A 2017 guidance provides a very detailed interpretation of the FDA’s stance on device changes warranting 510(k) submissions.1 Through flowcharts and descriptive questions, manufacturers can evaluate their changes against the criteria the FDA deems most critical to report. While comprehensive, the guidance is an immense amount of data for a design team to parse through and can take a significant amount of time to consider. There also remains an amount of subjectivity in these determinations, where a lenient viewpoint would arrive at a different conclusion than a conservative one.
Summary of Existing Guidance
The FDA summarizes the primary principles manufacturers must consider in determining whether their change warrants a 510(k). The more impactful principles from this list are summarized as follows:
- Changes made with intent to significantly affect device safety or effectiveness: If a manufacturer created the change to intentionally affect device safety or effectiveness, a 510(k) submission is warranted regardless of all other considerations in the guidance. This includes changes made to mitigate adverse events or known risks, whether observed or theoretical, as well as changes to improve clinical performance.
- Risk management and initial risk-based assessment: An initial risk-based assessment of the change is essential in determining when to submit a 510(k). Manufacturers should also incorporate compliant risk management QMS procedures throughout the implementation of a device change, documenting rationale on the acceptability of the risk profile and ensuring no new risks or harms are introduced. Should new harms or risks be identified, or if harms or risks from the original device are altered, a new 510(k) is required.
- The role of testing (i.e., verification and validation activities) in evaluating whether a change could significantly affect safety and effectiveness: Following a risk assessment where no new potential risks are identified, routine verification and validation activities must be performed. Any unexpected results in these activities should warrant additional consideration in submitting a 510(k).
- Evaluating simultaneous changes: Device changes can often come in great numbers, especially when considering multiple iterations of improvements or modifications. To address this, the FDA recommends evaluating these changes both independently and in aggregate. This is critical to avoid device creep, which can be a problem when each change is viewed individually.
- Change evaluation outcomes: Upon completion of the evaluation and risk assessment of the changes being implemented, manufacturers must complete one of two documentation pathways. If the changes do not warrant a 510(k), manufacturers must complete a “Letter to File” document, which describes the changes and includes reasons why a new FDA submission is not required. If the change evaluation indicates a 510(k) is warranted, manufacturers must receive FDA clearance before marketing. Importantly, changes made to a 510(k)-cleared device does not guarantee the original product will qualify as a predicate. A substantial change that significantly alters the device’s technology or intended use will most likely require a new predicate to be identified that better matches its characteristics.
Labeling changes can potentially significantly alter a device’s intended use. Subtle changes in labeling can result in monumental changes in device use; thus there is a significant onus put on manufacturers to fully evaluate these changes. Special attention should be paid to changes affecting indications for use, intended use, and the underlying disease/patient population. Any changes directly to indications for use require a traditional 510(k) submission.
Technology, engineering, and performance changes
Changes in technology, manufacturing, or performance warrant a great deal of consideration. As previously stated, any intentional or unintentional major changes to performance require a new submission. Other major changes in this category include modifications to operating principles, control mechanisms, sterilization, packaging, human factors, and device specifications.
A design change that would warrant careful thought, for example, might involve changing the size of a cleared implant to expand an available size range. Suppose the original device featured visualization holes, and user feedback supported a case for more holes. When the manufacturer reviews Flowchart B1 with the new implant size alone, internal documentation is the appropriate choice. However, when the manufacturer adds holes to allow better visualization, a 510(k) is warranted. Increasing the number of holes across the same surface area will decrease expected mechanical performance. Despite the overall device architecture remaining the same, the change in holes—and thus performance—would warrant a new 510(k). If the manufacturer did not improve visualization (more holes), then a Letter to File would be sufficient.
Depending on the device, any advanced manufacturing methods used, and the nature of patient contact, materials changes can greatly vary in terms of significance.
A materials change example would be adding a second PEEK supplier for manufacturing an orthopedic device. In following guidance questions, the manufacturer determines the change affects a material that contacts body tissues or fluids. Consequently, the manufacturer must perform a biocompatibility assessment to determine if any new biological risks are present. Since this material has already been used by the manufacturer in the cleared device, new biocompatibility risks do not necessarily warrant a 510(k) submission. But minor differences in the PEEK raw material processing could change the product’s mechanical and biocompatibility performance. In that case, a 510(k) would be required.
Another materials change example would entail modifying the manufacturing process itself, perhaps from subtractive to additive. In evaluating this change, it is important to follow the FDA guidance methodology. For spinal and orthopedic devices, there are two primary variables: biocompatibility and mechanical performance. Changes to the manufacturing process are generally addressed by Flowchart C1, which guides the reader through biocompatibility questions before performance specifications.
If this change affects part of a device that contacts body tissues or fluids, the manufacturer must conduct a biocompatibility risk assessment. Given the high level of biocompatibility concern surrounding additive manufacturing, great care is warranted in evaluating this change. This is due to distinct manufacturing processes and contact materials that differ between vendors. The “Biological Evaluation of Medical Devices” guidance provides details on performing these assessments. Should a new or increased biocompatibility concern be identified, and the material and manufacturing process have not been used in past submissions for a similar device, the change warrants a 510(k) submission. But if the manufacturer has cleared a device with the same material and manufacturing process, they might be able to move on to performance specifications. For orthopedic and spine implants, changing a product line to be additively manufactured generally introduces new biocompatibility questions stemming from the new material specifications and manufacturing process.
Focusing on Flowchart step C51, mechanical performance could be influenced by the microarchitecture of the additive manufacturing plan, and the overall process may be influenced by material powder standard, powder reuse, build plate location, and different power source inputs. In general, the mechanical test battery described in the respective FDA guidance must be repeated to ensure the additively manufactured product remains substantially equivalent to a predicate device. In this specific case, the performance specifications are affected, necessitating a new 510(k).
Similarly, a manufacturer may choose to add an additive manufacturing supplier to an implanted device that already featured additive manufactured components. This change would follow the same path through Flowchart C1 in the previous example. A biocompatibility assessment must be performed because the device contacts body tissue or fluids; then at step C5, the potential impact on mechanical performance must be determined. Given the complexity of additive manufacturing and the great potential for supplier variability, performance specifications could be impacted, thus requiring a new 510(k).
The risk assessments described here and in FDA guidance refer to practices consistent with ISO 14971. Risks are assessed for both the likelihood and severity of potential harms. If there is a negligible likelihood of harm from a change, then it is unlikely to prompt a 510(k) submission. Manufacturers are expected to have compliant risk assessment practices incorporated into their QMS that define the procedures required to fully evaluate device changes.
Software in a Medical Device (SiMD) or Software as a Medical Device (SaMD) have enough unique challenges and risks that it earned its own FDA guidance [“Deciding When to Submit a 510(k) for a Software Change to an Existing Device”].
As evidenced through SiMD and SaMD regulatory requirements, FDA has expressed more concerns with software development than hardware devices, which leads to a more complex paradigm to navigate following clearance. It is essential to the post-market compliance of medical device software that the manufacturer establish well-defined change management procedures, which include an assessment determining when regulatory oversight is required.
There are important nuances to consider when determining if medical device software changes require FDA oversight:
- Software failures due to design errors. There is no tolerance for failure upon device release and as such, FDA expects detailed documentation demonstrating the software is designed, implemented, and managed in a well-defined repeatable manner. Software verification and validation is comprehensively designed to address all foreseeable use cases; however, real-world user experience and user interaction plays an important and sometimes unpredictable role in maintaining software functions. Therefore, changes may be needed to address unforeseeable use cases.
- Software design changes are easily executed and happen often. Code maintenance is critical. Since no software is totally bug-free upon release, continuous changes are necessary to debug it. As such, software improves with age—a perplexing concept compared to hardware devices that wear over time. Aggregate changes can get the best of a software company so change/configuration management procedures should include a regulatory assessment that defines the threshold for a regulatory submission.
- Software changes have non-linear impact. Software changes could have a systemic impact and sometimes require regression testing, which is a gray area. If regression testing is completed successfully and specifications are met, the depth and complexity of a change may warrant a 510(k) submission.
- Cybersecurity updates. The software function maintenance process will inherently include enhancements to device security for any product that is connected to a hospital network or transmits data over the internet. FDA has clearly indicated that changes made to enhance cybersecurity alone do not require regulatory submissions.
Continued disregard to established guidelines could result in the adoption of new FDA enforcement policies. Firms should work diligently to establish proper methods of evaluating design changes and ensure their designs comply with FDA expectations, as later submissions could be hampered by prior submission failures. Following the guidance’s questioning, using compliant risk management procedures, and evaluating device changes in aggregate (and individually) are essential to 510(k) success.
FDA’s growing emphasis on the total product lifecycle has led to vested interest in more than the initial device clearance. The FDA intends to be involved at every step of a device’s lifecycle. As this new direction continues to evolve, it will be increasingly beneficial for any product line to appropriately utilize the Letter to File option as intended and to foster a collaborative relationship with the FDA to avoid any disagreements and potential delays in market entry.
Tom McDougal is a regulatory affairs associate focused on supporting and advising clients in completing key deliverables such as 510(k), PMA, and CER submissions. Tom brings experience from the medical device manufacturing industry, having held roles in regulatory affairs, quality assurance, and postmarket surveillance. His experience covers a range of device types, including orthopedic implants and imaging.