A host of interrelated factors complicate the FDA’s ability to determine the risk/benefit profile of medical devices. But does the FDA do any worse than comparable agencies abroad?
The US Food and Drug Administration (FDA) defines medical devices as instruments, implants, or contrivances indicated to diagnose, treat, mitigate, or prevent a disease, with the further clarification that devices are not metabolized as drugs by the body. The FDA classifies devices according to their intended use (as diagnostic, prosthetic, surgical, or therapeutic), their specific indications, and the degree of danger they pose.
Determining the risk a device creates is challenging. FDA reviewers require time and resources, as well as wide-ranging expertise and flexibility, to look critically at devices, which in some cases represent entirely novel technology. Political pressure makes the Agency cautious: it has to consider the potential fallout were an approved device to create significant harm.
Some of these challenges are universal and shared by the FDA’s counterparts in other countries. It is tempting—and, for manufacturers, can be an essential strategic step—to compare the FDA to Health Canada and the EU’s approval networks. But comparisons between these agencies are not straightforward, and where it ultimately makes sense for a manufacturer to gain approval for and market its device is best decided on a case-by-case basis.
FDA Device Approval
The FDA classifies devices based on their potential dangers. In ophthalmology, diagnostic devices such as corneal topographers, which pose little risk, are considered Class I devices. Contact lenses, which entail greater risk, are Class II devices. Class III devices are those that support or sustain life, and/or involve significant risk either in situations in which patients are exposed to the device or in the event that the device should fail.
Before a medical device can be marketed in the US, the FDA must grant either Premarket Notification 510(k) or Premarket Approval (PMA). Although there have been some notable exceptions (see box), Class II devices typically go through a 510(k) process; and Class III devices typically require a PMA.
The 510(k) process was established as a simplified method to classify and determine the safety, effectiveness, and risk profile of new devices that can be demonstrated to be “substantially equivalent” in indication, safety, performance, and risk profile to an already marketed device. Devices do not have to be identical, but they have to have the same intended use and similar technological characteristics. For higher-risk devices, the FDA is able to request clinical data to substantiate a 510(k) application.
The more rigorous PMA process applies to Class III devices, some Class II devices that require additional clinical data, and those devices that are not yet classified. The PMA application relies primarily on the results of well-controlled clinical trials to provide enough information on safety, efficacy, and risk for the FDA to determine a device’s risk classification and reasonable assurance that it is safe and effective for its intended use.
The European Union
In the EU, medical devices are awarded a CE mark after passing a staged process of review. While this is similar in certain respects to the FDA’s process, the European process differs significantly in that the review is not undertaken by a centralized body.
European medical device manufacturers develop a thorough technical file on each new device, and this file is submitted to a “notified body” in the EU nation in which the company plans to market. A notified body is an organization accredited by an EU member state for medical device assessment and approval. At the direction of the notified body, a “qualified expert” in the field reviews the technical file, comparing it against the EU’s comprehensive requirements for medical devices. The qualified expert is someone with experience and expertise in the clinical area in question. Qualified experts and notified bodies themselves come under the review of the “competent authority,” a state-appointed body responsible for ensuring that the EU’s medical device directives are applied and adhered to.
The EU puts great emphasis on collaborative action. When a notified body finds nonconformity with the EU’s medical device directives, it works with the company to develop a corrective action plan and monitor progress towards completing it. When the FDA finds a deficiency, there are also corrective and preventative actions, but the interactions tend to be more punitive and less directly collaborative than in the European system.
Every PMA submitted for a medical device in the US triggers an automatic data integrity audit, in which the FDA arranges an on-site inspection of either the sponsor or one or more of the clinical investigation sites. In the EU, notified bodies can undertake inspections, but this does not happen as a matter of course. Each device’s company-supplied technical file includes documentation on investigative and manufacturing processes and regulations—in addition to product safety and efficacy data—which is usually sufficient. Even for a Class-III device, CE mark approval is not contingent on an on-site inspection by a government regulatory body. This accounts, in part, for the perception that it is easier to get approval for a Class III-level product in the EU than the US.
But Is the FDA Slow?
Due to the perception that it is easier, quicker, and less expensive to go through the EU process and receive a CE mark, we see many medical device companies taking their development to Europe and then returning to the US once their clinical safety and efficacy data is fully characterized and the device CE marked. But is it true that medical devices, particularly high-risk devices, take longer to be approved in the US than abroad?
A recent study published in the New England Journal of Medicine evaluated this question, looking both at regulatory approval process and at the device’s incorporation into public and private insurance coverage (since device approval alone does not translate into immediate availability for most patients). This comparison found time from application to availability of high-risk devices to be similar or even shorter in the US than in top European markets (France, Italy, Britain, and Germany).1
However, the authors acknowledged that comparing review times alone typically leaves the FDA far behind. In 2011, PMA approvals averaged 13.1 months, including both FDA review time and time for sponsors to address application deficiencies; but time to CE marking for high-risk devices is 1 to 3 months.1 However, most people in European countries are publicly insured, and reimbursement decisions vary widely from country to country.
In my personal experience, the FDA is demanding more information than in the past from its 510(k) applicants and this is making the process longer. In the past, it was not necessarily the case that devices were reviewed by physicians in the specialty in which the device would be used. But now a device is typically reviewed by specialists from the field that will use it; and their review tends to be more rigorous, more clinically focused, and more time consuming.
Barriers and Red Flags
My impression is that the cost of doing a clinical trial is now about three to four times higher than what it was even 5 years ago, simply because the regulatory processes and the level of documentation required has increased. Often problems or safety concerns (“red flags”) that arise in one therapeutic area may cause all other devices in that area to undergo a level of scrutiny that may not be be warranted in every case.
Devices that can be used in children face a different barrier. In one recent case, a company with a humanitarian-use device indicated for a rare disease wanted to use the device in pediatric patients. FDA required that the company conduct a separate study of the device in a pediatric population, even though the differences between the pediatric and adult population were minimal and the number of pediatric patients with the rare disease are few in number. In effect, the FDA has requested that this company double its testing costs. This forces the company to make a business decision: Can it afford to develop this device for US children or not?
Medical device development entails significant financial risk; mitigating that risk requires careful strategic planning from early in the development process. In one case I observed, a company had developed an implant and had clinical experience with it in a large patient population via compassionate use device exemptions. Even with solid, multiyear follow-up data in humans, the FDA required the company to perform additional biocompatibility testing in animals before allowing a formal clinical study in humans. This considerably lengthened the time to the start and completion of the clinical study and hence to approval. Careful planning and working with the FDA is essential to preventing this type of delay.
In the EU, with this same device, the biocompatibility data was considered adequate without additional study. In fact, EU would not allow the tests requested by the FDA. In Europe, if the data that can be obtained from a biocompatibility study in animals does not outweigh the risk to the test animals, and if there are other ways to determine biocompatibility, then animal biocompatibility tests are deemed unwarranted.
Given the great cost and effort required, manufacturers have to ask with each new device: Where does it make most sense to get this device approved and marketed? And what can be done to ensure the largest possible market with the least effort and expense?
While the US is a huge and highly desirable market to be in, certain companies have decided not to sell here. Schwind excimer laser systems, for example, have been called “the best laser you will never see in the US,” since Schwind has determined that the cost of FDA approval is too high in comparison to potential US sales. Companies have to look at demographics, economics, and regulations when critically evaluating and developing a strategy.
THE BOTTOM LINE
Resources, politics, and its own regulations challenge the FDA in its careful review of medical devices. Likewise, the decisions medical device companies must make about where and how to seek regulatory approval must take into account many variables within the different regulatory environments around the world. Increasingly, companies must develop long-range, global strategies for navigating device regulation. And in order to ensure that only safe, effective devices are brought to market, the US FDA must find a balance between caution and efficiency.
Barbara Fant, PharmD, is founder of Visionary Excellence in Ophthalmology Research Consortium, president and CEO of Clinical Research Consultants, Inc, and a technical reviewer at the British Standards Institution (BSI). She was assisted in the preparation of this manuscript by Refractive Eyecare managing editor, Jennifer Zweibel.
1. Basu S, Hassenplug JC. Patient access to medical devices—a comparison of US and European review processes. N Engl J Med. 2012 Aug;367:485-8.