Clearing the Way to 510(k)

An independent review in 2012 of the U.S. Food and Drug Administration (FDA)’s 510(k) clearance process for medical devices showed that many submissions were inadequate—critical information was missing, documentation was incomplete, formats were confusing, and overall structure was inconsistent. This article will explore some of the reasons such mistakes happen and outline what companies must know to be successful in their 510(k) submissions.

In October 2012, the FDA developed completely new guidance, with the purpose of clarifying the submission process and speeding up the approval of medical devices within 90 days of receiving the application. The agency, however, did formalize the review structure and timelines in such a way that it can stop and start the 90-day clock as needed—for example, if it needs additional information from the submitter. 

The medical device industry is still adjusting to the FDA’s new regulations, approach and expectations. Even with the most recent guidelines in place that are meant to streamline the process, approval time for 510(k)s still can vary greatly by FDA branch, or from reviewer to reviewer. Reviewers have large amounts of discretion in asking for additional information for the 510(k) applications they are responsible for. For example, sometimes reviewers ask for additional testing to show compliance with standards that are not listed by FDA for that type of device—which often adds time and extra cost to the process. 

RTA Guidance
On Dec. 31, 2012, the FDA released its Refuse to Accept (RTA) Guidance. This document is intended to be crosschecked by the submitter to ensure the submission is complete. The 97-point checklist was developed as an administrative tool to help medical device companies be certain all required elements are present and complete in the submission—not for the FDA to determine if the results of testing are acceptable. As per the guidance, the reviewer may note that some results are problematic—but because the RTA criteria have been met, the submission should pass RTA, with the problematic issues to be discussed later during the substantive review.

Medical device companies—especially startups—are still catching on to the new system. The first and most critical step in the 510(k) process is being sure the submission will pass the RTA. The submission must be prepared so that each of these points is considered, with any data that may be required, so that any questions anticipated by the FDA can be adequately explained.

A key issue that requires patience and communication skills is the variability in the review process that can arise from differences in education and training among reviewers. For example, reviewers may concentrate on areas that they know the most about, depending on their backgrounds; mechanical engineers will ask for more information on bench testing, chemists for information on materials, etc. To create more consistency and reduce variability, the FDA is training its reviewers to be more consistent in their approach and the questions asked. This is an ongoing process.

Top Areas of Scrutiny
Reprocessing of reusable medical devices is a huge concern to the FDA. Given the recent “superbug” outbreaks and deaths associated with contaminated, reprocessed duodenoscopies, the agency has taken a hard stand on even the simplest instruments that manufacturers say can be used on a patient, cleaned, disinfected/sterilized and then reused.

The March 17, 2015, guidance “Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling” fundamentally alters the standard approach to orthopedic instrument cleaning and sterilization. In the past, the FDA relied on a manufacturer’s good manufacturing practices and adherence to the quality system regulation for these validations. In short, a manufacturer could tell the FDA how it planned to validate instrument reprocessing—yet the validation itself was not required to be complete at the time of the 510(k) submission. The FDA relied on manufacturer statements that they would conduct the necessary validations, as well as its own Office of Compliance routine site audits to review manufacturer validations.

With new 2015 guidance, the FDA explicitly states that the cleaning/sterilization/reprocessing information supplied in 510(k)s must already be validated. This presents major implications for manufacturers of simple instruments, since these validations take weeks or months to complete and can be expensive. For startups, this can create a 510(k) delay that could negatively impact their ability to raise the capital they need to perform these validations.

A second area of scrutiny by the FDA is validation of manufacturing cleaning processes. Complete removal of manufacturing fluids and oils from a medical device at the end of the manufacturing process is absolutely critical to the finished device’s biocompatibility. In order to avoid biocompatibility testing on the finished device, a manufacturer can start with a known biocompatible ASTM/ISO-grade raw material, perform the manufacturing operations, and then run the device through a validated cleaning process to ensure that manufacturing fluids/oils are removed and the only thing left is the biocompatible raw material from which the finished medical device is made.

The issue here is similar to the FDA’s recent change on reprocessing reusable medical devices, in that manufacturing clean line validations are typically not complete at the time of the 510(k) submission. However, more reviewers are insisting this validation data be available to review during the 510(k) process, rather than during routine compliance audits. Because clean line validations are site- and process-specific, this demand can result in significant delays and added expense for the manufacturer.

For example, if a medical device manufacturer is using a prototype shop to produce “production-equivalent” samples for mechanical testing, it cannot use those parts in a clean line validation because the prototype shop will likely not be performing the full-scale production.

To summarize, in the past a 510(k) could be submitted with design verification data gathered from prototypes, but now the FDA wants production validation data included in the 510(k), instead of relying  on a manufacturer’s quality system and FDA inspections to ensure the production validations are adequate. This significantly changes the point in the product development process at which a 510(k) can be submitted.

Getting It Right the First Time
The goal of the 510(k) submittal process is to provide the FDA everything it needs to move through the process smoothly and efficiently. Submitters should follow the RTA and not provide unneeded or confusing information. The best way to do this is to follow the FDA guidance documents, ASTM/ISO standards, and research how other manufacturers have tested their devices. Even if a medical device company does all of this perfectly, the FDA can still make requests for additional data, which must still be fulfilled. And it is not just the technical data that must be in order; even typographical errors can result in the submittal being returned for correction, delaying the submittal process. 

Some medical products have no recognized standards or FDA guidance to follow. The manufacturer must design a robust testing protocol, provide all necessary data, and have it meet or exceed FDA expectations. One might think this is the ideal situation for a pre-submission meeting with FDA, but in the world of medical device development where speed to market, regulatory milestones, and investment capital are critical to a company’s success, the requirements and time involved in the FDA presubmission program can often make it a non-starter.

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No medical device company wants to make a bad product. Everybody wants to abide by FDA guidelines and the FDA is working to make it a more efficient process. The FDA is also trying to interact with manufacturers in more constructive ways to get their input and technical knowledge on materials and testing methods. It is equally important for manufacturers to be proactive and welcome the FDA to tour their facilities to gain a deeper understanding of the science behind their products and manufacturing processes. Finally, develop positive relationships with FDA reviewers and don’t hesitate to contact them when preparing responses to questions they have posed.

Navigating the 510(k) process can seem daunting, especially for younger companies and start-ups who don’t have the resources or in-depth experience with the process. These companies, as well as larger and more established firms who want a larger, industry-wide perspective from experienced experts about how to submit a 510(k) in the most cost-efficient and time-efficient manner, should consider working with experienced contract manufacturers. A core strength for many of these companies is the ability to rapidly develop creative and compliant solutions to what are often unique problems, followed by crafting a 510(k) that has the best chance of moving quickly through the application process. 

Kellen Hills and Tim Lohnes work for the Orchid Design division of Orchid Orthopedic Solutions. Hills is a senior quality and regulatory consultant at the firm’s Memphis, Tenn., location, and  Lohnes is senior regulatory consultant in Shelton, Conn.