U.S. Premarket Submissions: Understanding the Necessary Regulatory Controls

Perhaps the most exciting and rewarding part of medical device manufacturing is bringing to market an effective, innovative, and safe healthcare solution for patients. Getting to that point, however, is no easy feat. Understanding the regulatory controls and premarketing pathways is critical—and challenging. Successfully navigating the regulatory hoops becomes even more complicated depending on the market in which manufacturers hope to launch their product.

The first in a two-part series on premarket submissions, this article highlights the critical steps necessary to proceed with U.S. premarket submissions.

The 1938 U.S. Food, Drug & Cosmetics Act is the legal framework that authorizes the U.S. Food and Drug Administration (FDA) to regulate medical device manufacturing and use. Today’s FDA adopts a risk-based approach to medical devices and, regarding safety data, expects a full biological evaluation of devices, including chemical characterization data, a toxicological risk assessment, and biological data in a comprehensive weight of evidence review.

The FDA’s focus on risk is important to remember because a crucial step in any premarket submission is classifying a device according to its risk level.

Medical Device Classification
The FDA has classified around 1,700 medical devices into 16 specialty areas—also called panels—and organized them in the Code of Federal Regulations (CFR). Classification depends on a device’s intended use and its indications for use. For example, a scalpel is used to cut tissue, but its indications for use may be more specialized. Scalpels designed to cut delicate corneal tissue will include a different indication than those used to cut thick dermal tissue. In this case, the different indications for these scalpels may impact their classification. Indications for use are most often found in the device’s labeling.

Regardless of classification, a device’s risk to patients and users determines the risk level and regulatory panel to which it is assigned. Class I devices pose the lowest risk; Class III includes the most significant potential risks. A device’s class dictates the premarket effort required to obtain regulatory clearance.

According to the FDA, “Most Class I devices are exempt from premarket notification 510(k); most Class II devices require premarket notification 510(k); and most Class III devices require premarket approval.”

Most medical devices obtain U.S. regulatory clearance via premarket notification [510(k) submission]. This submission must show the device is substantially equivalent (SE) to a predicate device (one with an identical intended use that is sold in the U.S.). Most manufacturers choose a product recently cleared under 510(k) guidelines as the predicate device, but any appropriate legally marketed device can be used.

The FDA considers a device substantially equivalent if, compared to a predicate, it:

• has an identical intended use to the predicate; and
• has identical technological characteristics to the predicate; or
• has an identical intended use to the predicate; and
• has different technological characteristics but has the same safety and effectiveness assurances; and
• information submitted to FDA demonstrates the device is as safe and effective as a legally marketed device.

Devices requiring a 501(k) submission cannot be distributed commercially until the manufacturer receives a letter of SE from the FDA. Non-SE devices require a premarket approval (PMA) application to obtain sales clearance.

Class I and specific Class II devices are considered exempt and do not require a PMA to be market-ready. Class III devices carry the highest risk and generally pose a significant risk of illness or injury. The PMA process can be more intricate, requiring about 20 percent of manufacturers to include clinical data in their 510(k) submissions. Class III devices that fail to meet PMA requirements are deemed “adulterated” and cannot be marketed.

Manufacturers unsure about their device’s classification can use the FDA’s classification database to find the regulation number corresponding to its classification. Manufacturers can also search by device panel (medical specialty) to identify their device and any pertinent regulatory specifics.

When No Predicate Device Exists
The existence of a predicate device makes risk evaluation and premarket submissions relatively straightforward. However, a “De Novo request” is a marketing pathway for novel medical devices that cannot claim a predicate device but can reasonably assure safety and effectiveness. A De Novo request is a risk-based classification that applies only to Class I or II devices. Manufacturers should make De Novo requests for:

• Devices deemed non-SE in response to a 510(k) application
• Devices wherein no predicate product exists in which to base an SE determination

The FDA recommends manufacturers submit a pre-submission evaluation with De Novo applications so the agency can provide feedback or offer specific guidance before an official premarket submission.

COVID-19 also changed the medical device regulatory pathway. The FDA is charged with protecting the public against biological, chemical, radiological, or nuclear threats; consequently, it granted emergency use authorization (EUA) to new medical devices designed to battle SARS-CoV-2.

An EUA allows the FDA to authorize unapproved devices or unapproved uses of approved devices in emergencies. Medical products that help diagnose, treat, or prevent serious or life-threatening diseases or conditions can be fast-tracked even if no predicate device exists.

Marketing Pathways for Humanitarian Devices
Class III medical devices that treat rare diseases or conditions may qualify for humanitarian use designation (HUD). To obtain clearance, manufacturers must apply for the designation through the FDA’s Office of Orphan Products Development (OOPD).

The OOPD works with medical researchers, professional organizations, academic institutions, governments, and patient groups to fast-track submissions for devices, drugs, biologics, or medical foods that promise to treat, prevent, or diagnose rare conditions.

A 2016 amendment to the HUD designation defines a “rare” disease or condition as one that affects no more than 8,000 U.S. individuals annually. Manufacturers applying for a HUD must be able to justify the patient need for their device and its indications for use.

Combination Product Complexity
An exception to the aforementioned guidance applies to combination products. The complexity and uniqueness of these devices requires additional guidance from the FDA’s Office of Combination Products (OCP).

Combination products contain a combination of drugs, devices, and biologics that, individually, would be regulated by one of three FDA centers: the Center for Biologics Evaluation and Research (CBER), Center for Drug Evaluation and Research (CDER), or Center for Devices and Radiological Health (CDRH).

A combination product’s primary mode of action (PMOA) may help manufacturers determine which regulatory center has primary jurisdiction and is ultimately responsible for its review. If the PMOA falls to the product’s device element, the CDRH is the principal reviewer. If a drug or biologic is responsible for the PMOA, the CBER or CDER is in charge. 

If a device has two independent modes of action, and neither is subordinate to the other, the FDA has an algorithm for determining center assignment. Together, the product category and PMOA determine how to engage the appropriate regulatory center.

Final Preparations Before Premarket Submission
Once a manufacturer appropriately classifies a device and determines the correct regulatory review process, there are administrative details that should not be overlooked.

• User fees: Certain applications have user fees. Manufacturers that qualify as “small businesses” or those seeking HUD are eligible for substantial fee reductions.
• Digital copies: The FDA requires all premarket submissions to include digital versions of all documents. CDs, DVDs, or flash drives fulfill this requirement.

A Final Recommendation
Introducing a new medical device to the U.S. market is not easy but the process is well-documented and the FDA provides guidance. In fact, regulators will conduct an initial administrative review of premarket submissions to ensure the submission is complete and the review process runs smoothly.

Yet compiling the necessary documentation for premarket submissions can be daunting and time-consuming. Device manufacturers new to the U.S. market or those introducing novel or humanitarian devices cannot risk missing a step or overlooking a critical part of the process. An experienced lab testing partner can ensure manufacturers are on the right track and improve their chances of regulatory success. 

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Sandi Schaible is the senior director of analytical chemistry and regulatory toxicology at WuXi AppTec Medical Device Testing, specializing in extractables and leachables studies. She is a U.S. delegate and international delegate for ISO 10993 part 18 in chemical characterization, and a U.S. delegate for ISO 10993 part 13 and the particulates committee.

Dr. Sherry Parker has over 20 years of toxicology and medical device experience and is an expert in biological evaluation of medical devices and combination products. Dr. Parker provides manufacturers with guidance on global regulatory and technical requirements and testing program design. In May 2019, Dr. Parker was appointed to a three-year term as co-chair of the Biological Evaluation Committee. She is an internationally recognized ISO expert and a U.S. delegate for TC 194, the technical committee for ISO 10993, and is a past president of the Medical Device and Combination Products Specialty Section of the Society of Toxicology.