DOI: 10.1542/peds.2008-3726 2009;124;e155-e162 PediatricsPediatrics

Cardiac Devices, Section on Cardiology and Cardiac Surgery, American Academy ofD. Kugler, John W. Moore, Kathy J. Jenkins and for the Workgroup on Pediatric

Robert H. Beekman, III, Brian W. Duncan, Donald J. Hagler, Thomas K. Jones, John Challenges and Solutions

Pathways to Approval of Pediatric Cardiac Devices in the United States:

http://www.pediatrics.org/cgi/content/full/124/1/e155located on the World Wide Web at:

The online version of this article, along with updated information and services, is

rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Grove Village, Illinois, 60007. Copyright © 2009 by the American Academy of Pediatrics. All and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elkpublication, it has been published continuously since 1948. PEDIATRICS is owned, published, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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Pathways to Approval of Pediatric Cardiac Devices inthe United States: Challenges and Solutions

abstractPatients treated by pediatric interventional cardiologists and cardiacsurgeons often have unmetmedical device needs that pose a challengeto the current regulatory evaluation and approval process in the UnitedStates. In this report we review current US Food and Drug Administra-tion regulatory processes, review some unique aspects of pediatriccardiology and cardiac surgery that pose challenges to these pro-cesses, and discuss possible alternate pathways to cardiac deviceevaluation and approval for children. Children deserve to benefit fromnew and refined cardiac devices and technology designed explicitly fortheir conditions. Pediatrics 2009;124:e155–e162

The fields of pediatric interventional cardiology and cardiac surgeryhave grown rapidly during the past 2 decades. These specialties pro-vide infants and children with innovative transcatheter and surgicaltherapies that often are the result of adapting medical devices thatwere developed and approved for use in adult patients with acquiredcardiovascular disorders. In some instances, device modifications areroutinely conducted in real time in the cardiac catheterization or op-erating room suites. Rarely, cardiac devices have been developed, eval-uated, and approved specifically for treatment of childrenwith congen-ital heart disease. The way in which cardiovascular devices aredesigned, evaluated in clinical studies, and submitted for regulatoryapproval has remained a considerable challenge for the field.

Unmet cardiovascular device needs in the pediatric population occurwhen a needed device does not exist or when a device exists for adifferent (typically adult) indication but must be modified or used in anoff-label fashion for children. An example of a needed device that doesnot exist is a transcatheter pulmonary artery flow restrictor, whichcould benefit many children who currently must undergo surgical pul-monary artery banding. Examples of existing devices that are used inchildren for unapproved indications include biliary stents (which areroutinely used in children for pulmonary artery stenosis and coarcta-tion stenting), angioplasty balloons (which are used to dilate valvesand vessels in unapproved locations), and peripheral vascular occlu-sion coils (which are used for transcatheter closure of the ductusarteriosus). None of these existing devices have been engineered for orformally approved as safe and efficacious for the common pediatricindications to which they are applied.

In this article we address the topic of cardiac device approval from theperspective of pediatric cardiology and cardiac surgery. We include areview of the current regulatory processes that exist in the UnitedStates, the challenges faced with the care of the diverse and complex

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,MPHg, for the Workgroup on Pediatric Cardiac Devices, Sectionon Cardiology and Cardiac Surgery, American Academy ofPediatrics

aDivision of Cardiology, Cincinnati Children’s Hospital MedicalCenter, Cincinnati, Ohio; bDivision of Cardiac Surgery, ClevelandClinic Foundation, Cleveland, Ohio; cDivision of PediatricCardiology, Mayo Clinic, Rochester, Minnesota; dDivision ofPediatric Cardiology, Seattle Children’s Hospital, Seattle,Washington; eDivision of Pediatric Cardiology, Children’sHospital of Omaha, Omaha, Nebraska; fDivision of PediatricCardiology, San Diego Children’s Hospital, San Diego, California;and gDepartment of Cardiology, Children’s Hospital Boston,Boston, Massachusetts

KEY WORDScardiac devices, medical devices, device approval, pediatriccardiology

ABBREVIATIONSFDA—Food and Drug AdministrationIDE—investigational device exemptionPMA—premarket approvalHDE—humanitarian device exemptionHUD—humanitarian use deviceOPC—objective performance criteriaPG—performance goalOUS—outside the United States

www.pediatrics.org/cgi/doi/10.1542/peds.2008-3726

doi:10.1542/peds.2008-3726

Accepted for publication Feb 27, 2009

Address correspondence to Robert H. Beekman, III, MD,Cincinnati Children’s Hospital Medical Center, Division ofCardiology, 3333 Burnet Ave, Cincinnati, OH 45229. E-mail:rbeekman@cchmc.org.

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2009 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they haveno financial relationships relevant to this article to disclose.

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patients with congenital heart disease,and possible novel strategies for en-hancing the review and approval pro-cesses for cardiac devices intendedfor use in children. Children deserve tobenefit from advances in medical de-vice technology in the same way thatadult patients have benefited foryears. Without exception, however, anychange in review processes for pediat-ric cardiac devices cannot be made atthe cost of patient safety or welfare.

THE CURRENT FOOD AND DRUGADMINISTRATION DEVICE-APPROVAL PROCESSES

The US Food and Drug Administration(FDA) is responsible for oversight of allmedical devices sold in the UnitedStates. Before a medical device can beshipped across state lines, either foruse in a clinical study or for sale, cer-tain FDA regulationsmust bemet. Mostmedical device manufacturers arequite familiar with these regulationsand the processes that will allow mar-keting of their devices. However, tomany practicing physicians, these reg-ulations and processes may seemmysterious and convoluted.

How can a physician legally use a med-ical device to treat or diagnose a pa-tient? If the device has been “cleared”or “approved” for marketing, the phy-sician can use the device freely. That is,the physician can use the device forthe types of patients and in themannerdescribed in the labeling (ie, as statedin the indications-for-use statement inthe instructions for use). Alternatively,the device may be used in a differentmanner or for a different indication(ie, off-label) if the physician believesthat this approachwould be in the bestinterest of a particular patient. How-ever, if the device has not been clearedor approved for marketing, the physi-cian can only use the device under spe-cial circumstances, most commonlyunder a protocol approved by the FDA

known as an investigational device ex-emption (IDE). The IDE can be regardedas a “contract” between the physicianand the FDA that specifies the termsunder which the device can be usedlegally.

To determine if a device can be“cleared” for marketing, the FDA regu-lates medical devices by using a risk-based approach, assigning each de-vice type to a regulatory class. Class Idevices are simple devices that pose alow risk to patients, such as certainhandheld surgical instruments (eg,scalpels, retractors). The great major-ity of these devices do not require pro-spective FDA review to begin market-ing (ie, they are considered “exempt”from the need for a marketing applica-tion); the only requirement is that themanufacturer and manufacturing fa-cility be registered with the FDA. ClassII devices are considered to pose amoderate risk to patients, and many ofthese devices will require the submis-sion of a marketing application to theFDA before marketing the product. Ex-amples of class II devices include guidewires, infusion catheters, and patientmonitors. These marketing applica-tions are called 510(k)’s, after the sec-tion of the law that described them.The 510(k) application should demon-strate that a new device is “substan-tially equivalent” in terms of intendeduse and device performance to an al-ready marketed device (sometimes re-ferred to as “noninferiority”), whichmeans that the new device must beat least as safe and effective as asimilar device already on the market.In most instances, only bench testingand, in certain cases, animal studiesare required; only 10% to 15% of510(k)’s require clinical data. When a510(k) application has successfullydemonstrated substantial equiva-lence, the application is said to be“cleared.”

Class III devices pose the highest risk

to patients and include devices such asseptal and vascular occluders, coro-nary stents, and ventricular assist de-vices. Themajority of these deviceswillrequire a premarket approval (PMA)application before marketing. PMAsrequire bench, animal, and clinicaldata to demonstrate that there is areasonable assurance of safety and ef-fectiveness when the device is used asintended. The clinical data to support aPMA application are typically obtainedunder an IDE protocol. The protocolgives specific directions about how adevice is to be used, and how data areto be obtained, and should be designedto collect information that is suffi-ciently interpretable such that reason-able safety and effectiveness can beinferred. After the clinical protocol hasbeen completed, the data are analyzedand presented to the FDA to support aPMA application. Before a PMA can beapproved, a manufacturer will also un-dergo a manufacturing inspection todemonstrate that the device can bemanufactured with consistently highquality.

Class III devices can also reach themarket through a humanitarian deviceexemption (HDE). The HDE programwas established to ensure availabilityof devices for the diagnosis or treat-ment of conditions that affect fewerthan 4000 patients in the United Statesper year. Because the number of pa-tients potentially available to partici-pate in a clinical trial is small, the HDEregulation provides an exemptionfrom the requirement to show effec-tiveness. An HDE can be approved if thedevice has been shown to provide areasonable assurance of safety andprobable benefit. A manufacturer whowishes to pursue an HDE must firstshow that the number of patients withthe disease or condition who would betreated with the device is fewer than4000 in the United States per year. De-vices that qualify on this basis will re-

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ceive a humanitarian use device (HUD)designation. Once the HUD designationhas been granted, the HDE can be sub-mitted to gain approval for marketing.Although an HDE allows for less clinicaldata collection than a PMA, there aredisadvantages as well. Amanufacturercannot ship an HDE-approved device toa hospital or clinic until its institu-tional review board has given approvalfor its use. Until recently, the manufac-turer was also prohibited frommakinga profit from the sale of a device thatpossessed HDE status; only the costs ofresearch and development could berecovered in the sale price. Recent leg-islation (see below) has lifted this re-striction so that pediatric devices ap-proved for marketing under an HDEcan now be sold for profit.

As discussed above, a device can bemarketed if it is the subject of acleared 510(k), an approved PMA orHDE, or is exempt from the require-ment for amarketing application. How-ever, it is common in pediatrics for de-vices to be developed by individualusers or to be available in other coun-tries before it is marketed in this coun-try. The FDAmakes provisions allowinglimited use of unapproved devices insome of these settings. If the device isbeing studied under an IDE, a physicianmay request the use of the devicethrough the manufacturer or sponsorof the IDE for a patient who does notmeet the clinical study criteria. TheFDA will ask that certain provisions befollowed for the patient’s protectionbut, in the majority of cases, will grantthese requests for “compassionateuse.” The patient-protection measuresinclude appropriate informed consentfrom the patient or patient’s guardian,approval of the institutional reviewboard, and the concurrence of an un-involved physician. If a device is not be-ing studied under an IDE, the prescrib-ing physician can apply directly to theFDA to obtain approval to use the de-

vice. If the application is approved, theFDA will require the same patient-protection measures described aboveto be in place.

Some devices are subject to furtherstudy after marketing approval, a pro-cess known as “postapproval” or “post-market” studies. Postmarket studiescanprovide data to further refine initial un-derstanding of device performance.Such studies may provide additionalinsights into appropriate patient se-lection, training of physicians, andpractical issues such as device perfor-mance in patients with multiple co-morbidities. In addition, the Safe Med-ical Devices Act requires reporting ofadverse events and significant devicemalfunctions to the FDA for any device,even those that are not subject to for-mal postapproval studies. Additionalinformation for reporting require-ments may be found at www.fda.gov/cdrh/medsun/about.html. To facilitateidentification of gaps in device avail-ability for pediatric indications, theFDA has established a formal postmar-ket surveillance partnership with clini-cal sites, known as KidNet (www.fda.gov/cdrh/medsun/about.html). This siteprovides a venue for institutions in-volved in pediatric care to record cir-cumstances in which acceptable pedi-atric devices were unavailable and inwhich adult devices needed to be sub-stituted or modified.

RECENT LEGISLATION

In 2007, Congress passed the PediatricMedical Device Improvement andSafety Act (Pub L No. 110-85) as part oflegislation to amend the Food Drug andCosmetic Act. In passing the act, Con-gress identified the need for improvedaccess to pediatric medical and surgi-cal devices as well as needed improve-ments in postmarket safety monitor-ing of existing devices used in children.As mentioned above, the act removedthe profit prohibition on devices ap-

proved through the HDE pathway for“the treatment or diagnosis of a dis-ease or condition that occurs in pe-diatric patients” (Pub L No. 110-85,§303[a]), which allows device produc-ers to make a profit on devices used infewer than 4000 children. The act alsocreated newmechanisms for pediatricdevice development through the cre-ation of nonprofit consortia to stimu-late innovation.

In the postmarket setting, the actgranted new authority to the FDA to ex-tend the current limit of 36 months forpostmarket studies of class II or III de-vices if needed for children and to re-quire postmarket studies as a condi-tion of approval. Finally, Congressinstructed the FDA, the National Insti-tutes of Health, and the Agency forHealthcare Research and Quality to de-velop a plan for expanding pediatricmedical device research and develop-ment. On July 23, 2008, the 3 federalagencies conducted the Pediatric Med-ical Devices Stakeholders’ Workshopto gain input on the plan, which is ex-pected to be presented to Congresssoon.

CHALLENGES FROM PEDIATRICCARDIOLOGY AND CARDIACSURGERY

The fields of pediatric cardiology andcardiac surgery share characteristics,distinct from their counterpart spe-cialties in adult medicine, that poseunique challenges to the developmentand approval of cardiac devices forchildren. First, congenital cardiac de-fects are relatively uncommon andinclude a diverse array of anatomicsubtypes. For example, moderate-to-severe congenital cardiac defects thatrequire therapy occur with an esti-mated total prevalence of only 6 per1000 live births.1 The relatively smallnumber of patients affected with anygiven congenital cardiac defect makesit difficult to design a traditional ran-

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domized clinical trial that is ade-quately powered. From an industryperspective, virtually all congenitalcardiac defects can be considered “or-phan” disorders that occur in smallpatient populations with a relativelylimited market potential for any givendevice.

A second challenge to the developmentof cardiac devices specifically for chil-dren exists because pediatric cardio-vascular anatomy presents a widerange of anatomic sizes which, in turn,require a demanding range of devicesizes. Unlike adult valves, ventricles,and great vessels which have a rela-tively narrow range of normal dimen-sions, pediatric cardiovascular anat-omy grows significantly from birth toyoung adulthood. For example, cardiacvalve diameters increase threefoldfrom birth to adulthood. The normalaortic and pulmonary valve annulus di-ameters increase from 7 to 22mm andfrom 8 to 26 mm, respectively, frombirth to adolescence.2 To be suitablefor children of all ages, semilunarvalve prostheses with diameters thatrange from 7 mm for newborns to themore familiar adult dimensionsshould be available; however, in cur-rent practice, the smallest approvedsemilunar valve prosthesis measures16mm in diameter. The changes in car-diac chamber volume that occur withgrowth are even more pronounced, asillustrated by the increase in normalleft ventricular diastolic volume from�10 mL in the newborn to 150 mL inthe adult.3 Clearly, the engineeringchallenges are substantial if a ventric-ular assist device is to benefit patientsof all ages and sizes. Table 1 demon-strates the wide range of “normal” di-mensions (ie, z value � 0) for repre-sentative cardiovascular structuresfor newborns, children, and youngadults.

A third challenge to the development ofpediatric cardiac devices relates to

the substantial somatic growth thatoccurs during childhood. Any cardiacdevice implanted into the cardiovascu-lar system of a growing child must beable to accommodate the child’s fu-ture growth while remaining safe, ef-fective, and intact. Atrial or ventricularseptal occlusion devices implanted ina child are known to be compatiblewith future cardiac growth becausethe cardiac septa grow “around” theendothelialized devices. However, asemilunar or atrioventricular valveprosthesis implanted into a small childwill often become too small and, there-fore, hemodynamically obstructive asthe child grows. Ventricular-arterialconduits or great artery grafts of ap-propriate dimension and capacity for achild but lacking growth potential willbecome diminutive, and need replace-ment, as the child grows. Similarly,ventricular assist devices of suitablesize for children may be outgrown,making the concept of “destinationtherapy” for long-term circulatory sup-port impracticablewhen using a singleimplanted device. All of these consider-ations related to somatic growth im-part substantial design and engineer-ing challenges for device developerswho aim to provide devices that canbe maintained long-term in growingchildren.

Finally, remarkable durability is re-quired of pediatric cardiac devices be-cause in pediatrics a patient’s life ex-pectancy is typically measured indecades. In reality, this is in markedcontrast to adult cardiovascular med-icine, inwhich patient longevity is often

described in months or several years.A muscular ventricular septal defectdevice that is implanted in a 6-month-old infant must remain intact on theventricular septum for 70 or 80 years.The prospect, and indeed the expecta-tion, that pediatric cardiac patientsmay survive for many decades de-mands unique long-term durabilityfrom the cardiac devices implanted inthem.

OFF-LABEL USE OF DEVICES

Because of the challenges to device de-sign and approval posed by the rela-tively uncommon cardiovascular de-fects of children, the off-label use ofdevices approved for other patientpopulations (typically adults) and indi-cations has become a routine, ac-cepted practice in pediatric cardiology(Table 2). For example, the large ma-jority of stents implanted in pediatricinterventional procedures are biliarystents used off-label to treat vascularstenoses within the pulmonary arte-rial tree, aorta, and large veins. Ap-proved medical devices can be usedlegally off-label by pediatric practitio-ners if this use is judged by the physi-cian to bemedically appropriate and inthe patient’s best interest. However,the off-label practice itself has impor-tant disadvantages. First, a deviceused off-label will not have been sub-ject to the FDA approval process to pro-vide reasonable assurance of safetyand effectiveness for this patient pop-ulation or for the specific pediatric in-dication. This absence of formal evalu-ation and approval can cause

TABLE 1 Mean Dimensions (z Value� 0) of Normal Cardiovascular Structures in Newborns,Children, and Young Adults

Cardiovascular Structure Newborn Child (6 y old) Adult

Aortic valve diameter, mm 7 14 22Pulmonary valve diameter, mm 8 16 26Mitral valve diameter, mm 10 19 28Aortic root diameter, mm 10 15 30Right pulmonary artery diameter, mm 6 12 18Left ventricular diastolic volume, mL 10 50 150

Data were derived from refs 2 and 3.

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difficulties for pediatric practitionerswho may be required to make deci-sions about device use on the basis ofinsufficient information, or who maybe subject to medical malpracticeclaims if their judgment is questioned.Second, a medical device that is usedfor an off-label indication may be de-prived of important industry researchand development to improve deviceperformance for that pediatric condi-tion. Because early generations of adevice used off-label for pediatric indi-cations may not have had sufficientdata to support such use, device en-hancements for pediatric indicationsand approval of these later-generationdevices may be difficult or impossible.Finally, the off-label use of devicestested in adults to treat pediatric con-ditions creates some special chal-lenges for the pediatric device-ap-proval process. In some instances,considerable information about how adevice may perform in children can beextrapolated from safety and efficacyinformation derived from adults. Inother instances, however, this infor-mation may not be useful because ofdifferences in pediatric anatomy, phys-iology, and pathophysiology. Determi-nations about when use of adult in-formation is appropriate are notstraightforward and can complicatethe design of studies in pediatricpatients.

POSSIBLE SOLUTIONS: NOVELAPPROVAL PATHWAYS

Many pediatric cardiologists and car-diac surgeons recognize the problemsin achieving safety and efficacy stan-dards for devices used in the care ofpatients with congenital heart disease.Safety standards require that theprobable benefits from use of the de-vice outweigh the probable risks. Rea-sonable assurance of effectiveness isestablished when it can be deter-mined, on the basis of valid scientificevidence, that in a significant portionof the target population the use of thedevice for its intended purpose andconditions of use will provide clinicallysignificant results.

The FDA is committed to the least bur-densome principle throughout the reg-ulatory process ofmedical devices andwill assist in the design of trials thatwill produce clear and interpretabledata. Randomized, controlled clinicaltrials (RCCTs) are considered the goldstandard for such clinical trials butare costly, technically challenging, long,and arduous. In small pediatric popula-tions the RCCT may not be statisticallypossible, and patients or families mayrefuse to accept randomization. Table 3lists several alternatives to the use ofthe RCCT which may be applicable tothe evaluation of pediatric cardiac de-vices, and a brief discussion of eachalternative is presented below.

Objective Performance Criteriaand Performance Goals

One alternative is the use of objectiveperformance criteria (OPC) or perfor-mance goals (PGs) in the evaluation ofmedical devices during the regulatoryapproval process. The essence of anOPC or PG is that themetrics to be usedto evaluate whether a devicemeets cri-teria for approval are specified in ad-vance and are not obtained as a part ofan IDE study. OPCs or PGs are often ex-pressed as a rate.4,5 Thus, the OPC orPG is used as a replacement for a tra-ditional randomized control group andserves as a benchmark, or minimallyacceptable value using a pass/fail ap-proach, to determine if a particular de-vice application is ultimately approvedfor marketing.

The estimate for an OPC or PG is neces-sarily derived from historical data. Thedevelopment of an OPC is a more for-mal process than that for a PG, requir-ing pooling of data across previouslypublished studies by using a formalmeta-analysis or similar approach.Ideally, historical trials should providepatient-level data including clinicaloutcomes and patient characteristics.Pocock6 described 5 requirements forvalid historical controlled studies:

1. Control group receives the pre-cisely defined treatment in a recentstudy.

2. Criteria for eligibility, workup, andevaluations must be the same.

3. Prognostic factors are completelyknown and the same in bothgroups.

TABLE 2 Approved Medical Devices That Are Commonly Used for Off-Label Pediatric Indications

Device Labeled Indications Off-Label Pediatric Applications

Stents Biliary tree stenosis Pulmonary artery stenosisCoronary artery disease Coarctation of the aorta

Systemic vein stenosisEmbolization coils Arteriovenous fistula Patent ductus arteriosusDilation balloons Pulmonary valve stenosis Aortic valve stenosis

Peripheral vascular disease Pulmonary artery stenosisCoarctation of the aorta

Cutting balloons Arteriovenous dialysis fistulastenosis

Pulmonary artery stenosis

Radiofrequency perforation wire Atrial transseptal puncture Pulmonary valve atresia

TABLE 3 Possible Pathways to DeviceApproval for Pediatric Cardiology(Alternatives to Randomized ClinicalTrials)

Use of OPC or PGsExtrapolation from existing data in studies ofadult patientsUse of registry dataEnhanced postmarket surveillanceUse of data generated OUS

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4. No unexplained indications leadingone to expect different results.

5. Differences in prognostic factorsare insufficient to explain observeddifferences in outcome.

Rigorous and scientifically valid meth-odologies have been developed andused in the derivation of any OPC foruse in the medical device-approvalprocess. An OPC must be derived fromrecognized and generally completehistorical data sets and be the productof appropriate statistical modelingand analytical techniques. Nonran-domized comparison data using pro-pensity scoring may also be a mecha-nism for achieving well-matchedpatient groups.7 There should also be adesignated provision for periodicallyevaluating and updating the OPC on thebasis of more recent experience anddata.

PGs are developedwhen less historicalinformation is available. A scientific orclinical rationale must be outlined forthe selection of studies on which thePG is based, including adjustments fordifferences in populations or other as-pects of the studies, in comparison tothe proposed methodology that will beused in the IDE study. Given the lessrobust data and analysis that contrib-ute to the development of a PG, anOPC is the preferred control for a non-randomized trial. Nevertheless, PGsmay provide an important alternative,especially for therapies for which off-label device treatment is routine (eg,numerous pediatric cardiac interven-tions), which makes randomized stud-ies using surgery or medical therapyas a control difficult to conduct.

OPCs have been used in the regulatoryapproval process in the past, and mul-tiple ongoing studies use PGs. OPCshave been used frequently in the studyof prosthetic heart valves. A more re-cently developed set of OPCs was usedduring the approval process for atranscatheter occluder device for

patent ductus arteriosus. These OPCswere developed, in part, by using com-parisons to published surgical data8

and to the PDA Coil Registry.9 Currently,2 occluder devices are approved foratrial septal defect closure. Additionalapprovals for atrial septal occlusionmay be facilitated by development ofappropriate PGs. Similarly, stents totreat pulmonary artery stenosis or co-arctation of the aorta could have ap-propriate PGs developed on the basisof published results, which could beused in conjunction with data from ro-bust long-term registries to follow pa-tients who have had a pulmonary ar-tery or aortic stent implanted.

Extrapolation From Existing Data inStudies of Adult Patients

Generally, the use of data obtainedfrom adult patients to inform deci-sions regarding device safety and effi-cacy in children is of limited applicabil-ity because of differences in patientgrowth and longevity and functionaldifferences between devices for coro-nary disease and congenital heart dis-ease. The option of developing a medi-cal device for pediatric use that hasfeatures similar to an adult device rep-resents a potential pathway for devicedesign and approval, but safety evalu-ation would require a separate trial todetermine device safety in children.Some special-function catheters (im-aging or therapeutic) for adult usemay be applicable for infants and chil-dren when manufactured in sizes ap-propriate for pediatric use. Prostheticcardiac valves may represent anotherclass of devices for which perfor-mance data from adults might be ex-trapolated to pediatric applications.Ideally, sponsors should include theirapproach to assessment of perfor-mance in pediatric patients at the timeof IDE application for adult devices thatultimately may be used in children aswell.

Use of Registry Data

This route is a similar approach to theuse of PGs described above, because itrelies on application of historical dataas a surrogate for data obtained froma more traditional contemporaneouscontrol group. However, this mecha-nism depends on the existence of rig-orous registry data that include a thor-ough capture of adverse events. Anexample of such a registry is the Inter-agency Registry for MechanicallyAssisted Circulatory Support(INTERMACS). This registry was devel-oped with the support of the Depart-ment of Health and Human Services,the National Heart, Lung, and Blood In-stitute, and the FDA. Some notable fea-tures of this registry include the use ofsequential patient enrollment, a well-defined data set, independent clinicalevaluations, well-designed clinical re-port forms, and a commitment to min-imize the amount of missing data.

Prospective databases have the poten-tial to provide important clinical datasupporting expansion of “labeled” indi-cations for cardiovascular devices.Databases currently enrolling patientswith congenital heart disease who un-dergo cardiac catheterization includethe Mid-Atlantic Group of Interven-tional Cardiology (MAGIC), CongenitalCardiac Catheterization Project onOutcomes (C3PO), and Congenital Car-diovascular Interventional Study Con-sortium (CCISC). Generally, these data-bases are too limited in scope or wereinaugurated too recently to provideprimary data sets to support FDA re-view and approval of new applicationsfor existing cardiovascular devices.However, over time, these registriesdo have potential to contribute valu-able clinical data sets for devices thatare used or implanted in children out-side approved indications; the inclu-sion of longitudinal follow-up data area key component of any registry dataset intended to support the expansion

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of “labeled” indications to pediatric ap-plications. An example of such a regis-try is the current CCISC registry of pa-tients having surgery, angioplasty, orstent therapy for coarctation of theaorta. This prospectively collecteddata set has defined patient inclusionand exclusion criteria as well as rec-ommended follow-up intervals, evalua-tions, and studies. Neither specific an-gioplasty balloon catheters norspecific stents are mandated, butacute and longitudinal data are cap-tured on all patients, effectively col-lecting data about all of the currentlyused (on-label and off-label) surgicaland catheter-based treatment strate-gies for coarctation. Thus, the CCISC isbuilding individual sets of data aboutseveral devices and has potential tosupport FDA review and approval ofnew pediatric cardiovascular indica-tions for these devices.

An important additional developmentis the recent creation of a congenitalheart disease registry, the ImprovingPediatric and Adult Congenital Treat-ment (IMPACT) registry, funded by theAmerican College of Cardiology Foun-dation through the National Cardiovas-cular Data Registry (NCDR) program.The IMPACT registry will aim to assessthe prevalence, demographics, man-agement, and outcomes of patients un-dergoing diagnostic catheterizationand catheter-based interventions forcongenital heart disease. Importantly,it will include a robust capture ofcatheterization-related adverse events.The registry plan involves a pilot phaselimited to 10 centers collecting acutecatheterization data only, with rapidexpansion to allow participation of alldedicated pediatric cardiac catheter-ization facilities. In its final implemen-tation phase (year 4), the registry planinvolves recruitment of �300 centersknown to provide catheterization ser-vices for congenital heart disease andto include longitudinal data collection

to assess the longer-term efficacy andsafety of selected procedures and de-vices. A broad data set will be derivedthat includes essentially all interven-tional procedures that are currentlybeing performed. Building on the suc-cessful use of adult NCDR registries toobtain information for regulatory pur-poses, it is an explicit goal of theIMPACT registry to provide a vehicle tofacilitate device approval for pediatricindications.

Enhanced Postmarket Surveillance

Historically, FDA approval of PMA appli-cations for cardiovascular devices hasincluded substantial postmarket sur-veillance plans. In some cases, how-ever, sponsors have not adequatelycomplied, and the FDA has lacked ei-ther the mechanisms or willingness toenforce the plans. This has placed indi-rect pressure on the FDA to “raise thepremarket bar” by requiring sponsorsto provide premarket studies withmore data and more follow-up of pa-tients. Conceivably, the pressures inthis situation could be reversed ifsponsors were to comply more fullywith postmarket surveillance plans. Ifpostmarket surveillance were en-hanced, the FDA might accept safetyand efficacy data from smaller pivotalstudies with shorter follow-up periodsto qualify devices for conditional ap-proval and to permit sales of the de-vices for pediatric conditions. Thesedevices could be eligible for final orunconditional approval after theagreed postmarket studies are com-pleted and demonstrate acceptablesafety and efficacy outcomes.

The approval in 2006 of the Gore Helexseptal occluder (W.L. Gore & Associ-ates, Inc, Flagstaff, AZ) is an example ofthis approach by the FDA. The pivotalstudy of the Helex reported on a devicearm that enrolled 143 patients withtechnical success in 119 patients. One-year follow-up outcomes were re-

ported for only 105 patients. This studywas considerably smaller than the piv-otal study on the Amplatzer septal oc-cluder (AGA Medical Corporation, Ply-mouth, MN), which reported on adevice arm with more than 300 en-rolled patients. The FDA, however, pro-vided Gore with approval conditionedon further characterization of the long-term safety and effectiveness of theHelex occluder. An additional 250 pa-tients must be followed for 5 years,and at least 80% of these patientsmustbe available for 2-year follow-up. An-nual reports and a final report to theFDA will be required.

Use of Data Generated Outside ofthe United States

Clinical data generated outside theUnited States (OUS) may be submittedfor FDA review in support of PMA appli-cations. These data may also comprisepart or all of the pivotal study data. Notsurprisingly, the FDA requires that thequality and verifiability of such clinicaldata meet the same standards as re-quired from data generated in theUnited States. In the past, OUS datahave not typically been of sufficientquality to allow immediate device ap-proval in the United States. Substantialpreliminary mechanical and animaltesting is required before allowing ini-tial human clinical studies. However,high-quality OUS data from well-controlled and monitored studiescould provide support in the setting oflimited preclinical or equivocal animaldata, or could take the place of a USfeasibility study. Global studies inwhich data are gathered from US andOUS clinical sites according to a singleprotocol could also be considered toprovide a reasonable alternative topivotal US-only studies. For these stud-ies, it will be important to be aware ofand plan to address potential populationor clinical practice differences thatmight affect the study outcome. When

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considering such efforts, the FDA hasstrongly suggested early and frequentinteractionwith theagency to ensureap-propriate development of such high-quality OUS and global studies.

CONCLUSIONS

The design, development, evaluation,and approval of cardiac devices forchildren pose significant challenges toindustry processes and to regulatorypathways originally intended for de-

vices developed to benefit adult pa-tients and their conditions. These chal-lenges relate to the relatively smallpopulation of children with cardiovas-cular disease, and to the unique as-pects of the pediatric cardiovascularsystem and the disorders that affect it.We have reviewed the current FDA reg-ulatory processes, reviewed someunique aspects of pediatric cardiologyand cardiac surgery that pose chal-lenges to these processes, and dis-

cussed possible alternate pathways todevice evaluation and approval. Chil-dren deserve to benefit from new andrefined cardiac devices and technol-ogy designed explicitly for their condi-tions. As the medical community, in-dustry, and the FDA work together toenhance the pathways to approval ofcardiac devices for children, all par-ties must also remain vigilant to safe-guard the safety and autonomy ofthese most vulnerable patients.

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