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U.S. Marketing Authorization of Novel Medical Devices

Common FDA Regulatory Pathways for Uncommon Devices

Technology is changing the landscape of the medical field. With advances in areas such as 3D printing, nano-materials and mobile medical applications, the range of novel and innovative medical devices is continuing to grow by leaps and bounds. The challenge, for both industry and the US FDA, is to determine within the existing regulatory framework the best way to get these new devices to health care providers and patients as soon as possible while ensuring safety and effectiveness.

The three most common pathways in which to place a medical device onto the US market are described very generally below:

No pre-market evaluation by the FDA – this option is limited to most Class I and some Class II devices that are considered lower risk, for which general controls (such as labeling, Good Manufacturing Processes (GMPs), and Establishment Registration/ Device listing) are deemed sufficient to provide reasonable assurance of the device’s safety and effectiveness for its intended use.

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Pre-market Notification (510(k)) – this process applies to most Class II and some Class I and Class III devices. These are generally devices that are not life-supporting or life-sustaining, and that have a moderate level of risk. Special controls apply, such as performance standards, postmarket surveillance, and testing requirements, and the device must be shown to be substantially equivalent to an existing Class II device with the same intended use.

Pre-market Approval Application (PMA) – this pathway is required for most devices that have been determined by the FDA to be Class III (those with the highest level of risk, and are life-supporting or life-sustaining). However, it is also the probable pathway for a novel type of device that has not yet been pre-designated by the FDA into a particular device classification. An innovative medical device with either a new intended use or novel fundamental technology, even if its use is probably low-risk, automatically falls into Class III by default.

The FDA’s classification system is based on an array of agency-assigned product codes that are tied to the intended use and certain technological characteristics of a device. Title 21 of the Code of Federal Regulations (21 CFR)1 provides the definition, device classification, and regulatory requirements for each product code.

If a device’s intended use and/or technological characteristics are not appropriately described by an existing product code, a medical device manufacturer is left to wonder what the classification is for their new device and how to get it onto the U.S. market.

What Does “Novel Device” Mean?

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Not every device that a manufacturer claims is novel really is; and in fact, from a regulatory viewpoint, it is usually of benefit not to claim your device is novel compared to all other devices on the U.S. market.

But if a device manufacturer develops a new device that does not adequately fit the description (intended use and/or technological features) of an existing FDA product code, it is generally thought of as a novel device. This can include use of an existing device for a new intended use, an innovative design or unique principle of operation.

For such devices, the manufacturer is wise to consult with the FDA in order to determine the regulatory pathway prior to moving too far forward with the device’s development.

What To Do If Your Device Is Truly Novel

Don’t panic! You are not completely alone in the quagmire of regulations and unknown requirements. The FDA has programs in place and has published related guidance documents (links provided as footnotes herein), to assist the medical device industry through the process. The following outlines the potential options in which a company may choose to engage the FDA, with descriptions as to the appropriateness and expectations of each.

Request for Information [FD&C Act section 513(g)]2

If a manufacturer is unsure if an existing product code appropriately fits their device’s intended use and technology, they can submit a Request for Information to the FDA soliciting their opinion. This submission is often simply called a 513(g) request.

The FDA response to a 513(g) request is intended to address questions related to the classification of a medical device or the requirements applicable to a device. The FDA attempts to respond within 60 days of receiving a written request, and will generally provide the following information to the requestor:

  • The agency’s assessment, based on the information submitted in the request, as to the generic type of device (e.g., classification regulation), or if the product is not a medical device;
  • The class of devices within that generic type which appears to cover the requestor’s device;
  • Whether a PMA, 510(k), or neither is required in order to market devices of the particular class within that generic type;
  • Other requirements applicable to devices of the particular class within that generic type;
  • Whether a guidance document has been issued regarding the exercise of enforcement discretion;
  • Whether additional FDA requirements may apply.

The FDA is clear that their response to a 513(g) Request for Information is non-binding, but is only a response based on information provided by the requestor. Also, they will not review or provide feedback on test plans or data. However, once a device manufacturer has the FDA’s opinion on the classification, product code, and applicable market pathway of their device, they can (and usually should) approach the FDA again to clarify specific requirements for subsequent clearance or approval, as discussed further below for a Pre-Submission.

Request for Designation [FD&C Act section 563]3

Some new products may incorporate more than one mode of action, or consist of materials or components that are pharmaceutical or biologically derived, as well as components that are mechanical or structural. For such products, it may be necessary to request that the FDA designate the agency Center with jurisdiction over the product, based on the device’s primary mode of action.

A Request for Designation (RFD) is submitted to the Office of Combination Products (OCP), even if the product in question is clearly not a combination product (i.e., a drug-device, biological-device, drug-biological, drug-device-biological). The OCP will review the intended use, principles of operation, mechanism of achieving its intended purpose, materials, and other relevant information in order to render a decision regarding the product’s primary mode of action. If the product acts on the body primarily in a structural or physical manner, in accordance with FDA’s definition of a medical device,4 then the product will be designated a device under the primary jurisdiction of the Center for Devices and Radiological Health (CDRH). If it has a secondary mode of action, the combination product will also undergo review, in part, by the Center with jurisdiction over that mode of action. Even if the product only has a single mode of action (e.g., device), but perhaps incorporates a drug or a biological material (e.g., a blood derivative such as human serum albumin), the Center of Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) may need to be included in the review of the marketing application.

If the product’s manufacturer has valid scientific evidence and justification to support a specific mode of action, it is critical to include those details in the RFD to support what the manufacturer believes to be the correct designation.

The OCP will provide a Letter of Designation with their response, which is a binding decision. The outcome of the designation will determine not only the FDA Center(s) that will review the product, but the type of application (PMA, NDA, BLA) as well as the type of quality system (QSR, GMP) required.

Pre-Submission (“Q-Sub”)5

A manufacturer may know the classification and applicable product code for their device based on its intended use, but there are enough differences in its design, principle of operation, or other technological characteristics as compared to existing devices to introduce a lot of uncertainty. Or conversely, a manufacturer may be seeking to use an existing device for a novel intended use. Even if the manufacturer has previously received a classification determination from the FDA via a 513(g) submission, it is still likely that they will not fully know what testing is required to support substantial equivalence or address the questions of safety and effectiveness related to the device’s unique features.

The Q-Sub process was formerly called a Pre-IDE; however, with the Medical Device User Fee Amendment of 2012 (MDUFMA III), the FDA broadened the scope of the program to include a wider range of subjects, and put into place a structure to manage and address such meetings. The primary purpose remains the same: to provide a mechanism for a sponsor to obtain FDA’s feedback prior to an intended product submission (e.g., 510(k), IDE, PMA, BLA). Q-Sub questions should pertain to the content or data required for the planned submission, and the information provided to the FDA in the Q-Sub request documentation must be comprehensive and accurate in order to enable the FDA to respond appropriately and confidently to the questions posed. The feedback to a Q-Sub is also non-binding; however, there are binding options (Determination and Agreement meetings) intended specifically to address questions related to clinical trials.

Marketing Approval for A Novel Device

Many novel devices will be designated Class III devices, requiring a PMA application to demonstrate a reasonable assurance of safety and effectiveness for their intended use with subsequent FDA approval. However, some devices, although novel, do not present a high enough level of risk to warrant classification as Class III devices. Such devices may be eligible for review and classification as Class I or II via the de novo process. Other novel devices may address an unmet need or be intended for a rare condition, for which other means of review and approval may be appropriate. These are further described below.

De Novo Process [FD&C Act section 513(f)(1) & 513(f)(2)] 6,7

If a novel device is not currently covered by an existing product code and has no appropriate predicate device for substantial equivalency determination, it will by default fall into Class III (automatic Class III designation, per 513(f)(1)), regardless of its risk level. Such a device is commonly referred to as a ‘De Novo’ device, and may be eligible for assessment via FDA’s De Novo pathway for classification into either Class I or Class II.

The first step a company should take, if they believe they have a de novo device, is to request a preliminary de novo meeting with the FDA in accordance with the Pre-Sub process described above. Basically, the request submission will include details on the device’s design, intended use, technology, risk assessment and testing conducted and planned, to allow the FDA to determine eligibility for the de novo process and to provide guidance on performance testing and potential special controls. The Pre-Sub should also include a description of how the sponsor established that no legally marketed device of the same type exists, as well as the manufacturer’s proposed classification and rationale. If the FDA agrees that the novel device is appropriate for review under the de novo process for classification into Class II or Class I, additional Pre-Sub meetings may subsequently be requested to support approval of the de novo submission, e.g., questions related to specific test protocols.

Humanitarian Device Exemption (HDE) [[FD&C Act section 520(m)]8

An Humanitarian Use Device (HUD)9 is one that is intended to benefit patients in the treatment or diagnosis of diseases or conditions that affect or are manifested in fewer than 4,000 individuals in the United States per year (21 CFR 814.3(n)), i.e., for a rare disease or condition. An HUD may be granted an exemption (HDE) from the effectiveness requirements of section 514 and 515 of the Act, and be approved for marketing via an HDE.

If a manufacturer believes that their device meets the criteria for an HUD, they must first submit an HUD designation request to FDA’s Office of Orphan Products Development (OOPD), which will assess if the applicant has demonstrated that fewer than 4,000 individuals per year would be subjected to diagnosis or treatment by the device in the United States.

If the FDA designates a device as a HUD, the manufacturer may then submit an HDE submission for approval. Additional information must be provided beyond simply showing that there are expected to be fewer than 4,000 new patients per year diagnosed with the disease or condition. Within the definition of a HUD is also the implication that there is no comparable device available to treat or diagnose that condition. Therefore, the HDE submission must include evidence to support this contention, as well as an explanation of why the expected benefits of the device outweigh risks. In addition, to be granted approval under an HDE, if the amount to be charged for the device is more than $250, a report by an independent Certified Accountant is required to justify the amount charged.

Again, as with any submission involving a novel device, the applicant should have early dialogue with the FDA using the Pre-Sub process.

It should also be noted that the HDE approval process is not automatically easier or faster, nor provides the optimal means of successfully marketing the device.

Often, the final indications approved via an HDE are narrower than the applicant originally requested, and issues of reimbursement must be taken into account. In addition, prior to using an HUD, approval by the Institutional Review Board (IRB) of each using facility is required (except in cases of emergency). The manufacturer must submit periodic reports to the FDA to support continued designation as a HUD, as well as information on the number of devices sold; based on the report or other information at their disposal, the FDA can revoke the HUD designation.

Expedited Access Pathway (“EAP”)10,11

In early 2015, the FDA introduced a new program for medical devices subject to a premarket approval application or de novo submission that demonstrate the potential to address unmet medical needs for life threatening or irreversibly debilitating diseases or conditions. The program is called the Expedited Access Pathway for Unmet Medical Needs for Life Threatening or Irreversibly Debilitating Diseases or Conditions, or EAP for short. It is intended to expedite the development, assessment and review of such devices while still requiring the demonstration of reasonable assurance of safety and effectiveness (section 515(d) of the Act). Devices eligible for the EAP process could be those that offer potential for greater clinically meaningful benefit, or that provide a break- through technology over existing devices (a novel technology, or a novel application of existing technology). The EAP includes the following four steps:

  1. Request for and designation as an EAP Device,
  2. Agreement with the FDA on a Data Development Plan,
  3. Submission and review of a PMA or de novo request for an EAP Device, and
  4. Postmarket data collection and evaluation (if approved and appropriate).

A “life threatening” condition is defined as one in which the likelihood of death is high unless the course of the disease is interrupted (e.g., hepatitis, serious trauma). “Irreversibly debilitating” means to have a substantial long-term impact on day-to-day functioning (e.g., stroke, ALS). A device meets the condition of an “unmet medical need” if there is no appropriate alternative treatment or means of diagnosis for the disease or condition, or if it provides a clinically meaningful advantage over existing legally marketed devices (e.g., due to a break-through technology).

If a device manufacturer is proposing or developing a novel device that it believes meets the definition for consideration under the EAP, it is important to request designation from the FDA early in the development process. The FDA expects to engage in interactions with the manufacturer very early in the process and proactively work with sponsors through the assessment and review process to try to reduce time and cost for approval. The agency’s Pre-Sub program is still applicable for requesting meetings and specific FDA feedback. It is important to understand that the EAP is not itself a mechanism for marketing approval, but is a process intended to offer potentially faster approval via the de novo or PMA pathway.

One of the key features of the EAP is the Data Development Plan, which is a description of the sponsor’s plan for device development, for collecting and analyzing non-clinical and clinical data (pre- and post-market), and the proposed timeline for marketing of the device. The FDA expects a sponsor who requests review via the EAP to commit to prioritizing device development and the resolution of any scientific and regulatory issues during the process.

As a new program, it remains to be seen how successful the EAP will be with regard to expediting approval.


Clearly, a device that is novel in terms of design, principles of operation, materials, intended use or indications for use presents challenges to the manufacturer. However, the rewards to the manufacturer and to the US public of bringing unique devices to the market may far outweigh those challenges. Some novel devices may still be found substantially equivalent to an existing legally marketed device if adequate data is presented to show that the technological differences do not raise different questions of safety and effectiveness and

can demonstrate that the new device is as safe and effectives as the predicate device. Manufacturers of novel devices for which substantial equivalence cannot be demonstrated via a 510(k) must determine the applicable pathway to the market, and are strongly encouraged to engage the FDA early in order to determine the most appropriate classification, approval pathway and requirements. Although most novel, higher risk devices will go through the standard PMA process, some may be eligible for approval via a de novo or HDE pathway, and for expedited review via the EAP process.



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