Regulatory Policies Regarding Pediatric Spinal Devices


Pediatric subgroup

FDA guidance on approximate age range for this subpopulation

Newborn (neonate)

From birth to 1 month of age

Infant

Greater than 1 month to 2 years of age

Child

Greater than 2–12 years of age

Adolescent

Greater than 12–21 years of agea


This table presents FDA guidance on the approximate age ranges for four main pediatric subpopulations as reported in the FDA document Guidance for Industry and FDA Staff: Premarket Assessment of Pediatric Medical Devices (2004, 2014)

aFor internal review purposes, the FDA has identified another subpopulation, transitional adolescent, to include those aged 18–21 years





56.3 Challenges Related to Advancing Pediatric Spinal Devices to Market


Challenges encountered in the development of pediatric spinal devices relate to economic factors, target population considerations, liability concerns, regulatory processes, and clinical trial design (Table 56.2).


Table 56.2
Challenges related to development of pediatric spinal devices

















Potential market for pediatric devices smaller than for adult devices

Single-device design and device size may be inadequate across all pediatric subpopulations due to anatomic and physiologic differences among pediatric subpopulations

Pediatric devices are associated with additional liability concerns for clinicians and device manufacturers compared to adult devices

Lack of pediatric device trial infrastructure results in increased burdens for large-scale studies

Difficulty in recruitment of adequate numbers of subjects for pediatric clinical device trials

Challenges regarding adequate study design for pediatric clinical device trials compared to adults

(i.e., treatment outcome measures are difficult to define; suitable control population may not exist)


56.3.1 Economic Factors


The economic incentives for development of medical devices for pediatric populations differ fundamentally from those in adult populations. In general, device developers consider pediatric medical devices as small volume product categories due to small target population sizes and the existence of substantial patient heterogeneity within these populations. Such factors limit future profitability and create financial disincentives to direct resources toward development of pediatric devices. Additional challenges include difficulties related to obtaining insurance reimbursement and lack of billing codes.


56.3.2 Target Population-Related Considerations


The pediatric population consists of different subpopulations which are accompanied by differences in size, growth rate, metabolism, and activity levels. Consequently, a manufacturer may need to develop and test a different device for each subpopulation, even though the disease or condition treated is the same. For example, a device which is appropriate for an infant may not be appropriate for use in an adolescent with the same disease or condition. It is a common experience that devices designed for adults are not adequate for use in children and require redesign. An additional consideration relates to limited knowledge regarding the etiology of specific pediatric spinal deformities such as idiopathic scoliosis, which occurs for unknown reasons [6].


56.3.3 Liability Concerns


Device manufacturers have expressed reluctance to pursue development of devices in pediatric populations due to concerns regarding potential future product liability. In the United States, due to the limited number of devices specifically cleared or approved for pediatric use, clinicians are likely to use medical devices for indications not contained in the approved labeling for a specific device. Such use is referred to as “off-label use,” practice of medicine, or physician-directed use. This practice is considered to be associated with higher risks to patients as there is less information available to physicians and patients regarding the safety and efficacy of such use. Although the FDA regulates the indications and intended uses of medical devices, it does not regulate the practice of medicine. Physicians may legally use devices for an indication not in the approved labeling if such use represents good medical practice and is in the best interests of the patient according to the physician’s best knowledge and judgment. Physicians have the responsibility to be well informed about the product, to base product use on firm scientific rationale and on sound medical evidence, and to maintain records regarding the product use and its effects [7, 8]. In contrast, medical device manufacturers are prohibited by law from promoting off-label use. The FDA has outlined specific practices which manufacturers should employ if they choose to disseminate scientific and medical journal articles, scientific and medical reference texts, and clinical practice guidelines (CPGs) that include information on unapproved new uses of approved, cleared, or 510(k) exempt products [9, 10]. Physicians are responsible to be informed regarding regulations and guidances concerning off-label use and should be aware of the potential for their specific actions to be perceived as promoting off‐label use for a company, especially if the clinician enters into any type of consulting arrangement with the manufacturer of a specific product.


56.3.4 Regulatory Process Related to Pediatric Medical Devices


The regulatory requirements for medical devices in the United States affect all phases of the product development cycle.

The regulatory process currently used in evaluating pediatric devices is not different than for adult devices [11]. The regulatory process implements the legislative framework established by Congress and includes device clearance and approval pathways that do not differ on the basis of whether a device is intended for use in a pediatric population or an adult population. Regulatory challenges related to pediatric device development include conservative criteria for pediatric device approval, lack of device-specific FDA guidance documents, limitations related to the number of devices eligible for the Humanitarian Device Exemption (HDE) pathway, restrictions on the use of off-label data in clinical studies, and challenges associated with the Institutional Review Board (IRB) oversight of pediatric clinical trials [12, 13]. As the FDA considers pediatric subjects as a vulnerable population, additional safeguards for pediatric patients involved in clinical trials are required for sponsors, investigators, and IRBs (21 CFR, Part 50, Subpart D).


56.3.5 Issues Related to Design of Clinical Trials for Pediatric Devices


Pediatric devices present unique challenges related to the design of clinical trials. Classic randomized double-blind comparative studies are often not feasible or ethical in small pediatric populations with limited alternative treatment options. Innovative trial designs and statistical methods are often necessary. Additional challenges arise due to mandated safeguards for pediatric patients involved in clinical trials (21 CFR, Part 50, Subpart D).


56.4 Overview of Medical Device Regulation in the United States



56.4.1 Responsible Regulatory Agency


In the United States, the FDA is the scientific, regulatory, and public health agency responsible for protecting and promoting public health through the regulation and supervision of a wide range of products including most food products (excluding meat and poultry); prescription and over-the-counter drugs; medical devices; radiation-emitting products for consumer, medical, and occupational use; vaccines, blood, and biologic agents; veterinary products; cosmetics; and tobacco products.


56.4.2 Legislative Overview


The FDA is an agency of the US Department of Health and Human Services, a part of the executive branch of the federal government of the United States. The FDA is responsible for implementing the laws which are written and enacted by the legislative branch of government (the US Congress). The legal authority of the FDA to regulate medical products, including medical devices, stems from the FD&C Act which contains regulatory requirements that define the FDA’s level of control over medical devices. To fulfill the provisions of the FD&C Act that apply to medical devices, the FDA develops, publishes, and implements regulations which are published in the Federal Register (FR) and codified in the Code of Federal Regulations (CFR). Most of the FDA’s medical device and radiation-emitting product regulations are in Title 21 CFR Parts 800–1299. The regulations most relevant to spinal devices are located in Title 21 (Food and Drugs), Chap. 1 (Food and Drug Administration), Subchapter H (Medical Devices), Part 888 (Orthopedic devices).

The regulatory authority of the FDA was established with passage of the Federal Food and Drug Act (1906) which granted authority to prohibit the sale or distribution of adulterated food or drug products in the United States. The FD&C Act of 1938 was a precedent for regulation of medical devices, but its scope was limited to regulation of marketed devices considered to be unsatisfactory, unsafe, or misbranded. Premarket regulation of medical devices was formally initiated in 1976 when the Medical Device Amendments to the FD&C Act expanded the FDA’s authority to include regulation of devices. Under the Medical Device Amendments, the FDA established panels of experts in individual specialties to develop definitions and classifications that would apply to all commercially available medical devices. The Medical Device Amendments defined a medical device as a product intended for diagnosis, cure, mitigation, treatment, or prevention of a disease or condition, or an entity intended to affect the structure or function of the body, which does not achieve its primary intended use through chemical action or metabolism. The mandate of the 1976 Medical Device Amendments provided the FDA with authority to ensure the safety and effectiveness of medical devices prior to marketing, established a classification system for medical devices, and outlined pathways to market for medical devices. Modifications and updates to regulations have been made in response to subsequent advances in medicine and technology. In 1990, the Safe Medical Devices Act (SMDA) required institutions to report any adverse events involving a medical device to the manufacturer and, under certain situations, to the FDA. In addition, the SMDA initiated the Humanitarian Use Device/Humanitarian Device Exemption (HUD/HDE) program. The Medical Device User Fee and Modernization Act of 2002 (MDUFMA) provided the FDA authority to collect user fees from sponsors to offset the expense of premarket review of devices in exchange for adherence to established timelines for agency review of specific types of premarket device applications. The Food and Drug Administration Amendments Act of 2007 (FDAAA) focused on pediatric safeguards, research, and innovation, in addition to strengthening the transparency of clinical study results. The Food and Drug Safety and Innovation Act (FDASIA) of 2012 included specific provisions to improve the safety and effectiveness of pediatric medical devices, drugs, and biological products.


56.4.3 Organizational Structure Relevant to Spinal Devices


The FDA is organized into multiple centers and offices. The Center for Devices and Radiological Health (CDRH) is responsible for review of medical devices through its eight offices. Within the CDRH, the Office of Device Evaluation guides the premarket regulation of orthopedic medical devices, while in vitro diagnostics and radiologic medical devices are evaluated in the Office of In Vitro Diagnostics and Radiological Health. The Office of Device Evaluation consists of seven divisions, each of which focuses on a different medical specialty area, and each division consists of multiple branches. Most devices used in the treatment of pediatric spinal disorders are under the authority of the Division of Orthopedic Devices. Responsibility for regulation of spinal devices is shared between the Posterior Spine Devices Branch (e.g., pedicle screw spinal systems) and the Anterior Spine Devices Branch (e.g., intervertebral body fusion cages, anterior spinal plate systems). Other products used in the spine (e.g., bone morphogenetic proteins, bone void fillers, bone cements) are reviewed by the Restorative and Repair Devices Branch. Additional offices within the CDRH other than the Office of Device Evaluation also participate in the regulation of orthopedic spinal devices. For example, the Office of Surveillance and Biometrics monitors adverse events and possesses the authority to mandate postmarket studies. Additionally, the Office of Compliance is responsible for conduct of inspections and audits to ensure adherence to quality system regulations and good manufacturing practices.


56.4.4 Classification of Medical Devices


Medical devices are classified by the FDA based on their level of risk to patients and the ability to mitigate these risks. Three classes of risk control are identified based on the level of evidence required to demonstrate the safety and effectiveness of a specific medical device. The classification assigned to a device determines the pathway required for marketing of a device.


56.4.4.1 Class I: General Controls


Class I devices are those devices for which general controls are sufficient to provide reasonable assurance of the safety and effectiveness of the device. General controls apply to all medical devices. These consist of basic standards for ensuring consistent safety and effectiveness and include a requirement for annual registration by manufacturers, importers, distributors, repackagers, and relabelers; annual listing of devices to be marketed and activities to be performed using specific devices; strategies for prevention of device mislabeling; and Premarket Notification. General controls also include quality systems regulations related to good design, manufacturing practices, record keeping, and reporting. Examples of class I devices include manual surgical instruments which are not system specific, such as scalpels, retractors, drills, soft tissue elevators, and general surgical instruments (e.g., Cobb elevator). While most class I devices are exempt from premarket review, a limited number of devices (e.g., surgical gloves, removable skin staples) require Premarket Notification through the 510(k) process.


56.4.4.2 Class II: Special Controls


Devices which cannot be classified into class I because general controls by themselves are insufficient to provide reasonable assurance of safety and effectiveness may be classified into class II if special controls are adequate to provide this assurance. Special controls are evaluations which are specific to the device. Special controls may include specific labeling requirements, preclinical performance testing based on FDA guidance or recognized standards such as those described by the American Society for Testing and Materials (ASTM) International or International Organization of Standards (ISO), patient registries, postmarket surveillance, or clinical data. Most orthopedic spinal devices are designated as class II (e.g., posterior thoracic and lumbar pedicle screw systems for scoliosis and kyphosis). Premarket Notification through the 510(k) process is generally required for marketing of class II devices.


56.4.4.3 Class III: Premarket Approval


Class III devices are those for which general controls are not adequate to provide reasonable assurance of safety and effectiveness and the available data are insufficient for establishment of special controls. Class III devices are usually intended to support or sustain life or prevent substantial health impairment but are accompanied by substantial risk of causing harm to the patient. Such devices may include technologies which raise new questions regarding safety or effectiveness as a consequence of associated novel technologies and/or novel indications.

Such devices are subjected to the highest level of scrutiny which generally includes a complete preclinical and clinical review conducted during the premarket approval (PMA) application. Some class III devices also require post-approval clinical studies. Examples of class III spinal devices include total disc replacement devices and facet replacement devices.


56.4.5 Additional Considerations Related to Device Classification



56.4.5.1 Preamendments Versus Postamendments Devices


The Medical Device Amendments of 1976 divided medical devices based on when they were introduced into commercial distribution. A preamendments device is one that was in commercial distribution before May 28, 1976, the date the Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act were signed into law. These devices were initially classified as class I, II, or III. A device that was not available on the market before the passage of the Medical Device Amendments of 1976 is generally referred to as a postamendments device.


56.4.5.2 Classified Devices Versus Reclassified Devices Versus Unclassified Devices Versus



Not-Classified Devices


Classified Devices

The FDA has established classifications for approximately 1700 different generic types of devices and grouped them into 16 medical specialties referred to as panels. Each of these generic types of devices is assigned to one of three regulatory classes based on the level of control necessary to assure the safety and effectiveness of the device. Searchable databases located on the FDA website provide information on how various devices are regulated by the CDRH.


Reclassified Devices

Based on new information, the FDA may, on its own initiative or upon petition by any interested person, change a device classification. The new information used in this determination must be publicly available valid scientific information as defined in Section 513(a)(3) of the FD&C Act and 21 CFR 860.7(c)(2).


Unclassified Devices

An unclassified device is a preamendments device for which a classification regulation has not been promulgated. Unclassified devices require submission of a 510(k) Premarket Notification to the CDRH. Until the unclassified device type has been formally classified and a regulation established, marketing of new devices within this type will require submission of a 510(k) Premarket Notification to the FDA. Once classified, these devices may require submission of a PMA application, a 510(k), or be exempt from any premarket submission requirement.


Not-Classified Devices

A not-classified device is a postamendments device for which the agency has not yet reviewed a marketing application or for which the agency has not made a final decision on such a marketing application.


56.4.6 Classification Product Code


Classification product codes are a method of internally classifying and tracking medical devices used by the FDA and are also used for import/export purposes [14]. CDRH-regulated medical device product codes consist of a 3-letter combination which associates a device’s type with a product classification. Classification product codes help to delineate technology and indication subgroups within a regulation and may be identified using the product classification database on the FDA’s website [15]. Classification product codes are a key element with respect to many aspects of device regulation including the reporting of adverse events and product problems in medical device reports (MDRs).


56.4.7 Major Regulatory Pathways for Medical Devices


The pathways to market for a medical device in the United Sates [16] are often complex from the perspective of someone outside of regulatory affairs and depend on multiple factors including device classification, existence of similar devices previously classified for use by the FDA, the identified target population, and the date at which a device was first legally marketed (Table 56.3).


Table 56.3
Comparison of 510(k), PMA, and HUD/HDE regulatory pathways
















































 
510(k)

PMA

HUD/HDE

Approval benchmark

Substantial equivalence

Safety and effectiveness

Safety and probable benefit

Clinical data requirements

Requirement limited to a small percentage of submissions

Clinical data generally required

Randomized controlled trial design is common

Clinical data generally required

Often limited to single-arm trial with safety and feasibility assessments

Population

Unrestricted

Unrestricted

Disease affects less than 4000 patients per year

No similar device available through 510(k) or PMA

Requirement for IRB approval after marketing

None

None

Yes

User fees required

Yes

Yes

No

Profit restriction for device manufacturers

No

No

Device may be sold for profit if the number of devices distributed in calendar year does not exceed the ADNa

FDA review cycle time

90 days

180 days

75 days

Sep 22, 2016 | Posted by in NEUROSURGERY | Comments Off on Regulatory Policies Regarding Pediatric Spinal Devices

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