A. Introduction

The premarket regulatory framework for cardiovascular devices differs from the premarket processes for cardiovascular drug and biological products. Perhaps the biggest reason for this is because drugs/biologics clearly differ from devices in terms of the means by which they accomplish their intended clinical use. In the 1976 Medical Device Amendments found in §201(h) of the Food, Drug and Cosmetic Act (FDCA) (1), the FDA specifically defined a medical device as: “an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is (emphasis added): (i) recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them; (ii) 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 (iii) intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of 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.”

Under the same 1976 amendments, medical devices were further segmented by a risk-based classification scheme consisting of three device classes. The established nomenclature used by FDA for the three-tiered medical device classes in the U.S. market is, from lowest to highest risk, Class I, Class II, and Class III. Determination of the level of risk, and therefore device classification category, is highly dependent on the degree of regulatory controls needed to provide reasonable assurance of safety and effectiveness (S&E) of the device as outlined in section 513 of FDCA. The classification category also drives the premarket submission required to be submitted to FDA before the device enters interstate commerce in the U.S. Each class will be discussed in more detail, but overall, Class I devices are only subject to general controls and are typically (but not always) exempted from premarket notification (commonly referred to as 510(k)); Class II devices, in addition to meeting general controls, also may require special controls and typically (but not always) require submission of a 510(k) and FDA clearance before going to market; and Class III devices typically require a premarket approval (PMA) application and FDA approval before being allowed to market the product in the U.S.

Since the inception of the 1976 Medical Device Amendments, CDRH has established classification regulations for more than 1,700 types of devices grouped into 18 medical specialties, referred to as panels. One of these panels, the Circulatory System Devices Panel or Cardiovascular Panel, is dedicated specifically to cardiovascular devices, under part 870 of the Code of Federal Regulations (21 CFR 870) (25). Information on previously classified cardiovascular devices is available in publicly-searchable databases (24, 25). Because most devices that will enter the market are typically not entirely new, these databases help answer the question “Is there a similar cardiovascular device already on the market?”, and whether there is an established classification with a regulation number for similar devices. The answer to this question can be used to help identify the correct classification of the new device (Fig. 1). Thus, these databases are important tools for any manufacturer or investigator planning to design, develop, sell, and/or use, in an investigative or non-investigative manner, a cardiovascular medical device and it is a good starting point to begin an interaction with FDA to initiate the premarket review process.

Figure 1 – Overview of Device Classification: This flowchart illustrates the initial thought process that can be used by investigators or manufacturers to help identify a possible classification for their medical device before submitting a premarket application to FDA. Alternate pathways, if applicable, include the classification process via a de novo request or the HDE submissions when certain criteria are met. (PMA: premarket approval application; 510(k): premarket notification; HDE: Humanitarian Device Exemption; CDRH: Center for Devices and Radiological Health; CDER: Center for Drug Evaluation and Research; CBER: Center for Biologics Evaluation and Research)

The remainder of this chapter focuses on the regulatory controls for each device class as outlined in section 513 of FDCA, and an overview of the main types of premarket submissions applicable to the different device classes. The overview will include current regulatory considerations for premarket notifications, premarket approval applications, and de novo requests. In addition, this chapter outlines the regulatory considerations for clinical trials using investigational devices under the investigation device exemption (IDE) program.

B. Class I medical Devices and General Controls

Class I Device Definition

Cardiovascular medical devices that fall under the Class I category are devices where a reasonable assurance of S&E can be assured by only applying the minimum regulatory criteria for medical devices, general controls. General controls are defined in sections 501, 502, 510, 516, 518, 519, and 520 of the FDCA (2) and are summarized below.

General Controls

General controls are applicable to all device classes, and require that all medical devices, except where specified, conform to the following:

• Devices are not Adulterated (section 501): device adulteration refers to a device that is unsanitary such that it has been contaminated with any filthy, putrid, poisonous or decomposed substance before or after packaging, which is detrimental to health. The device packaging itself must not be adulterated. Additionally, a device can become adulterated if it becomes a banned device or does not meet good manufacturing practices (i.e. fails to meet requirements in sections 516 and 520 below). This requirement is further extended for Class III devices that are investigational, but do not have an approved IDE for the clinical trial, or a Class III, non-investigational device in the commercial use that does not have an approved application for premarket approval.
• Devices are not Misbranded (section 502): device misbranding refers to device labeling that is false or misleading, such as false advertisement or inadequate directions for use. It also refers to failure to comply with section 510 below, and/or post-market study requirements (if applicable to Class II and Class III devices under section 522).
• Registration, Listing, and 510(k) (section 510): On or before December 31st of each year, any Entity (i.e. persons, manufacturing sites, or any processing establishment) involved in the production of the medical device for sale for human use must be registered with the Agency and must provide a list of the devices made at each site. This excludes any persons who manufacture or process devices solely for research or teaching and not for sale of the device, and any practitioners licensed to prescribe devices and who manufacture or process the device solely for use in the course of their professional practice. If this registration and listing is not completed for the required parties, the device is considered misbranded, as indicated in section 502 above.Under section 510(k), 90 days before device commercialization, each registrant must submit a report or notification declaring device classification per section 513 of FDCA and supporting data to establish equivalence to an already cleared device. This is a requirement for Class II devices and is the main criteria for a premarket notification, also known as the 510(k) process, as discussed in the next section of this chapter. Class I devices are typically exempted from having to submit a premarket notification required under section 510(k). This also does not apply to Class III devices, as they are subject to a PMA application.
• Devices cannot become Banned Devices (section 516): A device can become a banned device if, for any reason, it presents substantial deception or an unreasonable and substantial risk of illness or injury that was not initially anticipated. If any mediating actions can be implemented, such as labeling changes or corrective action to eliminate or reduce risk, the manufacturer will receive notice to take those actions within a specified time. If the actions are not implemented within the allotted time, the device can become a banned device through regulation.
• Notification (section 518): If a device presents an unreasonable risk of substantial harm to the public health, manufacturers (or responsible entities of the device) must disclose these issues, as fast as possible, to professionals who prescribe or use the device and to any other person (including manufacturers, importers, distributors, retailers, and device users) in order to eliminate or reduce the risk of harm. Additionally, whether mandated or voluntary, the entities may conduct additional actions and notify the Agency of actions taken related to repairs, replacement, refunds, reimbursements, or recalls necessary to address the risk.
• Device Records and Reports (section 519): All manufacturers must establish and maintain documentation related to the device such that it can serve as reasonable assurance that the device is not adulterated, misbranded, or otherwise compromised in its S&E. This documentation can include medical device reports (MDRs), which report any field adverse events that may be related to the device, User facility reports, and device tracking. Device tracking is limited to some Class II and all Class III devices that are intended to be implanted for more than one year, or that are life- sustaining or life supporting, or the failure of the device would likely have serious adverse health consequences when used outside a device user facility.
• Good Manufacturing Practices (GMP) (section 520): Manufacturers must establish and maintain quality system requirements that conform with the Quality System Regulations (in accordance with 21 CFR 820) to ensure the device conforms to current good manufacturing practices (i.e. proper control for the manufacturing, process validation, packaging, storage, etc.) and assures reasonable S&E of the device. For Class II and Class III devices, this also includes design controls (21 CFR 820.30).

As noted by the descriptions above, these general controls are sometimes interdependent with each other, and have been established this way such that medical devices maintain a reasonable assurance of S&E.

Class I Devices Are Typically Exempted from Premarket Notification (510(k))

For Class I devices, the application of general controls alone is typically enough to ensure a reasonable assurance of S&E of the device without the requirement for a premarket notification to FDA. Therefore, most Class I devices for which general controls are sufficient to provide a reasonable assurance of S&E are exempted from the required premarket notification to FDA (only a small percentage of Class I devices are not exempt from submission of a 510(k)). This permits manufacturers and/or investigators to introduce Class I devices into commercial distribution without first submitting a premarket notification. Devices that are Class I exempt are also subject to the limitations of exemption. If a device trips these limitations by exceeding the device technological characteristics or introducing a new intended use in comparison to other devices within that classification regulation (as identified in part xxx.9 of the device classification regulations, from 868 through 892, so for example 21 CFR 870.9), then it is subject to premarket notification requirements. When a device that trips the limitations of exemption is submitted for FDA review, and it is found substantially equivalent (SE) to a class I exempt predicate, then the limitations of exemption are expanded to include the characteristics and indications of the newly cleared device such that future devices with similar technological characteristics and indications are considered Class I exempt, and are not subject to premarket notification. As of December 2014, there are only 19 types of cardiovascular devices that have been designated as Class I, of which 16 are exempted from a premarket notification. A few examples of these exempted, Class I cardiovascular devices include line isolation monitors (21 CFR 870.2620), phonocardiographs (21 CFR 870.2390), and pacemaker chargers (21 CFR 870.3670).

C. Class II Medical Devices, Special Controls, and Premarket Notifications – The 510(k) Regulatory Program

Class II Devices

In accordance with section 513 of the FDCA (1), cardiovascular devices that are categorized as Class II devices pose a health risk significant enough such that general controls alone are not sufficient to ensure a reasonable assurance of device S&E. When general controls are not sufficient to ensure a reasonable assurance of S&E, but there is sufficient information about the risks associated with use of the device to establish special controls that will address the remaining risks and provide a reasonable assurance of S&E, then the device can be classified as Class II. These special controls can be tailored to the specific device. In addition to special controls, and as specified in the previous section under general controls, Class II devices are typically subject to the section 510(k) requirement and manufacturers (or other entities that wish to market the device) must submit a premarket notification, unless the device is specifically exempted from premarket notification requirements. As of December 2014, there are 209 Class II cardiovascular device types ranging from non-invasive blood pressure monitors (21 CFR 870.1130) and blood pressure alarms (21 CFR 870.1100) to diagnostic intravascular catheters (21 CFR 870.1200). It is worth noting that many devices can fit within the Class II bucket if there is sufficient evidence to ensure that special controls (i.e., performance testing, such as durability, biocompatibility, non-clinical, clinical, etc.), in combination with general controls, can adequately mitigate the risks to health for the device technology.

Class II Exempt Devices

Some Class II devices are also exempt from premarket notification. They have typically been exempted because the general and special controls established are sufficient to reasonably ensure S&E without the need for premarket notification and review by FDA. Devices that are Class II exempt have a limitation of exemption that defines the device technological characteristics and indications for use that are exempt. If a device trips these limitations, then it is subject to premarket notification requirements. When a device that exceeds the limitations of exemption is submitted for FDA review, and it is found SE to a class II device exempt from 510(k) review, then the limitations of exemption are expanded to include the technological characteristics and indications of the newly cleared device such that future devices with similar characteristics and indications are considered class II exempt, and are not subject to premarket notification. As of December 2014 there is only one Class II exempt cardiovascular device, the Electrocardiograph electrode, under regulation number 21 CFR 870.2360.

Special Controls

Special controls can include, but are not limited to, adherence to currently accepted performance standards, post-market surveillance programs, patient registries, clinical and/or non-clinical performance data and special labeling. Because special controls are dependent on what is known about the device, the applicable number and description of special controls can vary from one device type to another. For example, a cardiovascular intravascular filter (21 CFR 870.3375) is an implant that is placed in the inferior vena cava for the purpose of preventing pulmonary thromboemboli (blood clots generated in the lower limbs and broken loose into the blood stream) from flowing into the right side of the heart and the pulmonary circulation. In order to ensure that the filter will work as intended, this Class II device must meet special controls, which include compliance with International Standards Organization’s (ISO) 10993 for ‘Biological Evaluation of Medical devices Part I: Evalutation and Testing’, as well as FDA’s guidance identified as FDA’s: (i) “510(k) Sterility Review Guidance and Revision of 2/12/90 (K90-1)” and (ii) “Guidance for Cardiovascular Intravascular Filter 510(k) Submissions.”

Another example is an endovascular suturing system (21 CFR 870.3460), which is identified as a medical device intended to provide fixation and sealing between an endovascular graft and the native artery. The system is comprised of the implant device and endovascular delivery device used to implant the endovascular suture. Compared to the filter, an endovascular suturing system has different health risks, and thus the special controls are tailored to address those risks. Devices that are identified to fall under the 21 CFR 870.3460 regulations must meet the requirements outlined in seven special controls. These special controls include: (1) biocompatibility testing; (2) sterilization and shelf life testing; (3) non-clinical and clinical performance testing to demonstrate durability, compatibility, migration resistance, corrosion resistance and delivery and deployment; (4) Compatibility of device in magnetic resonance environment; (5) electromagnetic compatibility (EMC) and electrical safety testing; (6) limited to prescription use only, and (7) specific labeling requirements as outlined in the regulation.

Premarket Notifications – 510(k) Program

Manufacturers (entities responsible for the device) who believe they have a Class II device must submit a 510(k) submission (4), for that device to CDRH at least 90 days before they intend to place the device into commercial distribution and receive 510(k) clearance, unless the Class II device is exempted from submission of a 510(k). The purpose of this submission is two-fold. First, it gives manufacturers and CDRH the opportunity to ensure that the new (or proposed) device is properly classified as a Class II device. Second, it ensures that the new device is substantially equivalent to another legally marketed device. The 510(k) process entails a comparison analysis between the new device and a similar legally marketed device. This legally marketed device is termed the predicate device. The comparison between the new and predicate device serves to establish the new device’s “substantial equivalence” (or “SE” for short and not to be confused with “S&E”, which stands for safety and effectiveness) to the predicate device. This allows manufacturers to use an established S&E baseline to demonstrate that the new device is non-inferior – in S&E – to similar legally marketed device(s). The advantage of this process is that after CDRH determines that the new device is SE to its predicate, a manufacturer can use the new, cleared device as a predicate when making design changes to create future generations of the device to form a family of products (5). Class II devices that have been found SE to a predicate are said to be cleared (not approved) to be placed into commercial distribution. The remainder of this section will discuss how substantial equivalence is determined, the types of 510(k) submissions and requirements, and the various regulatory decisions that can result from a 510(k) review.

Determining Substantial Equivalence – The 510(k) Decision-Making Flowchart

CDRH uses the 510(k) program guidance document with accompanying decision flowchart (depicted in Fig. 2) to determine substantial equivalence of a proposed device to a predicate device (6). For devices that fall within the 510(k) program (i.e., devices already regulated as Class III are not eligible), applying the guidance and flowchart can result in either one of two possible final and mutually exclusive determinations for a proposed device: Substantially Equivalent (SE) or Not Substantially Equivalent (NSE) to a predicate device. The flowchart consists of a series of questions that focus on three key areas that the agency considers when making the final SE or NSE determination: (1) Intended Use of the device, (2) Technological Characteristics, and (3) Performance Data. Notably, in order to proceed to comparing the technological characteristics of the proposed and predicate devices, one must first establish that the intended uses are the same. Similarly, before one reviews performance data, one must first establish that any differences in technological characteristics do not trigger different questions of S&E. Each key area, with examples, is discussed in more detail below. It is important to note that the same predicate device must be used to assess substantial equivalence in terms of the three criteria listed above.

Figure 2 – 510(k) Decision-Making Flowchart: The Guidance for Industry and Food and Drug Administration Staff – The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)] (2014) along with this decision Flowchart, are used by FDA to determine substantial equivalence to a predicate device currently cleared in the U.S. Market. The main, general areas of focus are intended use, technological characteristics, and performance data to determine substantial equivalence. Please note that this Flowchart in not intended to be used as a ‘stand-alone’ document and should only be considered in conjunction with the accompanying text in the 510(k) program guidance (6). (SE, Substantially Equivalent; NSE, Not Substantially Equivalent)

The first key area, Intended Use, refers to the general purpose of the device or its function. For clarification, the intended use of a device encompasses the indications for use (IFU) of the device. The term indications for use, as defined in 21 CFR 814.20(b)(3)(i), describes the disease or condition the device will diagnose, treat, prevent, cure or mitigate, including a description of the patient population for which the device is intended. The intended use of a device is one criterion that determines whether a device can be cleared for marketing through the 510(k) process or must be evaluated in a PMA (or alternative submission type, such as a de novo request) (6). Consistency between the indications for use statement and the proposed labeling will facilitate the review of the 510(k) in determining a new intended use and therefore, substantial equivalence. Typically a finding of substantial equivalence means that the indications for use of the new device falls within the intended use of the predicate device and, therefore, the two devices have the same intended use. Although not every change in the indications for use will result in a new intended use, comparison of the IFU statements for the proposed device to a predicate to determine SE or NSE is a good place to start. From here, there are three possible scenarios:

• Identical IFUs, Same Intended Use: This first scenario is the simplest, where both the proposed and predicate device(s) have the identical – word for word – IFU statements. In this scenario, it is safe to say that the proposed device will have the same intended use as the predicate. This scenario is often seen when a firm already has a cleared device and is proposing minor design changes that do not alter the clinical use of the device. If this scenario applies, then one can proceed with the next set of questions on the flowchart relating to technological characteristics.
• Different IFUs, Same Intended Use because Any Differences Do Not Significantly Impact S&E: In this second scenario, the IFU statements of the proposed and predicate devices are not identical, but are similar enough that the difference does not change the intended use of the device and the differences do not impact S&E of the device use. For example, Company A has a cleared, non-implanted blood access device with an IFU that states the device is intended to provide access to a patient’s blood so that blood can, for example, be subjected to hemodialysis and the device is labeled for insertion into the femoral vein. New devices that are labeled for insertion into the subclavian vein may have the same intended use to the extent that labeling for the new and predicate devices indicates that both are intended to provide access to a patient’s blood for similar purposes. The differences in labeling described above (access via femoral vein versus subclavian vein) do not undercut the fact that the new and predicate devices have the same intended use. CDRH was further able to conclude that the differences in labeling are related only to a method of use not relevant to the effect that the insertion is to achieve. Therefore, the intended use remains the same because the differences do not have a significant impact on S&E for the patient population in which the device will be used. When this scenario is true, one can proceed with the next set of questions in the flowchart.
• Different IFUs, Different Intended Use, and the Differences Do Significantly Impact S&E: In this scenario, the IFU of the proposed and predicate device differ to the extent that the intended use of the device is different and as a result, the predicate device would not be an appropriate comparator for the proposed device. For example, Company A has a 510(k) for an existing surgical ablation device cleared for ablation of cardiac tissue. The same company has now submitted a new 510(k) for the same device for the treatment of atrial fibrillation. While the devices are similar in technology, additional clinical testing has been conducted to demonstrate that not only can the device ablate cardiac tissue, but also that doing so can treat atrial fibrillation safely and effectively. While the question of whether or not cardiac tissue can be safely and effectively ablated was raised by the predicate device, FDA has determined that the specific indication for the treatment of atrial fibrillation constitutes a new intended use because it raises questions of both safety and effectiveness not raised by the predicate device. Specifically, treatment of atrial fibrillation requires extensive ablation to create linear lines of conduction block in a maze-like pattern that eliminates fibrillatory conduction in the atria. The effectiveness assessment for the treatment of atrial fibrillation warrants a clinical outcome study. Furthermore, the risks of iatrogenic heart block and collateral cardiac or extra-cardiac damage are either raised or increased when such a complex and extensive lesion set is created (6). If this scenario is true, the proposed device would be determined NSE to the predicate device and one would not proceed with the remainder of the flowchart, because this determination alone, is enough to conclude a final NSE decision for new intended use. As a result, a PMA (or alternative submission type) is required.

Additional possible scenarios to consider that may (but not always) constitute a new intended use of a device are found in the 510(k) Program guidance (6) and listed below. It is important to note that the determination of a new intended use for these scenarios will depend on the impact it may have on S&E.

• a change from a functional/performance indication to a treatment or aesthetic indication;
• a change from a diagnostic indication to a screening indication, or vice versa;
• a change in the anatomical structure of use;
• a change in the patient population (e.g., adult versus pediatric; different disease populations);
• a change in the clinical context or setting (e.g., periodic monitoring versus continuous monitoring; hospital versus home use).

Once it is determined that the proposed and predicate device(s) have the same intended use, the next key area focuses on comparing the technological characteristics of the proposed and predicate device(s). Technological characteristics refer to device design, materials used, or energy used etc., that contribute to the fundamental function of the device to achieve its intended use. For example, a conventional scalpel uses a sharp blade to cut through tissue during a surgery procedure, while a CO₂ or YAG laser scalpel uses energy at different wavelengths to ablate through the tissue. The series of questions focus on deciding whether the technologies of the proposed and predicate devices have the same or different fundamental technology, and if different, ensure that it does not raise different types of questions of S&E. The following examples illustrate the possible scenarios that can occur from this section of the flowchart:

• Same Technological Characteristics and Same Questions of S&E: In this scenario, the proposed and predicate devices have the same device design, materials, and physical means by which they achieve their intended uses. If this scenario applies, then it would be appropriate to continue down the flowchart to the performance data and evaluate it to make a substantial equivalence (SE) determination.
• Different Technological Characteristics and Same Questions of S&E: In this scenario, the proposed and predicate devices may differ in one, or a combination of technological characteristics but that do not raise new questions of S&E. As an example, Company A holds a cleared device, an electrocardiograph. This device produces an analog visual display of the electrical signals produced by the heart. Company B wishes to market a similar device that displays these signals in a digital, rather than analog, form. This technological difference could affect the effectiveness of the device, i.e., the electronic components used to produce the digital display might not achieve the accuracy of an analog display. CDRH found that the technological modification presented the same question of effectiveness as posed by the predicate device, i.e., does the display accurately represent the electrical activity of the heart? Also, there are accepted bench test procedures to demonstrate comparability of accuracy between the new and predicate devices. If this scenario applies, it is appropriate to move down the flowchart and ensure that the difference does not change the S&E profile by evaluating the accepted bench testing results and other performance data.
• Different Technological Characteristics and Different Questions of S&E: In this third scenario, the technological characteristics of the predicate and proposed devices are different enough that different questions of S&E not originally raised by the predicate device are now raised by the proposed device. As an example, suppose the predicate device is a device inserted into the patient’s pharynx through the mouth to provide a patent airway by mechanically moving the soft tissue. Now suppose the new device is placed externally on the mandible and neck to apply a vacuum to move the soft tissue forward and thus “open” the airway. The intended use remains the same, but the technological differences raises different questions of S&E that were not necessary to take into account for the predicate device. For example, the predicate device is invasive and placed midline in the oropharynx and does not exert pressure on the vascular, respiratory, or nerve structures in the neck, whereas the new device exerts continuous external negative pressure on these areas, raising different types of safety questions, such as the risks and potential adverse events associated with the stimulation of the nerve structures in the neck (6). Therefore, if this scenario applies, these different types of questions of S&E due to differences in technology used to achieve the same outcome would render the proposed device NSE to the predicate.

The third key area is performance data, which is used to address the similarities or differences in technological characteristics between the proposed and predicate device(s). The purpose of performance data is to demonstrate that the proposed device is substantially equivalent to its predicate. Further, the data should demonstrate that the proposed device can perform at least as well as the predicate, and establish substantial equivalence. In general, performance data can consist of a combination of any applicable engineering bench testing, animal studies, clinical studies, software, biocompatibility, shelf life and/or sterilization testing, etc. Of course, not all data may be needed, as that depends on the regulation for that specific device category, its intended use, and technology. For example, not all devices have software, so verification and validation testing on software would not apply to all devices. Therefore, performance data can vary from one type of device to another, and should address any additional special controls required if the regulation for that device type calls for it. If the performance data is not sufficient to support substantial equivalence, then the proposed device can be found NSE to the predicate.

In summary, the flowchart FDA uses to structure its review process around these three key areas is a great tool to use in combination with the principles identified in the “510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications (510(k)) Guidance for Industry and Food and Drug Administration Staff” (6) to determine substantial equivalence. From the flowchart, it can be concluded that substantial equivalence is reached when any one of the following conditions are met:

1. Same intended use and same technological characteristics; OR
2. Same intended use and different technological characteristics that do not raise different questions of S&E and there are acceptable methods to produce performance data that demonstrates that the device is substantially equivalent to its predicate.

510(k) Submission Types and Requirements

Section 21 CFR 807 Subpart E describes the requirements for a 510(k) submission. FDA has established several guidance documents that will help manufacturers comply with those requirements. There are two major types of premarket notification formats: the Traditional 510(k) and Special 510(k) (there is also a third type called an Abbreviated 510(k), but it will not be discussed here). The Traditional 510(k) is used when a new device is being introduced into interstate commerce for the first time, and/or for which intensive data review will be required to determine substantial equivalence. A Special 510(k) submission (8) is appropriate when a submitter is making changes to their own cleared device and when the changes do not alter the indications for use or the fundamental scientific technology of the device. For a Special 510(k), only summary- level data is used to determine substantial equivalence. In addition to the specific formats recommended in guidance documents, all 510(k) submission types are subject to the Refuse to Accept (RTA) Policy, in which specific requirements detailed in the applicable Acceptance Checklist need to be met before substantive review of the submission can begin. For more information on the RTA policy and Acceptance checklist requirements, please refer to guidance document titled “Refuse to Accept Policy for 510(k)s: Guidance for Industry and Food and Drug Administration Staff” (20).

The recommended format for a Traditional 510(k) can be found in the guidance document titled “Guidance for Industry and FDA Staff Format for Traditional and Abbreviated 510(k)s” (7). Addtionally, as stated above, the “Refuse to Accept Policy for 510(k)s: Guidance for Industry and Food and Drug Administration Staff” (20) has a checklist of the recommended elements to meet the basic requirements for a Traditional 510(k) submission. Some of the basic elements are highlighted below:

1. Medical Device User Fee Cover Sheet (Form FDA 3601)
2. CDRH Premarket Review Submission Cover Sheet
3. 510(k) Cover Letter
4. Indications for Use Statement
5. 510(k) Summary or 510(k) Statement
6. Truthful and Accuracy Statement
7. Class III Summary and Certification
8. Financial Certification or Disclosure Statement
9. Declarations of Conformity and Summary Reports
10. Executive Summary
11. Device Description
12. Substantial Equivalence Discussion
13. Proposed Labeling
14. Sterilization and Shelf Life
15. Biocompatibility
16. Software
17. Electromagnetic Compatibility and Electrical Safety
18. Performance Testing – (i.e. Can include bench, animal, and/or clinical testing)

A detailed discussion of these requirements is outside the scope of this chapter. This information has been fine tuned in the guidance documents referenced above, and the reader is encouraged to review those guidances as they see fit to meet their needs. However, it is worthwhile to briefly describe some of these elements, as they make up the body of the three key areas described above that are used to determine substantial equivalence. As stated previously, it is important to have a clear Indications for Use (IFU) statement, as this will outline the intended use of the device and is the first line of comparison to the predicate device. Device Description and Substantial Equivalence Discussion are important areas in which the submitter should clearly explain what the device is and describe its mode of operation, and provide a side-by-side comparison of the technological similarities or differences between the proposed and predicate devices. Elements 14-18 are the body of the performance data that will be evaluated once FDA has determined that no high level issues exist regarding intended use or technological characteristics. These elements will be used to finalize the substantial equivalence determination. When the proposed device is found SE to the predicate, the firm must disclose the above-listed information, with the exception of any proprietary information, in a 510(k) Summary, (or provide a 510(k) Statement) per 21 CFR 807.93 (21, 22). A 510(k) Summary provides a brief description of the device included in the 510(k) and the supporting information, such as the type of testing conducted, summary of results, summary data of a clinical trial, etc. (21). The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications (510(k)) Guidance for Industry and Food and Drug Administration Staff” (6) also provides additional guidance on what should be included in a 510(k) Summary in accordance to 21 CFR 807.92. A 510(k) Statement is a certification that the 510(k) holder will provide a copy of the 510(k) submission, excluding proprietary information, to any person within 30 days of a written request (22). A 510(k) Summary is typically submitted with a 510(k), although either a 510(k) Summary or 510(k) Statement is required by law. When the proposed device is cleared and becomes eligible for use as a predicate for future devices within the device type, information in the 510(k) Summary becomes publicly available for 510(k) submitters to consider when making their SE claim to that or a similar predicate. FDA posts 510(k) information, including 510(k) Summaries in the searchable online database (24).

The eligibility of devices for review through the Special 510(k) process are outlined in the guidance document titled “The New 510(k) Paradigm: Alternate Approaches to Demonstrating Substantial Equivalence in Premarket Notifications” (8). A manufacturer can submit a Special 510(k) if the device design modification is for their own legally marketed device, and the modification does not affect the indications for use of the device or alter its fundamental scientific technology. The majority of these modifications only require review of summary information (i.e. no protocols or data) that results from the design control process under the Quality Systems Regulations, such as results from design validation and verification testing. Examples of the types of changes that may qualify for review under a Special 510(k) include, but are not limited to, minor device design changes, replacement of obsolete components, environmental specifications, performance specifications, ergonomics of the patient-user interface, dimensional specifications, sterilization, software or firmware updates, and packaging or expiration dating.

510(k) Review Process and Regulatory Decisions

Upon receipt of a Traditional 510(k) to the document control center (DCC), along with the user fee (if required) and a valid electronic copy (eCopy), FDA has 90 review days (“FDA days”) to reach a final decision (i.e. SE or NSE). For a Special 510(k), once the user fee (if required) and a valid electronic copy (eCopy) are received, FDA has 30 FDA days to reach a final decision (i.e. SE or NSE) (9). The timeframe is shortened for a Special 510(k), as the changes should be minor, and only summary information is needed to ensure that the modified version of the device is SE to the unmodified version of the device.

After review of the 510(k) submission, and under 21 CFR §807.100(a), FDA typically takes one of the following actions: (1) issue an order declaring the device substantially equivalent (SE) to a legally marketed predicate device (SE letter); (2) issue an order declaring the device not substantially equivalent (NSE) to a legally marketed predicate device (NSE letter); (3) request additional information (AI); or (4) advise the submitter that the 510(k) submission is not required (e.g., the product is not regulated as a device or the device is exempt from the premarket notification requirements of the Act). When a device is determined to be SE, the device can be placed on the market. When a device is determined to be NSE, the device is automatically classified as a Class III device, and would require a premarket approval application (PMA). An exception to this would be if a device is determined NSE due to lack of performance data, where the sponsor will first have the option to submit a new 510(k) to address the concern. In other cases, the device may be eligible for classification into Class II or Class I via the de novo process. Sections 13.4 and 13.5 that follow discuss the regulatory requirements and considerations for PMA and de novo respectively.

D. Class III Medical Devices and the Premarket Approval Application – PMA Regulatory Program

Class III Device Definition

Class III medical devices are considered to have the highest risk. In accordance with section §513 of the FDCA (1), cardiovascular devices are categorized as Class III if and when they cannot be classified as Class I or Class II, such that:

• General controls alone do not suffice to ensure a reasonable assurance of S&E (Class I), and
• There is not enough information about the device to establish special controls to reasonably ensure S&E (Class II), and
• They are purported or represented to be for a use in supporting or sustaining human life or for a use which is of substantial importance in preventing impairment of human health, or presents a potential unreasonable risk of illness or injury.

Therefore, Class III devices must establish S&E under a premarket approval application (PMA).

Premarket Approval Application – PMA

Only a small percentage of medical devices require an approved PMA to be legally marketed in the US, and these devices generally represent the riskiest medical devices often on the cutting edge of clinical science and technology. Unlike 510(k) submissions whose purpose is to include valid scientific evidence demonstrating substantial equivalence to an existing device, a PMA submission must include valid scientific evidence to demonstrate reasonable assurance of S&E before the PMA can be approved by FDA and the device can be legally marketed. A PMA submission typically includes extensive nonclinical and clinical data to establish the S&E of the device for its proposed indications for use (10, 11). Thus, a key consideration of a PMA review is both the data as well as the device labeling which includes the instructions for use.

PMAs are subject to additional premarket controls and post-market requirements beyond what is required for a 510(k) device. These include:

• Preapproval Quality System Regulation inspection
• Post-Approval Study requirements, as determined by FDA at the time an approval order is issued
• Annual reporting requirements that include a bibliography of published and unpublished reports of device use, device distribution numbers, and a description of all changes made in the past year whether or not the changes impact S&E
• Requirement for submission and approval of changes (e.g., design, labeling, manufacturing, etc.) that affect S&E. Additional device performance reporting may be required for permanent implants, such as pacemakers

Although a 510(k) is required for most Class II devices, and a PMA application is required for most Class III devices, an exception to the premarket notification or PMA application requirement is made for devices whose patient population is small, and more specifically, less than 4000 patients in the United States per year as defined in 21 CFR 814.3(n) (26). In these cases, the disease being treated or diagnosed is rare and the available treatment or diagnostic options are limited or none exist such that the device is considered eligible for a Humanitarian Use Device (HUD) designation. For devices that meet such a patient population size and have received a HUD designation, investigators or a manufacturer can submit a Humanitarian Device Exemption (HDE) to gain FDA approval. A Humanitarian Device Exemption (HDE) is an application that is similar to a PMA application, but is exempt from the effectiveness requirements of sections 514 and 515 of the Food, Drug, and Cosmetic Act (the Act). FDA approval of an HDE authorizes an applicant to market a HUD, subject to certain profit and use restrictions set forth in section 520(m) of the Act. Specifically, HUDs cannot be sold for profit, except in narrow circumstances (26).

As shown in Fig. 1, in addition to HDEs, a second exception to submitting a PMA for a device classified as Class III is when a Class III designation is not necessarily appropriate. In this case, the de novo regulatory pathway, which is discussed in the next section, may be applicable.

E. De Novo Classification

Any device that was not on the market prior to May 28, 1976, is not exempt, has not been approved via PMA, has not been found SE via the 510(k) process, or has not received FDA’s permission to market via any other means, such as an HDE, is automatically considered a Class III device. With that said, a Class III designation is not necessarily appropriate for every device. Low to moderate risk devices for which no appropriate predicate exists, or that would be found NSE to all available predicates in the device area due to new intended use or different technological characteristics raising different types of questions of S&E and for which special controls can be written to provide a reasonable assurance of S&E and to mitigate any known risks to health associated with the use of the device, may be eligible for classification into Class II or Class I via the de novo process. If FDA classifies the device into Class II or Class I via the de novo process, a new regulation is established, along with the necessary special controls (if applicable) to mitigate the risks associated with use of the device to provide a reasonable assurance of safety & effectiveness of the device (12). A device for which a de novo request is granted may then be marketed. That device is also eligible to serve as a predicate for future 510(k) submissions, if necessary. Please note that devices for which the risks to health cannot be identified or for which special controls cannot be written to provide a reasonable assurance of S&E and to mitigate the risks associated with use of the device, remain Class III devices that require a PMA approval prior to marketing. Devices for which a de novo request is granted are most often classified as Class II devices, although some are placed into Class I. Once a regulation and special controls (if applicable) are created, the device classified into Class II or I via the granting of a de novo request can subsequently serve as a predicate for 510(k) submissions for future devices within the new classification regulation. In other words, once a device with a given set of technological characteristics and intended use is classified into Class II or Class I via the de novo process, other similar devices can be found SE to that initial device via a 510(k) submission as described in section 13.3 above. FDA also has the option to exempt the device from premarket notification (Class II or I exempt) as previously described. It is important to note that submission of a 510(k) is not required prior to submitting a de novo request. This is described in detail in a guidance document that was published in draft form as of the writing of this chapter. Although the draft guidance is not for implementation until it is published in final form, it does represent current thinking on the de novo process (27).

F. Clinical Trials – Investicational Device Exemption Program

Typically all original PMA submissions and some original 510(k) submissions use clinical data to demonstrate the device is S&E or SE, respectively. A device manufacturer or physician-investigator who wishes to conduct a clinical trial using a significant risk device in the U.S. in order to collect S&E data on an investigational device that is not legally marketed for its intended use, must obtain approval of an Investigational Device Exemption (IDE) application prior to using the investigational device in a clinical trial (13). A significant risk device is defined in Section 21 CFR 812.3(m) as follows:

Significant risk device means an investigational device that:

1. Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject;
2. 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;
3. 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
4. Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.

An IDE can be submitted by a manufacturer that wishes to collect clinical data on a device for which they plan to submit a marketing application, or by a physician-investigator who wishes to conduct a trial using a marketed device for a purpose other than its approved or cleared intended use. The owner of the IDE application is known as the sponsor of the IDE, and whether a manufacturer or physician-investigator, the sponsor must comply with periodic reporting requirements, as well as data monitoring and record keeping requirements. Physician-investigators, also referred to as sponsor-investigators, have all of the responsibilities of a sponsor and an investigator combined. IDE requirements, including reporting and data requirements will be discussed below in section 13.6.2. All information in an IDE application, including the mere existence of the IDE, is confidential and is therefore not disclosed by FDA.

It is important for physician-investigators to submit an IDE, when required by law, before initiating a clinical investigation. FDA offers feedback before, during, and after an IDE submission via the Pre-submission program, where submitters can request a teleconference call or on-site meeting with FDA to ask questions and discuss issues to help prepare future IDE submissions (17). Choosing to use the Pre-submission process before submitting an IDE can be very advantageous, as it allows the sponsor-investigator the opportunity to obtain FDA’s feedback regarding patient protection and recommendations to make the study as scientifically sound as possible. The Pre-Submission review can be an interactive process in which FDA reviewers provide input, comments, and advice, that can potentially make the application process as streamlined and user-friendly as possible before the submission of an IDE application. This feedback can potentially increase the utility of the data collected in the clinical study and whether this data may be appropriate to approve a new device, expand the indications of a device, influence clinical practice, or to identify important safety or effectiveness considerations. It is important to note that there is no fee for submitting a Pre- submission and/or an IDE application to FDA.

Please note that this section is meant to be an overview of the contents of an IDE and IDE requirements that are most likely to be of interest to the sponsor-investigator. It is not an all- inclusive list, nor is it meant to in any way modify the requirements or guidance already established by existing regulations and formal guidance documents, respectively.

When is an IDE needed and how are they reviewed by FDA?

Prior approval of an IDE application is required for any study utilizing an investigational device on human subjects in the U.S. for clinical studies that pose a significant risk to enrolled subjects. An IDE application is not required for every clinical study conducted with medical devices (14). Circumstances under which an IDE application is not required include:

• Clinical studies conducted with a legally marketed device used in accordance with its cleared or approved intended use
• Clinical studies that are considered “Non-Significant Risk”
• Studies that are considered Basic Physiologic Research where the purpose is not evaluation or collection of safety and effectiveness of the unapproved device to support a marketing application
• Clinical studies conducted outside the U.S.

Following the implementation of the Food and Drug Administration Safety and Innovation Act (FDASIA) signed into law in 2012, FDA will make a decision on the IDE submission resulting in Approval, Approval with Conditions, or Disapproval. Below is an excerpt from the “FDA Decisions for Investigational Device Exemption Clinical Investigations Guidance” (16) that outlines the reasons why an IDE may be disapproved:

Consistent with 21 CFR 812.30(b) and section 520(g) of the FD&C Act, FDA may disapprove an IDE for any of the following reasons:

• There has been a failure to comply with any requirement in 21 CFR Part 812 or section 520(g) of the FD&C Act, any other applicable regulation or statute, or any condition of approval imposed by an IRB or FDA. (21 CFR 812.30(b)(1)).
• The application or a report contains an untrue statement of material fact, or omits material information required by 21 CFR Part 812. (21 CFR 812.30(b)(2)).
• The sponsor fails to respond to a request for additional information within the time FDA prescribes. (21 CFR 812.30(b)(3)).
• There is reason to believe that risks to the subjects are not outweighed by the anticipated benefits to the subjects and the importance of the knowledge to be gained (21 CFR 812.30(b)(4)). This assessment may be based on the following consideration:
  • Subject safety. The investigational plan contains elements that would expose subjects to unacceptable probable risks, or fails to adequately protect study subjects from probable risks (including adequate monitoring and review of the investigation).
  • Inadequate potential for benefit. Available data suggest the device is ineffective for the use that will be evaluated in the proposed study, or no information has been provided to suggest the device as used may result in patient benefit and the generation of knowledge adequate to justify the risks. For example, for a therapeutic device, the submission does not provide a scientifically plausible explanation for how the proposed mechanism of action of the device could have an impact on the outcome of interest, or for a diagnostic device, no data have been provided showing that the device is informative concerning the condition of interest. The amount of information or data to support scientific plausibility of the proposed use of the device will depend on the level of risk associated with the device/procedure and the alternatives available to the intended patient population. For a device with lesser risk, a scientific explanation for how the device could lead to patient benefit may be sufficient. However, for a device that poses more substantial risks to subjects, especially when alternative commercially available therapies, diagnostic devices or surgical procedures exist, initial evidence to support the likelihood of patient benefit would generally be necessary. If the study proposes to evaluate a significant risk device in patients for whom no alternatives exist, and/or if there is no way to evaluate the potential for benefit in a reasonable nonclinical model, FDA may allow limited enrollment as a feasibility study or staged pivotal study.
  • Device safety. The data and information provided are insufficient to adequately characterize the safety profile of the device such that, based on the data provided thus far, human clinical investigation is not considered reasonable. A specific safety concern may relate to the need for additional basic device evaluation (e.g., biocompatibility, mechanical durability, drug or biologic component characterization, electrical safety, software validation, or biological response in an animal model) or additional information regarding the methods, facilities, and controls used for the manufacturing, processing, packaging, storage, and, where appropriate, installation of the device.

FDA’s review of any IDE application focuses on ensuring that appropriate patient protection measures are put in place, and that the application in terms of scientific soundness of the proposed clinical study and statistical analysis plan are adequate. However, based on Section 520(g)(4)(C) of the FD&C Act states that, consistent with section 520(g)(1), FDA shall not disapprove an IDE because (16)

1. the investigation may not support a substantial equivalence or de novo classification determination or approval of the device;
2. the investigation may not meet a requirement, including a data requirement, relating to the approval or clearance of a device; or
3. an additional or different investigation may be necessary to support clearance or approval of the device.

If an IDE application is disapproved or approved with conditions, FDA will issue a letter that contains the basis for the decision. Additionally, and regardless of the decision reached, FDA will provide study design considerations thought to strengthen the scientific integrity of the study for the IDE sponsor to consider implementing in their study protocol or statistical analysis plan. Addressing study design considerations may be important to support future marketing applications. Physician-investigators often partner with device manufacturers to utilize the manufacturer’s device in a clinical study for use of an existing device for indications different than those approved or cleared by FDA. This partnership allows the physician-investigator to largely rely on existing non-clinical bench, engineering, and/or animal data obviating the need for the physician-investigator to conduct such studies before submitting an IDE application. The device manufacturer must grant FDA permission, via a “Right of Reference Letter” for FDA to use such nonclinical information in FDA’s files for purposes of supporting an IDE application submitted by a physician-investigator. This partnership is not a requirement, but many investigators prefer to establish such a partnership as the burden of conducting any necessary nonclinical testing is often beyond what the physician- investigator is able or willing to do in order to establish the basic safety of the device prior to submitting an IDE application to FDA.

IDE Requirements

21 CFR sections 812, 50, 54 and 56 cover Investigational Device Exemptions (IDEs), Informed Consent Requirements, Financial Disclosure by Clinical Investigator, and Institutional Review Boards requirements, respectively. Conducting a study under IDE consists of the following stages:

1. Submit to FDA and obtain approval of the IDE prior to beginning a clinical study where IDE approval is required.
2. Obtain IRB approval covering each investigational site where the study will be conducted.
3. Once approved and during the duration of the IDE study:
   • Register with clinicaltrials.gov, if the study is an applicable trial as defined in Public Law 110-85, Title VIII (18). Note: if a trial is registered with clinicaltrials.gov, the following statement must be included in the informed consent document: “A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.” 21 CFR 50.25(c) (19)
   • comply with record-keeping requirements per Good Clinical Practices (21 CFR 812.140)
   • comply with annual reporting requirements (21 CFR §812.150(b)(5)) as well as semi-annual investigator list reporting requirements ( 21 CFR §812.150(b)(4)).
   • sponsors and investigators are subject to FDA inspection as part of the Bioresearch Monitoring (BIMO) Compliance program (21 CFR §812.145).
   • submit notices within 5 days of implementation of: ( 21 CFR §812. 35(a)(3))
     • Protocol changes: the changes do not affect the validity of the data or information resulting from completion of the approved protocol, or the risk:benefit relationship relied upon to approve the protocol, the scientific soundness of the investigational plan, or the rights, safety, or welfare of the subjects involved in the investigation.
     • Device Changes: for developmental device changes (including manufacturing changes), the changes do not constitute a significant change in design or basic principles of operation and that are made in response to information gathered during the course of the investigation
   • Submit notices within 5 days of learning about: ( 21 CFR §812.150(b)(1))
     • Any unanticipated adverse event
     • Any anticipated adverse event which is occurring at a rate that is higher than anticipated.
4. Once the study is complete, submit a final report. The final report is to be submitted within 6 months of completion or termination of the study (21 CFR §812.150(b)(7)).
5. Within one year of study completion, update results of the study on clinicaltrials.gov, per Public Law 110-85, Title VIII (18).

IDE Submission Requirements

As mentioned in section 13.6.2 above, an IDE application must be submitted and approved by FDA prior to starting a clinical trial that requires an IDE. The contents of an IDE submission must include, in part, the following items per 21 CFR §812.20(b):

• Sponsor Information
• Manufacturing Information
• Investigator and IRB Information
• Sales Information
• Device description
• Report of prior investigations
• Investigational plan, including the protocol (812.25)
• Informed Consent Document
• Case report forms

Each of the last five items in the list above will be described in further detail below as they are the most relevant sections that require special attention by physicians involved in IDE clinical studies. The more detailed descriptions below are not intended to convey Guidance as the descriptions have not gone through the Good Guidance Practices process required of all formal Guidance issued by the Agency. They represent the best advice that would be provided by the authors if asked by a sponsor-investigator “what do I include in my IDE application”.

Device Description

IDE submissions for new investigational devices should include a detailed device description so that the technological characteristics can be readily understood by the FDA review team. For physician- investigator studies which often make use of legally marketed devices, a detailed listing of the devices to be used for an investigational indication in the study is important. This should include all model numbers of the device, device components and accessories to be used in the study. Illustrations, photos, and drawings with dimensions are encouraged in this section. This detailed device description or complete listing of devices to be used in the study is important in order to establish the potential risks of the devices and consequently any non-clinical data necessary to establish a reasonable degree of device safety in order to justify using the investigational device in study subjects.

Report of Prior Investigations

An IDE submission must contain a comprehensive report of prior investigations (21 CFR Section 812.27). This report must also include a bibliography of all published as well as any unpublished reports that the study sponsor could reasonably be expected to be aware of. The investigations that should be included in the report are not limited to clinical investigations, but should also include any non-clinical investigations conducted on the investigational device subject of the IDE submission. Any bench testing conducted by the sponsor to establish that the device is safe for experimental human use should be included in this report. Depending on the investigational device design, mechanism of action, and identified potential failure modes, these non-clinical investigations can, but do not always, include:

• Sterilization
• Biocompatibility
• Mechanical integrity and fatigue testing
• Corrosion
• Electrical safety and electromagnetic compatibility
• Human factors and usability testing
• Other relevant bench performance testing
• Animal safety and performance testing
• Results of prior clinical investigations, including any feasibility studies, or clinical studies conducted on the device outside the U.S.

Per 21 CFR 812.27(b)(3), the IDE must contain either a statement that all studies included in the IDE have been conducted in compliance with applicable requirements in the good laboratory practice regulations in part 58, or if any such study was not conducted in compliance with such regulations, a brief statement of the reason for the noncompliance.

These reports may include detailed test protocols, test results, and conclusions so that they can be assessed by a team of FDA reviewers and a determination of approvability can be made. It is important to note that the list above is neither comprehensive nor necessarily required for every investigational device. The type of testing used to establish adequacy to justify the proposed clinical testing depends largely on the device and the proposed study.

Investigational Plan

Regardless of who sponsors an IDE submission, IDE submissions must include an investigational plan, which includes the following items (21 CFR §812. 25):

• Purpose. The name and intended use of the device and the objectives and duration of the investigation.
• Protocol. A written protocol describing the methodology to be used and an analysis of the protocol demonstrating that the investigation is scientifically sound.
• Risk analysis. A description and analysis of all increased risks to which subjects will be exposed by the investigation; the manner in which these risks will be minimized; a justification for the investigation; and a description of the patient population, including the number, age, sex, and condition.
• Description of device. A description of each important component, ingredient, property, and principle of operation of the device and of each anticipated change in the device during the course of the investigation.
• Monitoring procedures. The sponsor’s written procedures for monitoring the investigation and the name and address of any monitor.
• Labeling. Copies of all labeling for the device.
• Consent materials. Copies of all forms and informational materials to be provided to subjects to obtain informed consent.
• IRB information. A list of the names, locations, and chairpersons of all IRB’s that have been or will be asked to review the investigation, and a certification of any action taken by any of those IRB’s with respect to the investigation.
• Other institutions. The name and address of each institution at which a part of the investigation may be conducted that has not been identified in paragraph (h) of this section.
• Additional records and reports. A description of records and reports that will be maintained on the investigation in addition to those prescribed in subpart G.

Although the following are not regulatory requirements under 21 CFR 812.25, the study protocol typically includes a detailed, clear, and unambiguous description of:

• the patient population to be enrolled in the clinical study using inclusion and exclusion criteria that can be objectively assessed,
• the clinical procedure, including any investigational portions of the procedure as well as any portions considered standard of care
• follow-up visit schedule and procedures
• the statistical analysis plan, if applicable
• any monitoring procedures employed to maximize patient protection as well as data integrity (e.g. the use of Data Safety and Monitoring Boards, core labs, and Clinical Event Committees.)

Informed Consent Document

The Informed Consent Document is considered an essential measure to maximize subject protections. For almost all investigational studies informed consent must be obtained for each patient enrolled. A subject is considered enrolled in the clinical study once they sign the Informed Consent Document. Per 21 CFR §50.25(a), the Informed Consent Document must contain the following (19):

• a statement that the study involves research
• an explanation of the purposes of the research
• the expected duration of the subject’s participation
• a description of the procedures to be followed
• identification of any procedures which are experimental
• a description of any reasonably foreseeable risks or discomforts to the subject, including non-study aspects like anesthesia or vascular access
• a description of any benefits to the subject or others
• a disclosure of appropriate alternative procedures or courses of treatment that might be advantageous to the subject
• a statement describing the extent to which confidentiality of the subject’s records will be maintained and that notes that FDA may inspect the records
• an explanation as to whether any compensation and/or medical treatments are available if injury occurs and, if so, what they consist of or sources of further information
• an explanation of whom to contact for answers to questions about the study and the subject’s rights and whom to contact in the event of a research-related injury
• a statement that participation is voluntary and that subjects may refuse to participate or discontinue participation at any time without penalty or loss of benefits

Per 21CFR§50.25(b) one or more of the following elements of information shall also be provided to each subject when appropriate:

• a statement that the procedure or treatment may involve unforeseeable risks to subject, or to the embryo or fetus should the subject become pregnant
• anticipated circumstances under which the investigator may terminate the subject’s participation without regard to the subject’s consent
• any additional costs to subject as a result of participation
• consequences of a subject’s decision to withdraw and procedures for withdrawal
• a statement that significant new findings which may relate to the subject’s willingness to participate will be provided to the subjects
• the approximate number of subjects involved in the study

Per 21CFR§50.25(c), if the study is a controlled pivotal trial, (e.g. “applicable clinical trial”), the consent form must contain the following statement word-for-word:

A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.

Please see “Guidance for Sponsors, Investigators, and Institutional Review Boards Questions and Answers on Informed Consent Elements, 21 CFR §50.25(c)” for further details on this recently added requirement for informed consent (23).

Case Report Forms

Finally, although not required by law, it is recommended that an IDE submission include case report forms designed to collect all necessary data per the investigational protocol, reduce missing data, and facilitate uniform reporting of each case among investigators. Case Report Forms should minimize the use of text fields, use definitions identical to those in the study protocol, and include a comprehensive list of questions to faithfully capture all observed adverse events and relevant measures of effectiveness. Finally, case report forms should be designed to:

• document the baseline characteristics of enrolled subjects,
• document that each subject meets the inclusion and exclusion criteria,
• document the acute outcome of the procedure, and
• document each follow-up visit with the pertinent assessments at each visit

Logistics for submitting an IDE

Section 520(g)(4)(A) of the FD&C Act states that:

An application, submitted in accordance with the procedures prescribed by regulations under paragraph (2), for an exemption for a device (other than an exemption from section 360f of this title) shall be deemed approved on the thirtieth day after the submission of the application to the Secretary unless on or before such day the Secretary by order disapproves the application and notifies the applicant of the disapproval of the application.

Based on this statutory requirement, FDA is required to notify the sponsor of the decision reached for the IDE application within 30 days following receipt of the IDE application. If the sponsor is not notified that the IDE is disapproved on or before the 30th day following submission, the application is deemed approved (21 USC 520(g)(4)(A); see also (16)). Possible decisions include Approval, Approval with Conditions, or Disapproval. FDA will provide a comprehensive list of reasons for disapproval and conditions of approval identified during the review of the IDE application. Reasons for disapproval may include non-clinical testing that was not conducted but needed to show the device is safe, animal studies that did not demonstrate reasonable device safety, or a study protocol that does not establish appropriate patient protection measures. In addition, FDA may recommend and provide a list of Study Design Considerations that FDA believes will improve the study design to support marketing approval or clearance.

Upon receipt of an Approval letter, the IDE sponsor may begin their investigation, provided they have obtained the appropriate IRB approval(s), according to the protocol included in the approved IDE application. The sponsor may choose to implement the recommendations made by FDA in the form of Study Design Considerations. If the sponsor chooses to modify the application to implement one or more Study Design Considerations, the sponsor should submit an IDE supplement to request approval for the proposed changes.

Upon receipt of an Approval with Conditions letter, the IDE sponsor may begin their investigation, provided they have obtained the appropriate IRB approval(s), and in accordance with the limits described in FDA’s decision letter, including the maximum numbers of U.S. subjects and investigational sites. The sponsor must also submit an IDE amendment within 45 days of the date on the IDE decision letter responding to the Approval with Conditions letter in order to demonstrate how they have complied with the Conditions of Approval.

Upon receipt of a Disapproval letter, the IDE sponsor may not begin their investigation. The sponsor may submit an IDE amendment addressing the reasons for disapproval outlined in the letter any time after receiving the Disapproval letter. FDA will review the amendment and issue another decision letter within 30 days of receipt of the IDE amendment.

It is often beneficial for the physician-investigator to seek FDA’s feedback regarding their approach for addressing reasons for disapproval, conditions of approval, or study design considerations. Again, the physician-investigator may submit a Pre-Submission (and specifically a “submission issue” request) (17), requesting written feedback, a teleconference or face-to-face meeting with the FDA review team to clarify any questions and provide an initial assessment of the approach for addressing any FDA questions.

G. Concluding Comments

This chapter outlines the regulatory approaches that FDA’s Center for Devices and Radiological Health uses to regulate cardiovascular medical devices in the premarket phase of device development. Device classification based on risk level and the general, or general and special controls, that can mitigate those risks, are the main driver for determining the premarket pathway. Class I devices pose the least risk and are typically exempt from premarket notification. Class II devices typically require a premarket notification (510(k)), while Class III devices that pose the highest risk typically require a PMA. The requirements for 510k, PMA and de novo submissions were discussed with the main message being that the source materials, manufacturing process, and final product should be sufficiently characterized to ensure a reasonable assurance of safety and effectiveness. This includes both nonclinical and/or clinical data gathered through bench testing, animal studies or clinical trials. Clinical trials for significant risk device studies in the US require approval of an investigational device exemptions (IDE) submission. Each regulatory submission must be presented with sufficient detail to allow FDA to review and make a determination. Although FDA guidance documents are a good source of general information, for submission- specific feedback, product developers and clinical investigators are encouraged to communicate with CDRH early in product development. To help achieve this goal, communication with CDRH is readily available via the pre-submission program (17). As stated in Section 13.6.4 of this chapter, a pre-submission meeting can consist of a face-to-face meeting with FDA review teams, a teleconference call, or written feedback. Investigators or companies can request a pre-submission meeting by submitting a “Pre-Submission” at any time during the product life cycle, and are especially encouraged to do so before a major premarket submission (Fig. 4). Taken together, the tools and programs available at CDRH and the Division of Cardiovascular Devices are meant to enable timely progression of safe and effective cardiovascular medical devices from bench-to- bedside in order to continue to meet a dynamic healthcare demand.

Figure 3 – Premarket Submissions by device classification. This flowchart illustrates some, but not all, possible regulatory pathways and outcomes for each device class. The questions included here are only a subset of general considerations that may be addressed for each device class and the corresponding premarket submissions to gain device market clearance or approval (IDE: investigational device exemption; 510(k): premarket notification; PMA: premarket approval application; HDE: humanitarian device exemption; pts.: patients; yr.: year; 4K = 4,000).

Figure 4 –Total Product Life Cycle and Pre-Submission Program: CDRH provides a pre-submission program available to any investigator or manufacturer to gain helpful feedback on current or future premarket submissions throughout the total product life cycle of medical devices. Total Product Life Cycle graphic taken from (28).

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