Urologic Oncology: Seminars and Original Investigations ] (2014) ∎∎∎–∎∎∎
Seminar article
Medical devices: US medical device regulation Jonathan P. Jarow, M.D.*, John H. Baxley, M.S. US Food and Drug Administration, Silver Spring, MD
Abstract Medical devices are regulated by the US Food and Drug Administration (FDA) within the Center for Devices and Radiological Health. Center for Devices and Radiological Health is responsible for protecting and promoting the public health by ensuring the safety, effectiveness, and quality of medical devices, ensuring the safety of radiation-emitting products, fostering innovation, and providing the public with accurate, science-based information about the products we oversee, throughout the total product life cycle. The FDA was granted the authority to regulate the manufacturing and marketing of medical devices in 1976. It does not regulate the practice of medicine. Devices are classified based on complexity and level of risk, and “pre-1976” devices were allowed to remain on the market after being classified without FDA review. Post-1976 devices of lower complexity and risk that are substantially equivalent to a marketed “predicate” device may be cleared through the 510(k) premarket notification process. Clinical data are typically not needed for 510(k) clearance. In contrast, higherrisk devices typically require premarket approval. Premarket approval applications must contain data demonstrating reasonable assurance of safety and efficacy, and this information typically includes clinical data. For novel devices that are not high risk, the de novo process allows FDA to simultaneously review and classify new devices. Devices that are not legally marketed are permitted to be used for clinical investigation purposes in the United States under the Investigational Device Exemptions regulation. Published by Elsevier Inc.
Keywords: Medical devices; Regulations; Investigational device exemption
Introduction The Food and Drug Administration (FDA) regulates approximately 25 cents of every dollar spent by US consumers, 75% of this comprises food. The scope of FDA regulation includes food (Center for Food Safety and Applied Nutrition), tobacco (Center for Tobacco Products), veterinary medicine and feed (Center for Veterinary Medicine), drugs and biologics (Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research), and the focus of this article—medical devices and radiological products (Center for Devices and Radiological Health). The Center for Devices and Radiological Health protects Americans with safeguards to ensure that medical devices and radiation-emitting products are reasonably safe to use and that they work as intended [1]. The
Corresponding author. Tel./fax: þ1-301-796-0149. E-mail address: [email protected] (J.P. Jarow). *
http://dx.doi.org/10.1016/j.urolonc.2014.10.004 1078-1439/Published by Elsevier Inc.
purpose of this review is to provide a high-level summary of the regulation of medical devices (Table). The FDA was granted the authority to regulate devices in the 1976 Medical Device Amendments of the Food Drug and Cosmetic (FD&C) Act passed by Congress [2,3]. Before the Medical Device Amendments, the FDA could bring charges of adulteration or misbranding, but it did not have the authority to request premarket testing, review, or approval. Subsequent laws, most recently the FDA Safety and Innovation Act of 2012, have modified FDA's medical device authority [4].
What is a medical device? Medical devices range from simple tongue depressors to complex technologies such as computer-assisted (robotic) surgical systems. In addition, medical devices include in vitro diagnostic products and radiation-emitting products for therapy and medical imaging. A medical device is defined as “an instrument, apparatus, implement, machine,
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J.P. Jarow, J.H. Baxley / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–5
Table Summary of the FDA device regulation process Step 1 Determine whether the product is a medical device Step 2 Identify the device class
Defined in Section 201(h) of the FD&C Act Class I Low risk of harm to the user Subject to general controls Typically exempt from premarket notification (i.e., “510(k)”) Class II Moderate risk of harm Subject to general and specific controls Typically require 510(k) Class III High risk of harm Typically require premarket approval (i.e., “PMA”) Step 3 Identify the premarket pathway 510(k) process “Substantial equivalence” to a legally marketed predicate device PMA process “Reasonable assurance of safety and effectiveness” based on submitted studies De novo request For low-to-moderate risk devices that do not have a legally marketed predicate device Risk-based classification into Class I or II Future devices of this type are reviewed in the 510(k) process Step 4 If clinical data need to be collected before commercialization, Allows manufacturers to collect safety and effectiveness data on an investigational submit an investigational device exemption device to support a future marketing submission (510(k), PMA, or de novo) (IDE) application Purpose of the IDE review is to ensure the safety and welfare of human research subjects
contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:
here, the antimicrobial-eluting urinary catheter is regulated as a device, whereas the 2 others are regulated as drugs.
recognized in the official National Formulary, or the
How are medical devices classified?
United States Pharmacopoeia, or any supplement to them;
intended for use in the diagnosis of disease or other
conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals; or intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes” [5].
Sometimes the use of a medical device also requires the use of a drug or biologic product to achieve its intended effect, forming a combination product [6]. The 2 components could be physically combined, such as in an antimicrobial-eluting urinary catheter, or they may be copackaged such as a drug and syringe used for administration of gonadotropin-releasing hormone analogues. The combination product rule also applies to components that are packaged separately but, according to its intended use and labeling, are used together. An example of this is systemically administered photosensitizing agent and a light source for intracorporeal photodynamic therapy, neither of which alone would have the intended effect. The regulation of a combination product is determined by the component with the primary mode of action [7]. For the examples listed
Medical devices are classified and regulated according to their complexity and degree of risk to the public. This classification scheme determines the requirements for marketing a device in the United States. The use of the term “marketed” is intentional as the FDA does not regulate the practice of medicine but rather the sale, distribution, and promotion of medical products. There are 3 FDA regulatory classifications of medical devices: Class I, Class II, and Class III [8]. The classifications are assigned by the risk the medical device presents to the patient and the level of regulatory control the FDA determines is needed to legally market the device. As the classification level increases, the risk to the patient and the degree of FDA regulatory control increase. The categories of medical devices that were marketed in the United States as of May 28, 1976, the date of passage of the Medical Device Amendments, were classified by FDA and were permitted to remain on the market. New medical devices entering the market after May 28, 1976, are classified through comparison with legally marketed medical devices with respect to intended use and technological characteristics. In the absence of a suitable comparable device, commonly referred to as the “predicate,” the device is automatically placed into the highest regulatory class (Class III, described further) until FDA reclassifies the device using a risk-based approach (if appropriate).
J.P. Jarow, J.H. Baxley / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–5
Class I provides the lowest level of regulatory control and is intended for devices for which there is sufficient information to conclude that safety and effectiveness can reasonably be ensured by General Controls alone. General Controls are defined in the Medical Device Amendments and include enforcement authority for misbranding, adulteration, registration and listing, device banning, consumer notification and recall, product reporting, premarket notification, and good manufacturing practices. Class I devices present minimal potential harm to the user and are typically simple in design and have a history of safe use. Examples of Class I devices include manual surgical instruments such as clamps and retractors, hand-operated urological tables, and manual biopsy forceps. Most Class I devices are exempt from the requirement for premarket notification (more commonly referred to as the “510(k)” submission; described further in the next section) and may also be exempt from compliance with the good manufacturing practice requirements of the quality system regulation. Medical devices designated as Class II are devices for which General Controls alone are not sufficient to reasonably ensure safety and effectiveness, but for which there is sufficient information to establish Special Controls to provide this assurance. Therefore, in addition to General Controls, these devices are subject to one or more Special Controls. Special Controls include the following:
special labeling requirements, mandatory performance standards, both International and United States,
postmarket surveillance, and FDA guidance documents. Although Class II devices typically require FDA review and clearance of a 510(k) submission before marketing, a few of them are exempt from the 510(k). Information on Class II exempt devices is located within the device regulations, 21 Code of Federal Regulations 862 through 892. Examples of Class II devices include urinary catheters, cryotherapy systems, x-ray systems, brachytherapy seed implants, and computer-assisted (robotic) surgical systems. Class III medical devices pose the most risk, and, therefore, are subject to the most stringent regulatory controls. For Class III medical devices, sufficient information is not available to ensure safety and effectiveness through the application of General and Special Controls. Instead, in addition to General Controls, these devices require FDA review and approval of a premarket approval (PMA) application before marketing. Class III devices support or sustain human life, are of substantial importance in preventing impairment of human health, or present a potential unreasonable risk of illness or injury to the patient. Additionally, as previously noted, devices that are not substantially equivalent to a predicate through the 510(k) process are automatically Class III by statute until reclassified by FDA through a risk-based review process. Examples
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of Class III devices that require a PMA are transurethral microwave thermotherapy (TUMT) systems for the benign prostatic hyperplasia (BPH), inflatable penile implants for erectile dysfunction, and high-intensity focused ultrasound systems for uterine fibroid ablation.
510(k) Pathway to marketing A 510(k) is a premarket notification made to the FDA to demonstrate that the device to be marketed is at least as safe and effective, i.e., substantially equivalent, to a legally marketed “predicate” device [9]. As described earlier, this is the premarket review process that is required for most Class II, and some Class I, devices. Most new medical devices proceed to market through the 510(k) process. In a 510(k), submitters must compare their “new” device to at least 1 similar legally marketed device and provide information to support their substantial equivalency claims. A legally marketed device is (1) a device that was legally marketed in the United States before May 28, 1976 (preamendments device), for which a PMA is not required; (2) a device which has been reclassified from Class III to Class II or I; or (3) a device that FDA previously found substantially equivalent through the 510(k) process. Legally marketed also means that the predicate cannot be one that is in violation of the FD&C Act. A device is substantially equivalent if, in comparison with a predicate, it has the same intended use as the predicate and has the same technological characteristics as the predicate or it has the same intended use as the predicate and has different technological characteristics, and the information submitted to FDA does not raise different questions of safety and effectiveness and demonstrates that the device is at least as safe and effective as the legally marketed device [10]. Before marketing a device, each submitter must receive an order, in the form of a letter, from the FDA that finds the device to be substantially equivalent and states that the device can be sold in the United States. This order “clears” the device for commercial distribution. Clinical studies can be used, but are typically not required, to support a finding of substantial equivalence. The following examples illustrate 2 devices types that proceeded to market via the 510(k) process: Brachytherapy seed implants were legally marketed before 1976. The medical device available before 1976, although similar in principle of operation and intended use, looks nothing like that used today. The seed implants available in 1976 were large radioactive pellets and were inserted during open surgery for the treatment of various cancers including prostate cancer. This medical device was classified as Class II, allowing technological modifications such as decreasing the size of the pellets, needle-loading, and advances in dosimetry
J.P. Jarow, J.H. Baxley / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–5
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planning to be cleared as substantially equivalent in a stepwise process. The computer-assisted (robotic) surgical system [11] is also classified as Class II. Laparoscopes and accessories used for laparoscopic surgery were legally marketed before 1976 and were classified as Class II. The shift from manual control to computer-assisted control of these devices, while technologically complex, was viewed as a design enhancement that does not change the basic function of this surgical tool. Therefore, substantial equivalence was evaluated in its equivalent ability to perform similar surgical tasks. PMA process PMA is the FDA process of scientific and regulatory review to independently evaluate the safety and effectiveness of Class III medical devices [12]. The evidentiary standard for PMA approval is reasonable assurance, based on valid scientific evidence, that the device is safe and effective for its intended use(s). This standard is slightly different from that of drugs or biologics, which require substantial evidence of safety and effectiveness. The substantial evidence standard for drugs and biologics has been interpreted to mean at least 2 positive randomized controlled studies [13]. In contrast, the valid scientific evidence used to establish reasonable assurance of safety and effectiveness can include any or all of the following: randomized controlled trials, single-arm studies, well-documented case series, and reports of significant human experience [14]. Isolated case reports, random experience, reports lacking sufficient details to permit scientific evaluation, and unsubstantiated opinions do not qualify as valid scientific evidence. The following example describes a device type that requires PMA approval: TUMT for the treatment of BPH was not legally marketed in the United States before 1976. Therefore, there are no substantially equivalent predicate devices intended for the treatment of BPH available on which to base a 510(k) premarket notification. Furthermore, this type of device carries high risk because of the risk of serious injury to extraprostatic structures from excess uncontrolled heating. The device was classified as Class III and PMA applications are required for marketing. These PMA applications require support by valid scientific evidence (i.e., a clinical trial) to demonstrate that each new TUMT system has reasonable assurance of safety and effectiveness. (Note: The first PMA for a TUMT device was received before the de novo provisions of the FD&C Act, which are discussed further in the next section.) De novo requests Devices of a new type that FDA has not previously classified based on risk are “automatically” or
“statutorily” classified into Class III by operation of section 513(f)(1) of the FD&C Act, regardless of the level of risk they pose. This is because, by definition, a new type of device would not be within a type that was on the market before the 1976 Medical Device Amendments or that has since been classified into Class I or Class II. In 1997, Congress enacted the FDA Modernization Act, which added a new path to market for new, lower risk device types that automatically fall into Class III. This process is referred to as de novo classification and was further amended with passage of the FDA Safety and Innovation Act in 2012 [15]. FDA reviews de novo requests for new categories of devices that are not high risk if they meet 2 threshold criteria. The first is that the new device is not within a device type that has previously been classified based on risk. In addition, the following additional criteria should be met for a new device for which a de novo request is submitted:
The new device should be low-to-moderate risk and
likely to meet the statutory standards for classification into Class I or Class II under section 513(a)(1) of the FD&C Act, e.g., General or Special controls would provide reasonable assurance of the safety and effectiveness of the device and The risks and benefits of the new device are sufficiently understood, such that all risks can be effectively mitigated through the application of General or Special controls.
If these criteria are met, FDA will grant the de novo, creating a new Class I or Class II regulation for this new type of device [16]. Future devices within this device type can be cleared through the regular 510(k) process using the de novo device as the “predicate.” The example below illustrates a case where a device entered the market via the de novo process: Capsule camera systems for imaging the gastrointestinal tract did not exist before 1976, and, therefore, were not originally classified by FDA. As a result, when the first such system was proposed for marketing (after the 1997 de novo provisions to the FD&C Act), there was no substantially equivalent predicate device to support 510(k) clearance, a de novo was submitted for this device. The provided studies demonstrated that gastrointestinal capsule camera systems have low-tomoderate risks, which could be mitigated by certain Special controls such as specific bench studies and labeling statements. This de novo was granted, classifying this new device type into Class II and establishing this new capsule camera system as a predicate device that can be used in future 510(k)s for subsequent devices.
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When is an investigational device exemption needed and determination of significant risk An investigational device exemption (IDE) application is a request to conduct clinical research on an investigational device with “significant” risk in the United States [17]. The IDE exempts certain regulatory requirements and allows an investigational medical device to be shipped lawfully to clinical study sites and is the main vehicle by which clinical evidence may be collected to support a future marketing application. The purpose of an IDE is to ensure the safety and welfare of human research subjects. The IDE should include the clinical protocol, risk analysis, informed consent, and investigational labeling. Devices with “significant” risk require both an IDE approval by the FDA and an institutional review board (IRB) approval, whereas use of investigational devices without significant risk requires IRB approval only. The following attributes of a medical device connote significant risk [18]:
it is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject;
it is purported or represented to be for a use in supporting
or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject; it is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or it otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.
For example, new devices used to ablate prostatic tissue in the treatment of localized prostate cancer may pose significant risk of injury, and, therefore, typically require submitting an IDE application to FDA for investigation within the United States. In contrast, investigating the use of a new manual surgical instrument during an otherwise traditional radical prostatectomy procedure would typically not pose a significant risk, and, therefore, may proceed following IRB approval without FDA approval of an IDE application. Conclusion Since 1976, the FDA has been responsible for ensuring the safety and effectiveness of medical devices in the
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United States. An underlying concept of its medical device regulatory framework is the classification of devices into Class I, II, or III. Various pathways to market are available for new devices entering the market (such as 510 (k), PMA, and de novo) depending on multiple factors including the device's classification, the availability of a substantially equivalent predicate, and the level of risk. Before commercialization, investigational devices may be clinically investigated within the United States through the IDE process.
References [1] Kessler L, Richter K. Technology assessment of medical devices at the Center for Devices and Radiological Health. Am J Manag Care 1998;4:(Spec No:SP129–35). [2] Medical device amendments of 1976 to the Federal Food, Drug, and Cosmetic Act. Pub Law No. 94-295, 90 Stat 539 (1976). [3] Monsein LH. Primer on medical device regulation. Part I. History and background. Radiology 1997;205:1–9. [4] FDA Safety and Innovation Act. Available at: http://www.fda.gov/ MedicalDevices/DeviceRegulationandGuidance/Overview/ucm310 927.htm. [5] Food, Drug, and Cosmetic Act. 21 U.S.C. Section 201(h). [6] Combination Products Definition. Available at: http://www.fda. gov/CombinationProducts/AboutCombinationProducts/ucm118332. htm. [7] 21 CFR Part 3. [8] 21 CFR 860. [9] 21 CFR 807 Subpart E. [10] Food, Drug, and Cosmetic Act. 21 U.S.C. Section 513(i). [11] Computer-Assisted (Robotic) Surgical Systems. Available at: http:// www.fda.gov/medicaldevices/productsandmedicalprocedures/surger yandlifesupport/computerassistedroboticsurgicalsystems/default.htm. [12] 21 CFR Part 814. [13] Guidance for industry: providing clinical evidence of effectiveness for human drug and biological products. Available at: http://www.fda. gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM078749.pdf. [14] 21 CFR 860.7. [15] Evaluation of automatic class III designation (de novo) summaries. Available at: http://www.fda.gov/aboutfda/centersoffices/officeofmedi calproductsandtobacco/cdrh/cdrhtransparency/ucm232269.htm. [16] New Section 513(f)(2)—Evaluation of automatic class III designation, guidance for industry and CDRH staff. Available at: http://www.fda. gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocu ments/ucm080195.htm. [17] 21 CFR 812. [18] 21 CFR 812.3(m).
Seminar article
Medical devices: US medical device regulation Jonathan P. Jarow, M.D.*, John H. Baxley, M.S. US Food and Drug Administration, Silver Spring, MD
Abstract Medical devices are regulated by the US Food and Drug Administration (FDA) within the Center for Devices and Radiological Health. Center for Devices and Radiological Health is responsible for protecting and promoting the public health by ensuring the safety, effectiveness, and quality of medical devices, ensuring the safety of radiation-emitting products, fostering innovation, and providing the public with accurate, science-based information about the products we oversee, throughout the total product life cycle. The FDA was granted the authority to regulate the manufacturing and marketing of medical devices in 1976. It does not regulate the practice of medicine. Devices are classified based on complexity and level of risk, and “pre-1976” devices were allowed to remain on the market after being classified without FDA review. Post-1976 devices of lower complexity and risk that are substantially equivalent to a marketed “predicate” device may be cleared through the 510(k) premarket notification process. Clinical data are typically not needed for 510(k) clearance. In contrast, higherrisk devices typically require premarket approval. Premarket approval applications must contain data demonstrating reasonable assurance of safety and efficacy, and this information typically includes clinical data. For novel devices that are not high risk, the de novo process allows FDA to simultaneously review and classify new devices. Devices that are not legally marketed are permitted to be used for clinical investigation purposes in the United States under the Investigational Device Exemptions regulation. Published by Elsevier Inc.
Keywords: Medical devices; Regulations; Investigational device exemption
Introduction The Food and Drug Administration (FDA) regulates approximately 25 cents of every dollar spent by US consumers, 75% of this comprises food. The scope of FDA regulation includes food (Center for Food Safety and Applied Nutrition), tobacco (Center for Tobacco Products), veterinary medicine and feed (Center for Veterinary Medicine), drugs and biologics (Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research), and the focus of this article—medical devices and radiological products (Center for Devices and Radiological Health). The Center for Devices and Radiological Health protects Americans with safeguards to ensure that medical devices and radiation-emitting products are reasonably safe to use and that they work as intended [1]. The
Corresponding author. Tel./fax: þ1-301-796-0149. E-mail address: [email protected] (J.P. Jarow). *
http://dx.doi.org/10.1016/j.urolonc.2014.10.004 1078-1439/Published by Elsevier Inc.
purpose of this review is to provide a high-level summary of the regulation of medical devices (Table). The FDA was granted the authority to regulate devices in the 1976 Medical Device Amendments of the Food Drug and Cosmetic (FD&C) Act passed by Congress [2,3]. Before the Medical Device Amendments, the FDA could bring charges of adulteration or misbranding, but it did not have the authority to request premarket testing, review, or approval. Subsequent laws, most recently the FDA Safety and Innovation Act of 2012, have modified FDA's medical device authority [4].
What is a medical device? Medical devices range from simple tongue depressors to complex technologies such as computer-assisted (robotic) surgical systems. In addition, medical devices include in vitro diagnostic products and radiation-emitting products for therapy and medical imaging. A medical device is defined as “an instrument, apparatus, implement, machine,
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J.P. Jarow, J.H. Baxley / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–5
Table Summary of the FDA device regulation process Step 1 Determine whether the product is a medical device Step 2 Identify the device class
Defined in Section 201(h) of the FD&C Act Class I Low risk of harm to the user Subject to general controls Typically exempt from premarket notification (i.e., “510(k)”) Class II Moderate risk of harm Subject to general and specific controls Typically require 510(k) Class III High risk of harm Typically require premarket approval (i.e., “PMA”) Step 3 Identify the premarket pathway 510(k) process “Substantial equivalence” to a legally marketed predicate device PMA process “Reasonable assurance of safety and effectiveness” based on submitted studies De novo request For low-to-moderate risk devices that do not have a legally marketed predicate device Risk-based classification into Class I or II Future devices of this type are reviewed in the 510(k) process Step 4 If clinical data need to be collected before commercialization, Allows manufacturers to collect safety and effectiveness data on an investigational submit an investigational device exemption device to support a future marketing submission (510(k), PMA, or de novo) (IDE) application Purpose of the IDE review is to ensure the safety and welfare of human research subjects
contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:
here, the antimicrobial-eluting urinary catheter is regulated as a device, whereas the 2 others are regulated as drugs.
recognized in the official National Formulary, or the
How are medical devices classified?
United States Pharmacopoeia, or any supplement to them;
intended for use in the diagnosis of disease or other
conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals; or intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes” [5].
Sometimes the use of a medical device also requires the use of a drug or biologic product to achieve its intended effect, forming a combination product [6]. The 2 components could be physically combined, such as in an antimicrobial-eluting urinary catheter, or they may be copackaged such as a drug and syringe used for administration of gonadotropin-releasing hormone analogues. The combination product rule also applies to components that are packaged separately but, according to its intended use and labeling, are used together. An example of this is systemically administered photosensitizing agent and a light source for intracorporeal photodynamic therapy, neither of which alone would have the intended effect. The regulation of a combination product is determined by the component with the primary mode of action [7]. For the examples listed
Medical devices are classified and regulated according to their complexity and degree of risk to the public. This classification scheme determines the requirements for marketing a device in the United States. The use of the term “marketed” is intentional as the FDA does not regulate the practice of medicine but rather the sale, distribution, and promotion of medical products. There are 3 FDA regulatory classifications of medical devices: Class I, Class II, and Class III [8]. The classifications are assigned by the risk the medical device presents to the patient and the level of regulatory control the FDA determines is needed to legally market the device. As the classification level increases, the risk to the patient and the degree of FDA regulatory control increase. The categories of medical devices that were marketed in the United States as of May 28, 1976, the date of passage of the Medical Device Amendments, were classified by FDA and were permitted to remain on the market. New medical devices entering the market after May 28, 1976, are classified through comparison with legally marketed medical devices with respect to intended use and technological characteristics. In the absence of a suitable comparable device, commonly referred to as the “predicate,” the device is automatically placed into the highest regulatory class (Class III, described further) until FDA reclassifies the device using a risk-based approach (if appropriate).
J.P. Jarow, J.H. Baxley / Urologic Oncology: Seminars and Original Investigations ] (2014) 1–5
Class I provides the lowest level of regulatory control and is intended for devices for which there is sufficient information to conclude that safety and effectiveness can reasonably be ensured by General Controls alone. General Controls are defined in the Medical Device Amendments and include enforcement authority for misbranding, adulteration, registration and listing, device banning, consumer notification and recall, product reporting, premarket notification, and good manufacturing practices. Class I devices present minimal potential harm to the user and are typically simple in design and have a history of safe use. Examples of Class I devices include manual surgical instruments such as clamps and retractors, hand-operated urological tables, and manual biopsy forceps. Most Class I devices are exempt from the requirement for premarket notification (more commonly referred to as the “510(k)” submission; described further in the next section) and may also be exempt from compliance with the good manufacturing practice requirements of the quality system regulation. Medical devices designated as Class II are devices for which General Controls alone are not sufficient to reasonably ensure safety and effectiveness, but for which there is sufficient information to establish Special Controls to provide this assurance. Therefore, in addition to General Controls, these devices are subject to one or more Special Controls. Special Controls include the following:
special labeling requirements, mandatory performance standards, both International and United States,
postmarket surveillance, and FDA guidance documents. Although Class II devices typically require FDA review and clearance of a 510(k) submission before marketing, a few of them are exempt from the 510(k). Information on Class II exempt devices is located within the device regulations, 21 Code of Federal Regulations 862 through 892. Examples of Class II devices include urinary catheters, cryotherapy systems, x-ray systems, brachytherapy seed implants, and computer-assisted (robotic) surgical systems. Class III medical devices pose the most risk, and, therefore, are subject to the most stringent regulatory controls. For Class III medical devices, sufficient information is not available to ensure safety and effectiveness through the application of General and Special Controls. Instead, in addition to General Controls, these devices require FDA review and approval of a premarket approval (PMA) application before marketing. Class III devices support or sustain human life, are of substantial importance in preventing impairment of human health, or present a potential unreasonable risk of illness or injury to the patient. Additionally, as previously noted, devices that are not substantially equivalent to a predicate through the 510(k) process are automatically Class III by statute until reclassified by FDA through a risk-based review process. Examples
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of Class III devices that require a PMA are transurethral microwave thermotherapy (TUMT) systems for the benign prostatic hyperplasia (BPH), inflatable penile implants for erectile dysfunction, and high-intensity focused ultrasound systems for uterine fibroid ablation.
510(k) Pathway to marketing A 510(k) is a premarket notification made to the FDA to demonstrate that the device to be marketed is at least as safe and effective, i.e., substantially equivalent, to a legally marketed “predicate” device [9]. As described earlier, this is the premarket review process that is required for most Class II, and some Class I, devices. Most new medical devices proceed to market through the 510(k) process. In a 510(k), submitters must compare their “new” device to at least 1 similar legally marketed device and provide information to support their substantial equivalency claims. A legally marketed device is (1) a device that was legally marketed in the United States before May 28, 1976 (preamendments device), for which a PMA is not required; (2) a device which has been reclassified from Class III to Class II or I; or (3) a device that FDA previously found substantially equivalent through the 510(k) process. Legally marketed also means that the predicate cannot be one that is in violation of the FD&C Act. A device is substantially equivalent if, in comparison with a predicate, it has the same intended use as the predicate and has the same technological characteristics as the predicate or it has the same intended use as the predicate and has different technological characteristics, and the information submitted to FDA does not raise different questions of safety and effectiveness and demonstrates that the device is at least as safe and effective as the legally marketed device [10]. Before marketing a device, each submitter must receive an order, in the form of a letter, from the FDA that finds the device to be substantially equivalent and states that the device can be sold in the United States. This order “clears” the device for commercial distribution. Clinical studies can be used, but are typically not required, to support a finding of substantial equivalence. The following examples illustrate 2 devices types that proceeded to market via the 510(k) process: Brachytherapy seed implants were legally marketed before 1976. The medical device available before 1976, although similar in principle of operation and intended use, looks nothing like that used today. The seed implants available in 1976 were large radioactive pellets and were inserted during open surgery for the treatment of various cancers including prostate cancer. This medical device was classified as Class II, allowing technological modifications such as decreasing the size of the pellets, needle-loading, and advances in dosimetry
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planning to be cleared as substantially equivalent in a stepwise process. The computer-assisted (robotic) surgical system [11] is also classified as Class II. Laparoscopes and accessories used for laparoscopic surgery were legally marketed before 1976 and were classified as Class II. The shift from manual control to computer-assisted control of these devices, while technologically complex, was viewed as a design enhancement that does not change the basic function of this surgical tool. Therefore, substantial equivalence was evaluated in its equivalent ability to perform similar surgical tasks. PMA process PMA is the FDA process of scientific and regulatory review to independently evaluate the safety and effectiveness of Class III medical devices [12]. The evidentiary standard for PMA approval is reasonable assurance, based on valid scientific evidence, that the device is safe and effective for its intended use(s). This standard is slightly different from that of drugs or biologics, which require substantial evidence of safety and effectiveness. The substantial evidence standard for drugs and biologics has been interpreted to mean at least 2 positive randomized controlled studies [13]. In contrast, the valid scientific evidence used to establish reasonable assurance of safety and effectiveness can include any or all of the following: randomized controlled trials, single-arm studies, well-documented case series, and reports of significant human experience [14]. Isolated case reports, random experience, reports lacking sufficient details to permit scientific evaluation, and unsubstantiated opinions do not qualify as valid scientific evidence. The following example describes a device type that requires PMA approval: TUMT for the treatment of BPH was not legally marketed in the United States before 1976. Therefore, there are no substantially equivalent predicate devices intended for the treatment of BPH available on which to base a 510(k) premarket notification. Furthermore, this type of device carries high risk because of the risk of serious injury to extraprostatic structures from excess uncontrolled heating. The device was classified as Class III and PMA applications are required for marketing. These PMA applications require support by valid scientific evidence (i.e., a clinical trial) to demonstrate that each new TUMT system has reasonable assurance of safety and effectiveness. (Note: The first PMA for a TUMT device was received before the de novo provisions of the FD&C Act, which are discussed further in the next section.) De novo requests Devices of a new type that FDA has not previously classified based on risk are “automatically” or
“statutorily” classified into Class III by operation of section 513(f)(1) of the FD&C Act, regardless of the level of risk they pose. This is because, by definition, a new type of device would not be within a type that was on the market before the 1976 Medical Device Amendments or that has since been classified into Class I or Class II. In 1997, Congress enacted the FDA Modernization Act, which added a new path to market for new, lower risk device types that automatically fall into Class III. This process is referred to as de novo classification and was further amended with passage of the FDA Safety and Innovation Act in 2012 [15]. FDA reviews de novo requests for new categories of devices that are not high risk if they meet 2 threshold criteria. The first is that the new device is not within a device type that has previously been classified based on risk. In addition, the following additional criteria should be met for a new device for which a de novo request is submitted:
The new device should be low-to-moderate risk and
likely to meet the statutory standards for classification into Class I or Class II under section 513(a)(1) of the FD&C Act, e.g., General or Special controls would provide reasonable assurance of the safety and effectiveness of the device and The risks and benefits of the new device are sufficiently understood, such that all risks can be effectively mitigated through the application of General or Special controls.
If these criteria are met, FDA will grant the de novo, creating a new Class I or Class II regulation for this new type of device [16]. Future devices within this device type can be cleared through the regular 510(k) process using the de novo device as the “predicate.” The example below illustrates a case where a device entered the market via the de novo process: Capsule camera systems for imaging the gastrointestinal tract did not exist before 1976, and, therefore, were not originally classified by FDA. As a result, when the first such system was proposed for marketing (after the 1997 de novo provisions to the FD&C Act), there was no substantially equivalent predicate device to support 510(k) clearance, a de novo was submitted for this device. The provided studies demonstrated that gastrointestinal capsule camera systems have low-tomoderate risks, which could be mitigated by certain Special controls such as specific bench studies and labeling statements. This de novo was granted, classifying this new device type into Class II and establishing this new capsule camera system as a predicate device that can be used in future 510(k)s for subsequent devices.
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When is an investigational device exemption needed and determination of significant risk An investigational device exemption (IDE) application is a request to conduct clinical research on an investigational device with “significant” risk in the United States [17]. The IDE exempts certain regulatory requirements and allows an investigational medical device to be shipped lawfully to clinical study sites and is the main vehicle by which clinical evidence may be collected to support a future marketing application. The purpose of an IDE is to ensure the safety and welfare of human research subjects. The IDE should include the clinical protocol, risk analysis, informed consent, and investigational labeling. Devices with “significant” risk require both an IDE approval by the FDA and an institutional review board (IRB) approval, whereas use of investigational devices without significant risk requires IRB approval only. The following attributes of a medical device connote significant risk [18]:
it is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject;
it is purported or represented to be for a use in supporting
or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject; it is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or it otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.
For example, new devices used to ablate prostatic tissue in the treatment of localized prostate cancer may pose significant risk of injury, and, therefore, typically require submitting an IDE application to FDA for investigation within the United States. In contrast, investigating the use of a new manual surgical instrument during an otherwise traditional radical prostatectomy procedure would typically not pose a significant risk, and, therefore, may proceed following IRB approval without FDA approval of an IDE application. Conclusion Since 1976, the FDA has been responsible for ensuring the safety and effectiveness of medical devices in the
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United States. An underlying concept of its medical device regulatory framework is the classification of devices into Class I, II, or III. Various pathways to market are available for new devices entering the market (such as 510 (k), PMA, and de novo) depending on multiple factors including the device's classification, the availability of a substantially equivalent predicate, and the level of risk. Before commercialization, investigational devices may be clinically investigated within the United States through the IDE process.
References [1] Kessler L, Richter K. Technology assessment of medical devices at the Center for Devices and Radiological Health. Am J Manag Care 1998;4:(Spec No:SP129–35). [2] Medical device amendments of 1976 to the Federal Food, Drug, and Cosmetic Act. Pub Law No. 94-295, 90 Stat 539 (1976). [3] Monsein LH. Primer on medical device regulation. Part I. History and background. Radiology 1997;205:1–9. [4] FDA Safety and Innovation Act. Available at: http://www.fda.gov/ MedicalDevices/DeviceRegulationandGuidance/Overview/ucm310 927.htm. [5] Food, Drug, and Cosmetic Act. 21 U.S.C. Section 201(h). [6] Combination Products Definition. Available at: http://www.fda. gov/CombinationProducts/AboutCombinationProducts/ucm118332. htm. [7] 21 CFR Part 3. [8] 21 CFR 860. [9] 21 CFR 807 Subpart E. [10] Food, Drug, and Cosmetic Act. 21 U.S.C. Section 513(i). [11] Computer-Assisted (Robotic) Surgical Systems. Available at: http:// www.fda.gov/medicaldevices/productsandmedicalprocedures/surger yandlifesupport/computerassistedroboticsurgicalsystems/default.htm. [12] 21 CFR Part 814. [13] Guidance for industry: providing clinical evidence of effectiveness for human drug and biological products. Available at: http://www.fda. gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM078749.pdf. [14] 21 CFR 860.7. [15] Evaluation of automatic class III designation (de novo) summaries. Available at: http://www.fda.gov/aboutfda/centersoffices/officeofmedi calproductsandtobacco/cdrh/cdrhtransparency/ucm232269.htm. [16] New Section 513(f)(2)—Evaluation of automatic class III designation, guidance for industry and CDRH staff. Available at: http://www.fda. gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocu ments/ucm080195.htm. [17] 21 CFR 812. [18] 21 CFR 812.3(m).
