Synthes, Palo Alto, Calif.), as well as pediatric pedicle screws down classified to include adolescent patients (CD Horizon System, Medtronic Sofamor Danek, Memphis, Tenn.).

However, challenges remain for continued development in this arena. Ultimately, we are going to need further cooperation and assistance from the FDA in this respect since the pathway through either an IDE or 510K process is extremely time consuming, expensive and difficult from many aspects to gain approval of these infrequently used but extremely necessary devices. It is also important to gain some form of FDA approval to be able to train surgeons on the safe and efficacious use of whatever devices are developed to treat the early onset scoliosis patients of the future.

Sucato: Innovation is always challenging on several levels. The easy part is identifying clinical problems that need a better solution. There are certainly many clinical scenarios that require better solutions in the field of spinal deformity. The challenges to innovation are to understand the anatomic and biologic causes of the condition and next to develop a viable solution. Once a potential solution has been identified, the external barriers to innovation become involved. These include time since busy clinicians only have limited time. The second challenge is financial – obtaining intramural or the more challenging extramural funding to study the innovation. Finally, the regulatory pressures from a variety of sources, especially when trying to develop a solution that can be utilized in patients, are barriers to innovation.

Most innovations can be carried out when careful consideration of the clinical problem has been made and careful understanding of the anatomy and challenges to a young patient’s anatomy is clarified. The rigors of developing a research project, with considerable paperwork and limitations imposed by various regulatory bodies have made it somewhat challenging. Hopefully with continued advocacy through our professional societies, we can overcome some of these challenges and pave the road to an easier innovative path. The regulatory restrictions/guidelines in spinal deformity development are important to a certain degree, however, it seems that the federal regulatory bodies have become too stringent to allow paradigm-shifting technology to have a strong effect on patient care. There must be some give and take in the near future to find the correct balance to maintain safe patient safety without stifling productive innovation that has the patient’s best interest in mind.

References:

• Campbell RM, Smith MD. Thoracic insufficiency syndrome and exotic scoliosis. J Bone Joint Surg Am. 2007;89: Suppl 1:108-122.
• Crawford CH, Lenke LG. Growth modulation by means of anterior tethering resulting in progressive correction of juvenile idiopathic scoliosis: a case report. J Bone Joint Surg Am. 2010;92(1):202-209.
• Goldberg CJ, Gillic I, Connaughton O, et al. Respiratory function and cosmesis at maturity in infantile-onset scoliosis. Spine. 2003;28 (20):2397-2406.
• Karol L, Johnston C, Mladenov K, et al. The effect of early thoracic fusion on pulmonary function in non-neuromuscular scoliosis. J Bone Joint Surg Am. 2008;90:1272-1281.

• Robert M. Campbell, MD, can be reached at The Center for Thoracic Insufficiency Syndrome, The Division of Orthopaedics, The Children’s Hospital of Philadelphia, 34th and Civic Center Blvd., 2nd Floor, Wood Bldg., Philadelphia, PA 19104-4399; 215-590-1527; email: campbellrm@email.chop.edu.
• Alvin Howell Crawford, MD, can be reached at Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH 45229-3039; 513-636-0974; email: Alvin.Crawford@cchmc.org.
• Lawrence G. Lenke, MD, can be reached at Washington University School of Medicine, Department of Orthopaedic Surgery – Spine Service, 660 S. Euclid Ave., Campus Box 8233 1100 WP, St. Louis, MO 63110; 314-747-2535; email: lenkel@wudosis.wustl.edu.
• Daniel J. Sucato, MD, MS, can be reached Texas Scottish Rite Hospital, 2222 Welborn Street, Dallas, TX 75219; 214-559-7557; email: Dan.Sucato@tsrh.org.
• Michael Vitale MD, MPH, can be reached at Morgan Stanley Children’s Hospital of New York – Presbyterian, 3959 Broadway - 8 North; New York, NY 10032; 212-305-5475; email: mgv1@columbia.edu.
• Disclosures:Campbell reported that he has received royalities for the Vertical Expandable Prosthetic Titanium Rib until last year, but he is no longer a consultant for any company. Crawford is consultant for DePuy Spine. Lenke recieves royalties from Medtronic and Quality Medical Publishing, as well as research support from DePuy Spine and Axial Biotech. Sucato has no relevant financial disclosures. Vitale is a consultant for Biomet (chest wall and spinal deformity group), Styker Spine and receives royalities from Biomet Spine.