8.2: Market Submission Options

Premarket Notification (PMN) 510(k)

In section 510(k) of the FD&C Act, device manufacturers are required to notify the FDA of their intent to market a medical device as a Premarket Notification (PMN) or 510(k). The purpose of a 510(k) is for a manufacturer to demonstrate that the device is as safe and effective (substantially equivalent) to a device already on the market. If FDA rules the device is "substantially equivalent," the manufacturer can market the device. Some Class I, most Class II, and a few Class III require a 510(k). https://www.fda.gov/medicaldevices/premarket-submissions/premarket-notification-510k

What is Substantial Equivalence?

A 510(k) requires a demonstration of substantial equivalence to another legally U.S. marketed device. Substantial equivalence means that the new device is at least as safe and effective as the predicate. A device is substantially equivalent if, in comparison to a predicate it:

• has the same intended use as the predicate; and
• has the same technological characteristics as the predicate; or
• has the same intended use as the predicate; and
• has different technological characteristics and does not raise different questions of safety and effectiveness; and
• the information submitted to the FDA demonstrates that the device is at least as safe and effective as the legally marketed device.

A claim of substantial equivalence does not mean the new and predicate devices must be identical. Substantial equivalence is established concerning the intended use, design, energy used or delivered, materials, chemical composition, manufacturing process, performance, safety, effectiveness, labeling, biocompatibility, standards, and other characteristics, as applicable.

A device may not be marketed in the U.S. until the submitter receives a letter declaring the device substantially equivalent. If FDA determines that a device is not substantially equivalent, the applicant may:

• resubmit another 510(k) with new data,
• request a Class I or II designations through the De Novo Classification process
• file a reclassification petition, or
• submit a premarket approval application (PMA).

Premarket Approval (PMA) 21 CFR 814

A Premarket Approval (PMA) application must be submitted if a manufacturer wants to market a new product that differs from products already on the market. PMA only applies to Class III devices! "A PMA is the most stringent of the submissions and must provide valid scientific evidence collected from human clinical trials showing the device is safe and effective for its intended use. If the device is life-sustaining or presents a potential, unreasonable risk of illness or injury, it may have special approval processes (under Class III)" (FDA.gov). www.fda.gov/medical-devices/premarket-submissions/premarket-approvalpma

Devices Used in Blood Establishments

The Center for Biologics, Evaluation, and Research (CBER) has expertise in blood, blood products, and cellular therapies as well as the integral association of certain medical devices with these biological products. To utilize this expertise, marketing, and investigational device submissions (Premarket Notification, Premarket Approval, an Investigational Device Exemption) for medical devices associated with the blood collection and processing procedures as well as those associated with cellular therapies are reviewed by CBER. Although these products are reviewed by CBER, the medical device laws and regulations still apply.

Class I/II Exemptions

Certain Class I and Class II devices are exempt from premarket notification [510(k)] requirements as well as the Medical Device Good Manufacturing Practices (GMPs), also referred to as the Quality System (QS) Regulation. A Class I or Class II device that is exempt from 510(k) requirements must still comply with other requirements (known as regulatory controls) unless the device is explicitly exempt from those requirements, as indicated in the regulation for that device type. Anyone can determine whether a device is exempt from 510(k) or GMP requirements by searching the FDA’s Product Classification database. https://www.fda.gov/medical-devices/classify-your-medical-device/class-i-ii-exemptions

510(k) Exemptions

Most Class I and some Class II devices are exempt from 510(k) requirements, subject to certain limitations (see sections 510(l) and 510(m) of the Federal Food, Drug & Cosmetic Act). A device may be exempt from 510(k) requirements if the FDA determines that a 510(k) is not required to provide reasonable assurance of safety and effectiveness for the device.

Devices which may be exempt from 510(k) requirements are:

1. Preamendments devices; and
2. Class I and Class II devices specifically exempted by the FDA

The term “preamendments device” refers to a device legally marketed in the U.S. before the enactment of the Medical Device Amendments on May 28, 1976, and that has not been significantly changed or modified since then; and for which the FDA has not determined a Premarket Approval (PMA) application is needed to provide reasonable assurance of the device’s safety and effectiveness.

Humanitarian Device Exemption

Through the Orphan Drug Act (ODA) of 1984, a rare disease is defined as a disease or condition that affects fewer than 200,000 people in the United States. Currently, in the United States, only a portion of the 7,000 known rare diseases have approved treatments. By definition, rare diseases or conditions occur in a small number of patients. As a result, it has been difficult to gather enough clinical evidence to meet the FDA standard of reasonable assurance of safety and effectiveness. To address this challenge, Congress included a provision in the Safe Medical Devices Act of 1990 to create a new regulatory pathway for products intended for diseases or conditions that affect small (rare) populations. This is the Humanitarian Device Exemption (HDE) Program.

Definitions:

• Humanitarian Use Device (HUD): a medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in not more than 8,000 individuals in the United States per year (Section 3052 of the 21st Century Cures Act (Pub. L. No. 114-255).
• Humanitarian Device Exemption (HDE): a marketing application for a HUD (Section 520(m) of the Federal Food, Drug, and Cosmetic Act (FD&C Act)). An HDE is exempt from the effectiveness requirements of Sections 514 and 515 of the FD&C Act and is subject to certain profit and use restrictions.

Prohibition on Profit

The Food and Drug Administration Amendments Act of 2007 (FDAAA) contained incentives to facilitate the development of medical devices for pediatric populations (defined as patients who are younger than 22 years of age). Under section 520(m)(6)(A)(i) of the FD&C Act, an HUD is only eligible to be sold for profit after receiving an HDE approval if the device is intended for the treatment or diagnosis of a disease or condition that either (1) occurs in pediatric patients or a pediatric subpopulation, and such device is labeled for use in pediatric patients or in a pediatric subpopulation in which the disease or condition occurs; or (2) occurs in adult patients and does not occur in pediatric patients or occurs in pediatric patients in such numbers that the development of the device for such patients is impossible, highly impracticable, or unsafe. HDE applicants whose devices meet one of the eligibility criteria and wish to sell their HUD for profit should provide adequate supporting documentation to FDA in the original HDE application. HDE holders who wish to sell their devices for profit and who did not submit the request in the original HDE application may submit a supplement and provide adequate supporting documentation to demonstrate that the HUD meets the eligibility criteria.

Other Exemptions: Investigational Device Exemption (IDE) 21 CFR 812

An investigational device exemption (IDE) allows the investigational device to be used in a clinical study to collect safety and effectiveness data. Clinical studies are most often conducted to support a PMA. Only a small percentage of 510(k)s require clinical data to support the application. Investigational use also includes clinical evaluation of certain modifications or new intended uses of legally marketed devices. All clinical evaluations of investigational devices require an approved IDE.

Depending on the class of device (Class I, II, or III), the application may take a different regulatory route. For example, a Class III device requires a Pre-Market Application (PMA) and clinical studies, a Class II may not require clinical studies, and Class I do not need FDA approval to market the product (but it must be registered with FDA). More on devices in a later chapter! www.fda.gov/medical-devices/howstudy-and-market-your-device/device-advice-investigational-device-exemption-ide

Institutional Review Board (IRB)

Device clinical studies are monitored by the Institutional Review Boards (IRB) located at the clinical studies site. Recall the IRB's purpose is to ensure ethical practices such as informed consent and patient selection criteria. If the IRB determines that a device is a significant risk to the patient, they must submit an IDE application to the FDA. The FDA must approve the application before the applicant enrolling patients in the clinical study. If the IRB determines that the device is not a significant risk, they may enroll patients without submitting an IDE. The clinical study will be monitored by the IRB under the IDE regulations in 21 CFR 812.2(b). Confidentiality requirements ensure the FDA will not disclose the existence of an IDE. This review process is not only rigorous, but it is also expensive. The FDA reported, in 2013, the PMA process fee was $248,000, and the 510(k)-processing fee was an additional $4,900.

Test Your Knowledge!

Decorative Contact Lenses – A Case Study: Explore this webpage and watch the accompanying video on decorative contact lenses. https://www.fda.gov/forconsumers/consumerupdates/ucm275069.htm and consumer information here: https://www.fda.gov/medicaldevices/productsandmedicalprocedures/homehealthandconsumer/consumerproducts/contactlenses/ucm270953.htm

1. Why are decorative contact lenses considered devices?
2. What are the risks of decorative contact lenses?
3. Imagine you are a company wanting to sell a decorative contact lens. Map out your application process, consider:
   1. What class of device?
   2. What Center will you contact?
   3. Will you require PMN, PMA, IDE, or IRB?