The release of Netflix Inc.'s documentary "The Bleeding Edge" in July has stirred up questions around medical device safety and regulation in the U.S. — a multilayered system that has evolved over four decades.
The documentary primarily focuses on the injuries people have reported from using medical devices such as metal-on-metal hip replacements or Bayer AG's controversial permanent birth control implant Essure. But the film also shines a spotlight on the industry overall and the approval process that devices go through before hitting the U.S. market.
Stuart Goldman, a senior consultant with Emergo Group Inc., which works with medical device companies, summed up U.S. regulation this way: "It can get kind of complicated."
Even before getting into the process of approving medical devices, there is the matter of defining what a medical device is. The term covers such a broad spectrum — from manual toothbrushes to robotic surgery systems — that more than 50,000 products approved or cleared by the U.S. Food and Drug Administration between 2001 and 2016 are all considered to be medical devices.
Because of this wide range of devices and the risks associated with them, different standards and clearance processes are required before a product is allowed to be introduced to the market. As a result, the U.S. has established one of the most complex regulatory systems in the world, according to Goldman.
The FDA's process for reviewing applications includes a device classification system, product stress tests, manufacturing regulations and separate testing standards for product codes that can get as specific as endosseous dental implants, he said.
Medical devices are regulated by the Center for Devices and Radiological Health, which is part of the FDA. The CDRH is responsible for making sure that devices are safe and marketed according to their use, and its Office of Device Evaluation reviews applications for new devices before they can be sold or marketed.
Because devices can vary so much, divisions within the Office of Device Evaluation focus on specific areas including neurological, cardiovascular or dental devices, and teams within these specialist groups review the thousands of applications the FDA receives each year.
These teams can be made up of engineers, physicians and academics, all with different areas of expertise, said Deborah Kotz, an FDA spokesperson.
Even before an application can be submitted and the review process can begin, a device needs to be categorized in one of three classes depending on its level of risk: Class I is for low-risk products, such as a manual toothbrush or tongue depressor; Class II indicates moderate risk; and Class III involves high-risk devices, such as a replacement heart valve.
A product's classification will determine which application will be submitted for marketing approval and the pathway it takes through the FDA.
Because Class I devices are considered to be low risk, most do not need to go through an extensive pre-market approval process. They still need to follow standard FDA manufacturing regulations and pass some tests, but the scrutiny is not anywhere near the level of Class II or III products.
If a device is high risk and completely new to the market, it is considered to be in Class III, and the manufacturer is required to submit what is called a pre-market application, or PMA. If a product is considered to have moderate risk, which makes it Class II, and can show that it is similar to another device already on the market, then it will submit what is called a pre-market notification, or 510(k), after the section of the Food, Drug and Cosmetic Act that spells out the procedure.
The 510(k) program
The 510(k) is the most common application submitted, according to the FDA. In a 2017 report, the U.S. Government Accountability Office, Congress' investigative arm, stated that over 61,000 applications were submitted under this program from 2001 to 2016, compared to only 651 PMAs.
The program is unique because it depends on the idea of "substantial equivalence," which means that a device can avoid a longer, more complex review by showing that it is similar to one or more products that have already been approved or cleared by the FDA. These similar products are referred to as predicate devices.
While safety questions regarding predicate devices can be part of the process, there is no requirement to review a predicate device's safety history, according to Kotz. When reviewing whether substantial equivalence can be established, Kotz said, the Office of Device Evaluation will look at factors such as whether the device is intended for the same use as a predicate device, whether it is made with the same materials or whether it is designed in a similar way.
After a product completes the 510(k) process, it is considered to be cleared by the FDA but not approved like a product that has gone through the PMA protocol. Cleared products are still subject to FDA manufacturing inspections that can come years after a device first enters the market, Goldman said.
Of all the application types, 510(k)s have the cheapest user fees, which are paid by applicants to fund FDA reviews. A 510(k) application can come with a user fee of nearly $11,000, while a de novo or PMA application fee can be closer to $100,000 and $325,000, respectively. Depending on the size of the company submitting an application, the FDA can also choose to waive or lower the amount.
Other fees are also attached to supplement tests, annual reports, and notices, and there is an annual establishment registration fee of $4,624 that cannot be waived.
The de novo process and PMAs
Not all devices have a similar product that has been cleared or approved by the FDA.
Class II devices that do not have a predicate device go through what is called the de novo process, a newer option that allows these moderate risk devices to avoid having to go through the scrutiny required of Class III devices.
The PMA review for Class III devices is the most rigorous process for a device. These products are either completely new to the market or are entering the market after significant alterations. PMAs take a longer time, cost more money in user fees and have stricter review procedures, usually requiring clinical data that are only required in some 510(k) reviews.
The FDA can also demand that studies be conducted after marketing approval in order to show that the device is safe and operating as expected.
Products such as glucose-monitoring systems for diabetics and Medtronic PLC's Deep Brain Stimulation, an implant that uses small electrical pulses to reduce the frequency of seizures, have been approved through the PMA process.
The FDA did not become responsible for medical devices until 1976. Since then, several regulatory and process changes have been made to better reflect the requirements of the products being evaluated every year.
The agency's Center for Devices and Radiological Health is now thinking of making a larger, structural change. The center is looking to integrate aspects from the entire life cycle of a device and put them on to one team. Kotz said the goal is to have "a team that can really evaluate devices from the beginning, from conception ... all the way through our review, and going on the market, and once it's on the market."
The change is currently in a pilot program and would need to be approved by Congress before it is fully implemented, Kotz said.