AAP Section on Cardiology and Cardiac Surgery

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AAP Section on Cardiology and Cardiac Surgery

  1. 1. Pathways to Approval of Pediatric Cardiac Devices in the United States: Challenges and Solutions Robert H. Beekman, III, Brian W. Duncan, Donald J. Hagler, Thomas K. Jones, John D. Kugler, John W. Moore, Kathy J. Jenkins and for the Workgroup on Pediatric Cardiac Devices, Section on Cardiology and Cardiac Surgery, American Academy of Pediatrics Pediatrics 2009;124;e155-e162 DOI: 10.1542/peds.2008-3726 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.pediatrics.org/cgi/content/full/124/1/e155 PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2009 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Downloaded from www.pediatrics.org at Amer Acad of Pediatrics on July 1, 2009
  2. 2. SPECIAL ARTICLES Pathways to Approval of Pediatric Cardiac Devices in the United States: Challenges and Solutions CONTRIBUTORS: Robert H. Beekman, III, MD,a Brian W. Duncan, MD, MBA,b Donald J. Hagler, MD,c Thomas K. Jones, MD,d John D. Kugler, MD,e John W. Moore, MD, MPH,f and Kathy J. Jenkins, MD, abstract MPHg, for the Workgroup on Pediatric Cardiac Devices, Section Patients treated by pediatric interventional cardiologists and cardiac on Cardiology and Cardiac Surgery, American Academy of surgeons often have unmet medical device needs that pose a challenge Pediatrics to the current regulatory evaluation and approval process in the United aDivision of Cardiology, Cincinnati Children’s Hospital Medical States. In this report we review current US Food and Drug Administra- Center, Cincinnati, Ohio; bDivision of Cardiac Surgery, Cleveland Clinic Foundation, Cleveland, Ohio; cDivision of Pediatric tion regulatory processes, review some unique aspects of pediatric Cardiology, Mayo Clinic, Rochester, Minnesota; dDivision of cardiology and cardiac surgery that pose challenges to these pro- Pediatric Cardiology, Seattle Children’s Hospital, Seattle, cesses, and discuss possible alternate pathways to cardiac device Washington; eDivision of Pediatric Cardiology, Children’s Hospital of Omaha, Omaha, Nebraska; fDivision of Pediatric evaluation and approval for children. Children deserve to benefit from Cardiology, San Diego Children’s Hospital, San Diego, California; new and refined cardiac devices and technology designed explicitly for and gDepartment of Cardiology, Children’s Hospital Boston, their conditions. Pediatrics 2009;124:e155–e162 Boston, Massachusetts KEY WORDS cardiac devices, medical devices, device approval, pediatric The fields of pediatric interventional cardiology and cardiac surgery cardiology have grown rapidly during the past 2 decades. These specialties pro- ABBREVIATIONS FDA—Food and Drug Administration vide infants and children with innovative transcatheter and surgical IDE—investigational device exemption therapies that often are the result of adapting medical devices that PMA—premarket approval were developed and approved for use in adult patients with acquired HDE— humanitarian device exemption cardiovascular disorders. In some instances, device modifications are HUD— humanitarian use device OPC— objective performance criteria routinely conducted in real time in the cardiac catheterization or op- PG—performance goal erating room suites. Rarely, cardiac devices have been developed, eval- OUS— outside the United States uated, and approved specifically for treatment of children with congen- www.pediatrics.org/cgi/doi/10.1542/peds.2008-3726 ital heart disease. The way in which cardiovascular devices are doi:10.1542/peds.2008-3726 designed, evaluated in clinical studies, and submitted for regulatory Accepted for publication Feb 27, 2009 approval has remained a considerable challenge for the field. Address correspondence to Robert H. Beekman, III, MD, Unmet cardiovascular device needs in the pediatric population occur Cincinnati Children’s Hospital Medical Center, Division of Cardiology, 3333 Burnet Ave, Cincinnati, OH 45229. E-mail: when a needed device does not exist or when a device exists for a rbeekman@cchmc.org. different (typically adult) indication but must be modified or used in an PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). off-label fashion for children. An example of a needed device that does Copyright © 2009 by the American Academy of Pediatrics not exist is a transcatheter pulmonary artery flow restrictor, which FINANCIAL DISCLOSURE: The authors have indicated they have could benefit many children who currently must undergo surgical pul- no financial relationships relevant to this article to disclose. monary artery banding. Examples of existing devices that are used in children for unapproved indications include biliary stents (which are routinely used in children for pulmonary artery stenosis and coarcta- tion stenting), angioplasty balloons (which are used to dilate valves and vessels in unapproved locations), and peripheral vascular occlu- sion coils (which are used for transcatheter closure of the ductus arteriosus). None of these existing devices have been engineered for or formally approved as safe and efficacious for the common pediatric indications to which they are applied. In this article we address the topic of cardiac device approval from the perspective of pediatric cardiology and cardiac surgery. We include a review of the current regulatory processes that exist in the United States, the challenges faced with the care of the diverse and complex PEDIATRICS Volume 124, Number 1, July 2009 e155 Downloaded from www.pediatrics.org at Amer Acad of Pediatrics on July 1, 2009
  3. 3. patients with congenital heart disease, known as an investigational device ex- to patients and include devices such as and possible novel strategies for en- emption (IDE). The IDE can be regarded septal and vascular occluders, coro- hancing the review and approval pro- as a “contract” between the physician nary stents, and ventricular assist de- cesses for cardiac devices intended and the FDA that specifies the terms vices. The majority of these devices will for use in children. Children deserve to under which the device can be used require a premarket approval (PMA) benefit from advances in medical de- legally. application before marketing. PMAs vice technology in the same way that To determine if a device can be require bench, animal, and clinical adult patients have benefited for “cleared” for marketing, the FDA regu- data to demonstrate that there is a years. Without exception, however, any lates medical devices by using a risk- reasonable assurance of safety and ef- change in review processes for pediat- based approach, assigning each de- fectiveness when the device is used as ric cardiac devices cannot be made at vice type to a regulatory class. Class I intended. The clinical data to support a the cost of patient safety or welfare. devices are simple devices that pose a PMA application are typically obtained low risk to patients, such as certain under an IDE protocol. The protocol THE CURRENT FOOD AND DRUG handheld surgical instruments (eg, gives specific directions about how a ADMINISTRATION DEVICE- scalpels, retractors). The great major- device is to be used, and how data are APPROVAL PROCESSES ity of these devices do not require pro- to be obtained, and should be designed The US Food and Drug Administration spective FDA review to begin market- to collect information that is suffi- (FDA) is responsible for oversight of all ing (ie, they are considered “exempt” ciently interpretable such that reason- medical devices sold in the United from the need for a marketing applica- able safety and effectiveness can be States. Before a medical device can be tion); the only requirement is that the inferred. After the clinical protocol has shipped across state lines, either for manufacturer and manufacturing fa- been completed, the data are analyzed use in a clinical study or for sale, cer- cility be registered with the FDA. Class and presented to the FDA to support a tain FDA regulations must be met. Most II devices are considered to pose a PMA application. Before a PMA can be medical device manufacturers are moderate risk to patients, and many of approved, a manufacturer will also un- quite familiar with these regulations these devices will require the submis- dergo a manufacturing inspection to and the processes that will allow mar- sion of a marketing application to the demonstrate that the device can be keting of their devices. However, to FDA before marketing the product. Ex- manufactured with consistently high many practicing physicians, these reg- amples of class II devices include guide quality. ulations and processes may seem wires, infusion catheters, and patient Class III devices can also reach the mysterious and convoluted. monitors. These marketing applica- market through a humanitarian device How can a physician legally use a med- tions are called 510(k)’s, after the sec- exemption (HDE). The HDE program ical device to treat or diagnose a pa- tion of the law that described them. was established to ensure availability tient? If the device has been “cleared” The 510(k) application should demon- of devices for the diagnosis or treat- or “approved” for marketing, the phy- strate that a new device is “substan- ment of conditions that affect fewer sician can use the device freely. That is, tially equivalent” in terms of intended than 4000 patients in the United States the physician can use the device for use and device performance to an al- per year. Because the number of pa- the types of patients and in the manner ready marketed device (sometimes re- tients potentially available to partici- described in the labeling (ie, as stated ferred to as “noninferiority”), which pate in a clinical trial is small, the HDE in the indications-for-use statement in means that the new device must be regulation provides an exemption the instructions for use). Alternatively, at least as safe and effective as a from the requirement to show effec- the device may be used in a different similar device already on the market. tiveness. An HDE can be approved if the manner or for a different indication In most instances, only bench testing device has been shown to provide a (ie, off-label) if the physician believes and, in certain cases, animal studies reasonable assurance of safety and that this approach would be in the best are required; only 10% to 15% of probable benefit. A manufacturer who interest of a particular patient. How- 510(k)’s require clinical data. When a wishes to pursue an HDE must first ever, if the device has not been cleared 510(k) application has successfully show that the number of patients with or approved for marketing, the physi- demonstrated substantial equiva- the disease or condition who would be cian can only use the device under spe- lence, the application is said to be treated with the device is fewer than cial circumstances, most commonly “cleared.” 4000 in the United States per year. De- under a protocol approved by the FDA Class III devices pose the highest risk vices that qualify on this basis will re- e156 BEEKMAN et al Downloaded from www.pediatrics.org at Amer Acad of Pediatrics on July 1, 2009
  4. 4. SPECIAL ARTICLES ceive a humanitarian use device (HUD) vice. If the application is approved, the proved through the HDE pathway for designation. Once the HUD designation FDA will require the same patient- “the treatment or diagnosis of a dis- has been granted, the HDE can be sub- protection measures described above ease or condition that occurs in pe- mitted to gain approval for marketing. to be in place. diatric patients” (Pub L No. 110-85, Although an HDE allows for less clinical Some devices are subject to further §303[a]), which allows device produc- data collection than a PMA, there are study after marketing approval, a pro- ers to make a profit on devices used in disadvantages as well. A manufacturer cess known as “postapproval” or “post- fewer than 4000 children. The act also cannot ship an HDE-approved device to market” studies. Postmarket studies can created new mechanisms for pediatric a hospital or clinic until its institu- provide data to further refine initial un- device development through the cre- tional review board has given approval derstanding of device performance. ation of nonprofit consortia to stimu- for its use. Until recently, the manufac- Such studies may provide additional late innovation. turer was also prohibited from making insights into appropriate patient se- In the postmarket setting, the act a profit from the sale of a device that lection, training of physicians, and granted new authority to the FDA to ex- possessed HDE status; only the costs of practical issues such as device perfor- tend the current limit of 36 months for research and development could be mance in patients with multiple co- postmarket studies of class II or III de- recovered in the sale price. Recent leg- morbidities. In addition, the Safe Med- vices if needed for children and to re- islation (see below) has lifted this re- ical Devices Act requires reporting of quire postmarket studies as a condi- striction so that pediatric devices ap- adverse events and significant device tion of approval. Finally, Congress proved for marketing under an HDE malfunctions to the FDA for any device, instructed the FDA, the National Insti- can now be sold for profit. even those that are not subject to for- tutes of Health, and the Agency for As discussed above, a device can be mal postapproval studies. Additional Healthcare Research and Quality to de- marketed if it is the subject of a information for reporting require- velop a plan for expanding pediatric cleared 510(k), an approved PMA or ments may be found at www.fda.gov/ medical device research and develop- HDE, or is exempt from the require- cdrh/medsun/about.html. To facilitate ment. On July 23, 2008, the 3 federal ment for a marketing application. How- identification of gaps in device avail- agencies conducted the Pediatric Med- ever, it is common in pediatrics for de- ability for pediatric indications, the ical Devices Stakeholders’ Workshop vices to be developed by individual FDA has established a formal postmar- to gain input on the plan, which is ex- users or to be available in other coun- ket surveillance partnership with clini- pected to be presented to Congress tries before it is marketed in this coun- cal sites, known as KidNet (www.fda. soon. try. The FDA makes provisions allowing gov/cdrh/medsun/about.html). This site limited use of unapproved devices in provides a venue for institutions in- CHALLENGES FROM PEDIATRIC some of these settings. If the device is volved in pediatric care to record cir- CARDIOLOGY AND CARDIAC being studied under an IDE, a physician cumstances in which acceptable pedi- SURGERY may request the use of the device atric devices were unavailable and in The fields of pediatric cardiology and through the manufacturer or sponsor which adult devices needed to be sub- cardiac surgery share characteristics, of the IDE for a patient who does not stituted or modified. distinct from their counterpart spe- meet the clinical study criteria. The cialties in adult medicine, that pose FDA will ask that certain provisions be RECENT LEGISLATION unique challenges to the development followed for the patient’s protection In 2007, Congress passed the Pediatric and approval of cardiac devices for but, in the majority of cases, will grant Medical Device Improvement and children. First, congenital cardiac de- these requests for “compassionate Safety Act (Pub L No. 110-85) as part of fects are relatively uncommon and use.” The patient-protection measures legislation to amend the Food Drug and include a diverse array of anatomic include appropriate informed consent Cosmetic Act. In passing the act, Con- subtypes. For example, moderate-to- from the patient or patient’s guardian, gress identified the need for improved severe congenital cardiac defects that approval of the institutional review access to pediatric medical and surgi- require therapy occur with an esti- board, and the concurrence of an un- cal devices as well as needed improve- mated total prevalence of only 6 per involved physician. If a device is not be- ments in postmarket safety monitor- 1000 live births.1 The relatively small ing studied under an IDE, the prescrib- ing of existing devices used in children. number of patients affected with any ing physician can apply directly to the As mentioned above, the act removed given congenital cardiac defect makes FDA to obtain approval to use the de- the profit prohibition on devices ap- it difficult to design a traditional ran- PEDIATRICS Volume 124, Number 1, July 2009 e157 Downloaded from www.pediatrics.org at Amer Acad of Pediatrics on July 1, 2009
  5. 5. domized clinical trial that is ade- the substantial somatic growth that described in months or several years. quately powered. From an industry occurs during childhood. Any cardiac A muscular ventricular septal defect perspective, virtually all congenital device implanted into the cardiovascu- device that is implanted in a 6-month- cardiac defects can be considered “or- lar system of a growing child must be old infant must remain intact on the phan” disorders that occur in small able to accommodate the child’s fu- ventricular septum for 70 or 80 years. patient populations with a relatively ture growth while remaining safe, ef- The prospect, and indeed the expecta- limited market potential for any given fective, and intact. Atrial or ventricular tion, that pediatric cardiac patients device. septal occlusion devices implanted in may survive for many decades de- A second challenge to the development a child are known to be compatible mands unique long-term durability of cardiac devices specifically for chil- with future cardiac growth because from the cardiac devices implanted in dren exists because pediatric cardio- the cardiac septa grow “around” the them. vascular anatomy presents a wide endothelialized devices. However, a semilunar or atrioventricular valve OFF-LABEL USE OF DEVICES range of anatomic sizes which, in turn, require a demanding range of device prosthesis implanted into a small child Because of the challenges to device de- sizes. Unlike adult valves, ventricles, will often become too small and, there- sign and approval posed by the rela- and great vessels which have a rela- fore, hemodynamically obstructive as tively uncommon cardiovascular de- the child grows. Ventricular-arterial fects of children, the off-label use of tively narrow range of normal dimen- conduits or great artery grafts of ap- devices approved for other patient sions, pediatric cardiovascular anat- propriate dimension and capacity for a populations (typically adults) and indi- omy grows significantly from birth to child but lacking growth potential will cations has become a routine, ac- young adulthood. For example, cardiac become diminutive, and need replace- cepted practice in pediatric cardiology valve diameters increase threefold ment, as the child grows. Similarly, (Table 2). For example, the large ma- from birth to adulthood. The normal ventricular assist devices of suitable jority of stents implanted in pediatric aortic and pulmonary valve annulus di- size for children may be outgrown, interventional procedures are biliary ameters increase from 7 to 22 mm and making the concept of “destination stents used off-label to treat vascular from 8 to 26 mm, respectively, from therapy” for long-term circulatory sup- stenoses within the pulmonary arte- birth to adolescence.2 To be suitable port impracticable when using a single rial tree, aorta, and large veins. Ap- for children of all ages, semilunar implanted device. All of these consider- proved medical devices can be used valve prostheses with diameters that ations related to somatic growth im- legally off-label by pediatric practitio- range from 7 mm for newborns to the part substantial design and engineer- ners if this use is judged by the physi- more familiar adult dimensions ing challenges for device developers cian to be medically appropriate and in should be available; however, in cur- who aim to provide devices that can the patient’s best interest. However, rent practice, the smallest approved be maintained long-term in growing the off-label practice itself has impor- semilunar valve prosthesis measures children. tant disadvantages. First, a device 16 mm in diameter. The changes in car- diac chamber volume that occur with Finally, remarkable durability is re- used off-label will not have been sub- growth are even more pronounced, as quired of pediatric cardiac devices be- ject to the FDA approval process to pro- cause in pediatrics a patient’s life ex- vide reasonable assurance of safety illustrated by the increase in normal pectancy is typically measured in and effectiveness for this patient pop- left ventricular diastolic volume from decades. In reality, this is in marked ulation or for the specific pediatric in- 10 mL in the newborn to 150 mL in contrast to adult cardiovascular med- dication. This absence of formal evalu- the adult.3 Clearly, the engineering icine, in which patient longevity is often ation and approval can cause challenges are substantial if a ventric- ular assist device is to benefit patients of all ages and sizes. Table 1 demon- TABLE 1 Mean Dimensions (z Value 0) of Normal Cardiovascular Structures in Newborns, Children, and Young Adults strates the wide range of “normal” di- Cardiovascular Structure Newborn Child (6 y old) Adult mensions (ie, z value 0) for repre- Aortic valve diameter, mm 7 14 22 sentative cardiovascular structures Pulmonary valve diameter, mm 8 16 26 for newborns, children, and young Mitral valve diameter, mm 10 19 28 adults. Aortic root diameter, mm 10 15 30 Right pulmonary artery diameter, mm 6 12 18 A third challenge to the development of Left ventricular diastolic volume, mL 10 50 150 pediatric cardiac devices relates to Data were derived from refs 2 and 3. e158 BEEKMAN et al Downloaded from www.pediatrics.org at Amer Acad of Pediatrics on July 1, 2009
  6. 6. SPECIAL ARTICLES TABLE 2 Approved Medical Devices That Are Commonly Used for Off-Label Pediatric Indications Objective Performance Criteria Device Labeled Indications Off-Label Pediatric Applications and Performance Goals Stents Biliary tree stenosis Pulmonary artery stenosis One alternative is the use of objective Coronary artery disease Coarctation of the aorta Systemic vein stenosis performance criteria (OPC) or perfor- Embolization coils Arteriovenous fistula Patent ductus arteriosus mance goals (PGs) in the evaluation of Dilation balloons Pulmonary valve stenosis Aortic valve stenosis medical devices during the regulatory Peripheral vascular disease Pulmonary artery stenosis Coarctation of the aorta approval process. The essence of an Cutting balloons Arteriovenous dialysis fistula Pulmonary artery stenosis OPC or PG is that the metrics to be used stenosis to evaluate whether a device meets cri- Radiofrequency perforation wire Atrial transseptal puncture Pulmonary valve atresia teria for approval are specified in ad- vance and are not obtained as a part of an IDE study. OPCs or PGs are often ex- pressed as a rate.4,5 Thus, the OPC or difficulties for pediatric practitioners POSSIBLE SOLUTIONS: NOVEL PG is used as a replacement for a tra- who may be required to make deci- APPROVAL PATHWAYS ditional randomized control group and sions about device use on the basis of serves as a benchmark, or minimally Many pediatric cardiologists and car- acceptable value using a pass/fail ap- insufficient information, or who may diac surgeons recognize the problems proach, to determine if a particular de- be subject to medical malpractice in achieving safety and efficacy stan- vice application is ultimately approved claims if their judgment is questioned. dards for devices used in the care of for marketing. Second, a medical device that is used patients with congenital heart disease. for an off-label indication may be de- The estimate for an OPC or PG is neces- Safety standards require that the prived of important industry research sarily derived from historical data. The probable benefits from use of the de- development of an OPC is a more for- and development to improve device vice outweigh the probable risks. Rea- mal process than that for a PG, requir- performance for that pediatric condi- sonable assurance of effectiveness is ing pooling of data across previously tion. Because early generations of a established when it can be deter- published studies by using a formal device used off-label for pediatric indi- mined, on the basis of valid scientific meta-analysis or similar approach. cations may not have had sufficient evidence, that in a significant portion Ideally, historical trials should provide data to support such use, device en- of the target population the use of the patient-level data including clinical hancements for pediatric indications device for its intended purpose and outcomes and patient characteristics. and approval of these later-generation conditions of use will provide clinically Pocock6 described 5 requirements for devices may be difficult or impossible. significant results. valid historical controlled studies: Finally, the off-label use of devices The FDA is committed to the least bur- 1. Control group receives the pre- tested in adults to treat pediatric con- densome principle throughout the reg- cisely defined treatment in a recent ditions creates some special chal- ulatory process of medical devices and study. lenges for the pediatric device-ap- will assist in the design of trials that 2. Criteria for eligibility, workup, and proval process. In some instances, will produce clear and interpretable evaluations must be the same. considerable information about how a data. Randomized, controlled clinical device may perform in children can be 3. Prognostic factors are completely trials (RCCTs) are considered the gold extrapolated from safety and efficacy known and the same in both standard for such clinical trials but information derived from adults. In groups. are costly, technically challenging, long, other instances, however, this infor- and arduous. In small pediatric popula- mation may not be useful because of tions the RCCT may not be statistically TABLE 3 Possible Pathways to Device differences in pediatric anatomy, phys- Approval for Pediatric Cardiology possible, and patients or families may (Alternatives to Randomized Clinical iology, and pathophysiology. Determi- refuse to accept randomization. Table 3 Trials) nations about when use of adult in- lists several alternatives to the use of Use of OPC or PGs formation is appropriate are not the RCCT which may be applicable to Extrapolation from existing data in studies of adult patients straightforward and can complicate the evaluation of pediatric cardiac de- Use of registry data the design of studies in pediatric vices, and a brief discussion of each Enhanced postmarket surveillance patients. alternative is presented below. Use of data generated OUS PEDIATRICS Volume 124, Number 1, July 2009 e159 Downloaded from www.pediatrics.org at Amer Acad of Pediatrics on July 1, 2009
  7. 7. 4. No unexplained indications leading patent ductus arteriosus. These OPCs Use of Registry Data one to expect different results. were developed, in part, by using com- This route is a similar approach to the 5. Differences in prognostic factors parisons to published surgical data8 use of PGs described above, because it are insufficient to explain observed and to the PDA Coil Registry.9 Currently, relies on application of historical data differences in outcome. 2 occluder devices are approved for as a surrogate for data obtained from Rigorous and scientifically valid meth- atrial septal defect closure. Additional a more traditional contemporaneous odologies have been developed and approvals for atrial septal occlusion control group. However, this mecha- used in the derivation of any OPC for may be facilitated by development of nism depends on the existence of rig- use in the medical device-approval appropriate PGs. Similarly, stents to orous registry data that include a thor- process. An OPC must be derived from treat pulmonary artery stenosis or co- ough capture of adverse events. An recognized and generally complete arctation of the aorta could have ap- example of such a registry is the Inter- historical data sets and be the product propriate PGs developed on the basis agency Registry for Mechanically of appropriate statistical modeling of published results, which could be Assisted Circulatory Support and analytical techniques. Nonran- used in conjunction with data from ro- (INTERMACS). This registry was devel- domized comparison data using pro- bust long-term registries to follow pa- oped with the support of the Depart- pensity scoring may also be a mecha- tients who have had a pulmonary ar- ment of Health and Human Services, nism for achieving well-matched tery or aortic stent implanted. the National Heart, Lung, and Blood In- patient groups.7 There should also be a stitute, and the FDA. Some notable fea- designated provision for periodically Extrapolation From Existing Data in tures of this registry include the use of evaluating and updating the OPC on the Studies of Adult Patients sequential patient enrollment, a well- basis of more recent experience and Generally, the use of data obtained defined data set, independent clinical data. from adult patients to inform deci- evaluations, well-designed clinical re- PGs are developed when less historical sions regarding device safety and effi- port forms, and a commitment to min- information is available. A scientific or cacy in children is of limited applicabil- imize the amount of missing data. clinical rationale must be outlined for ity because of differences in patient Prospective databases have the poten- the selection of studies on which the growth and longevity and functional tial to provide important clinical data PG is based, including adjustments for differences between devices for coro- supporting expansion of “labeled” indi- differences in populations or other as- nary disease and congenital heart dis- cations for cardiovascular devices. pects of the studies, in comparison to ease. The option of developing a medi- Databases currently enrolling patients the proposed methodology that will be cal device for pediatric use that has with congenital heart disease who un- used in the IDE study. Given the less features similar to an adult device rep- dergo cardiac catheterization include robust data and analysis that contrib- resents a potential pathway for device the Mid-Atlantic Group of Interven- ute to the development of a PG, an design and approval, but safety evalu- tional Cardiology (MAGIC), Congenital OPC is the preferred control for a non- ation would require a separate trial to Cardiac Catheterization Project on randomized trial. Nevertheless, PGs determine device safety in children. Outcomes (C3PO), and Congenital Car- may provide an important alternative, Some special-function catheters (im- diovascular Interventional Study Con- especially for therapies for which off- aging or therapeutic) for adult use sortium (CCISC). Generally, these data- label device treatment is routine (eg, may be applicable for infants and chil- bases are too limited in scope or were numerous pediatric cardiac interven- dren when manufactured in sizes ap- inaugurated too recently to provide tions), which makes randomized stud- propriate for pediatric use. Prosthetic primary data sets to support FDA re- ies using surgery or medical therapy cardiac valves may represent another view and approval of new applications as a control difficult to conduct. class of devices for which perfor- for existing cardiovascular devices. OPCs have been used in the regulatory mance data from adults might be ex- However, over time, these registries approval process in the past, and mul- trapolated to pediatric applications. do have potential to contribute valu- tiple ongoing studies use PGs. OPCs Ideally, sponsors should include their able clinical data sets for devices that have been used frequently in the study approach to assessment of perfor- are used or implanted in children out- of prosthetic heart valves. A more re- mance in pediatric patients at the time side approved indications; the inclu- cently developed set of OPCs was used of IDE application for adult devices that sion of longitudinal follow-up data are during the approval process for a ultimately may be used in children as a key component of any registry data transcatheter occluder device for well. set intended to support the expansion e160 BEEKMAN et al Downloaded from www.pediatrics.org at Amer Acad of Pediatrics on July 1, 2009
  8. 8. SPECIAL ARTICLES of “labeled” indications to pediatric ap- to assess the longer-term efficacy and ported for only 105 patients. This study plications. An example of such a regis- safety of selected procedures and de- was considerably smaller than the piv- try is the current CCISC registry of pa- vices. A broad data set will be derived otal study on the Amplatzer septal oc- tients having surgery, angioplasty, or that includes essentially all interven- cluder (AGA Medical Corporation, Ply- stent therapy for coarctation of the tional procedures that are currently mouth, MN), which reported on a aorta. This prospectively collected being performed. Building on the suc- device arm with more than 300 en- data set has defined patient inclusion cessful use of adult NCDR registries to rolled patients. The FDA, however, pro- and exclusion criteria as well as rec- obtain information for regulatory pur- vided Gore with approval conditioned ommended follow-up intervals, evalua- poses, it is an explicit goal of the on further characterization of the long- tions, and studies. Neither specific an- IMPACT registry to provide a vehicle to term safety and effectiveness of the gioplasty balloon catheters nor facilitate device approval for pediatric Helex occluder. An additional 250 pa- specific stents are mandated, but indications. tients must be followed for 5 years, acute and longitudinal data are cap- and at least 80% of these patients must tured on all patients, effectively col- Enhanced Postmarket Surveillance be available for 2-year follow-up. An- lecting data about all of the currently Historically, FDA approval of PMA appli- nual reports and a final report to the used (on-label and off-label) surgical cations for cardiovascular devices has FDA will be required. and catheter-based treatment strate- included substantial postmarket sur- gies for coarctation. Thus, the CCISC is veillance plans. In some cases, how- Use of Data Generated Outside of building individual sets of data about ever, sponsors have not adequately the United States several devices and has potential to complied, and the FDA has lacked ei- Clinical data generated outside the support FDA review and approval of ther the mechanisms or willingness to United States (OUS) may be submitted new pediatric cardiovascular indica- enforce the plans. This has placed indi- for FDA review in support of PMA appli- tions for these devices. rect pressure on the FDA to “raise the cations. These data may also comprise An important additional development premarket bar” by requiring sponsors part or all of the pivotal study data. Not is the recent creation of a congenital to provide premarket studies with surprisingly, the FDA requires that the heart disease registry, the Improving more data and more follow-up of pa- quality and verifiability of such clinical Pediatric and Adult Congenital Treat- tients. Conceivably, the pressures in data meet the same standards as re- ment (IMPACT) registry, funded by the this situation could be reversed if quired from data generated in the American College of Cardiology Foun- sponsors were to comply more fully United States. In the past, OUS data dation through the National Cardiovas- with postmarket surveillance plans. If have not typically been of sufficient cular Data Registry (NCDR) program. postmarket surveillance were en- quality to allow immediate device ap- The IMPACT registry will aim to assess hanced, the FDA might accept safety proval in the United States. Substantial the prevalence, demographics, man- and efficacy data from smaller pivotal preliminary mechanical and animal agement, and outcomes of patients un- studies with shorter follow-up periods testing is required before allowing ini- dergoing diagnostic catheterization to qualify devices for conditional ap- tial human clinical studies. However, and catheter-based interventions for proval and to permit sales of the de- high-quality OUS data from well- congenital heart disease. Importantly, vices for pediatric conditions. These controlled and monitored studies it will include a robust capture of devices could be eligible for final or could provide support in the setting of catheterization-related adverse events. unconditional approval after the limited preclinical or equivocal animal The registry plan involves a pilot phase agreed postmarket studies are com- data, or could take the place of a US limited to 10 centers collecting acute pleted and demonstrate acceptable feasibility study. Global studies in catheterization data only, with rapid safety and efficacy outcomes. which data are gathered from US and expansion to allow participation of all The approval in 2006 of the Gore Helex OUS clinical sites according to a single dedicated pediatric cardiac catheter- septal occluder (W.L. Gore & Associ- protocol could also be considered to ization facilities. In its final implemen- ates, Inc, Flagstaff, AZ) is an example of provide a reasonable alternative to tation phase (year 4), the registry plan this approach by the FDA. The pivotal pivotal US-only studies. For these stud- involves recruitment of 300 centers study of the Helex reported on a device ies, it will be important to be aware of known to provide catheterization ser- arm that enrolled 143 patients with and plan to address potential population vices for congenital heart disease and technical success in 119 patients. One- or clinical practice differences that to include longitudinal data collection year follow-up outcomes were re- might affect the study outcome. When PEDIATRICS Volume 124, Number 1, July 2009 e161 Downloaded from www.pediatrics.org at Amer Acad of Pediatrics on July 1, 2009
  9. 9. considering such efforts, the FDA has vices developed to benefit adult pa- cussed possible alternate pathways to strongly suggested early and frequent tients and their conditions. These chal- device evaluation and approval. Chil- interaction with the agency to ensure ap- lenges relate to the relatively small dren deserve to benefit from new and propriate development of such high- population of children with cardiovas- refined cardiac devices and technol- quality OUS and global studies. cular disease, and to the unique as- ogy designed explicitly for their condi- pects of the pediatric cardiovascular tions. As the medical community, in- CONCLUSIONS system and the disorders that affect it. dustry, and the FDA work together to The design, development, evaluation, We have reviewed the current FDA reg- enhance the pathways to approval of and approval of cardiac devices for ulatory processes, reviewed some cardiac devices for children, all par- children pose significant challenges to unique aspects of pediatric cardiology ties must also remain vigilant to safe- industry processes and to regulatory and cardiac surgery that pose chal- guard the safety and autonomy of pathways originally intended for de- lenges to these processes, and dis- these most vulnerable patients. REFERENCES 1. Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39(12): 1890 –1900 2. Zilberman MV, Khoury PR, Kimball TR. Two-dimensional echocardiographic valve measurements in healthy children: gender-specific differences. Pediatr Cardiol. 2005;26(4):356 –360 3. Gutgesell HP, Rembold CM. Growth of the human heart relative to body surface area. Am J Cardiol. 1990;65(9):662– 668 4. O’Malley AJ, Normand ST, Kuntz RE. Sample size calculation for a historically controlled clinical trial with adjustment for covariates. J Biopharm Stat. 2002;12(2):227–247 5. O’Malley AJ, Normand ST, Kuntz RE. Application of models for multivariate mixed outcomes to medical device trials: coronary artery stenting. Stat Med. 2003;22(2):313–336 6. Pocock SJ. The combination of randomized and historical controls in clinical trials. J Chronic Dis. 1976;29(3):175–188 7. Blackstone EH. Breaking down barriers: helpful breakthrough statistical methods you need to understand better. J Thorac Cardiovasc Surg. 2001;122(3):430 – 439 8. Proposed standards for clinical evaluation of patent ductus arteriosus occlusion devices. Multi- organization Advisory Panel to FDA for Pediatric Cardiovascular Devices. Catheter Cardiovasc Interv. 2000;51(3):293–296 9. Lloyd TR, Beekman RH, Moore JW, et al. The PDA coil registry: report of the first 535 procedures. Circulation. 1995;92(suppl 1):I-380 e162 BEEKMAN et al Downloaded from www.pediatrics.org at Amer Acad of Pediatrics on July 1, 2009
  10. 10. Pathways to Approval of Pediatric Cardiac Devices in the United States: Challenges and Solutions Robert H. Beekman, III, Brian W. Duncan, Donald J. Hagler, Thomas K. Jones, John D. Kugler, John W. Moore, Kathy J. Jenkins and for the Workgroup on Pediatric Cardiac Devices, Section on Cardiology and Cardiac Surgery, American Academy of Pediatrics Pediatrics 2009;124;e155-e162 DOI: 10.1542/peds.2008-3726 Updated Information including high-resolution figures, can be found at: & Services http://www.pediatrics.org/cgi/content/full/124/1/e155 References This article cites 9 articles, 2 of which you can access for free at: http://www.pediatrics.org/cgi/content/full/124/1/e155#BIBL Citations This article has been cited by 1 HighWire-hosted articles: http://www.pediatrics.org/cgi/content/full/124/1/e155#otherarticl es Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Heart & Blood Vessels http://www.pediatrics.org/cgi/collection/heart_and_blood_vessel s Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.pediatrics.org/misc/Permissions.shtml Reprints Information about ordering reprints can be found online: http://www.pediatrics.org/misc/reprints.shtml Downloaded from www.pediatrics.org at Amer Acad of Pediatrics on July 1, 2009

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