I’ve conducted medtech regulatory submissions for more years than I care to mention and I have been surprised on several occasions by the failure of a predicate device to be “cleared” by the U.S. Food and Drug Administration (FDA). In those instances, the device received 510(k) clearance but the consent did not apply to the particular products for which I was seeking substantial equivalence justification. Each time that happened, I thought, “How can that be?” Now I know the culprit: iterative design changes outlined in a letter to a sponsor’s file rather than a new 510(k) application.
What then, is the difference between a letter to file and a new 510(k) application? A letter to file is internal documentation justifying that design changes do not need a new regulatory submission. I’ve found a letter to file to be a faster route to commercialization because the reviewers are internal to the company and decisions are made well within the 90-day timeframe for a 510(k) approval process. If done properly, a letter to file does not decrease the corporate testing or documentation burden, but it can improve time to market. With such emphasis nowadays on cost and operational efficiency, a letter to file might seem like the better regulatory submission option. However, it may not always be the best choice. Here’s why: With a 510(k), companies are assured the FDA agrees with their substantial equivalence assessment but that consensus is not guaranteed with a letter to file. Having conducted countless regulatory submissions and defended design changes to a device in audits, I prefer the FDA be (unquestionably) on my side.
In past years, a letter to file approach was used quite frequently to fix medical device deficiencies discovered through postmarket surveillance data. This approach generally was accepted because the improved device was better than its older version. Last October, the FDA released new guidance about the evaluation of product changes and within that document, the agency uses the word “significantly” to clarify the circumstances in which product safety or efficacy changes require a new 510(k). This word, of course, is bound to foster much debate, as companies’ definition of “significant” could be as varied as the products they manufacture.
Risk-Based Assessment of Changes
A risk-based assessment must be conducted to determine the impact of the change (i.e., defining “significant”). The assessment should identify all new risks resulting from any change. Most device companies base their product changes on post-market feedback—something goes awry in a clinical situation, a complaint is made, and product development engineers decide on a fix. Organizations seeking design change verification through a letter to file would be well-served getting a disinterested third party to review their risk-based assessment. It’s very easy to get caught up in the mindset that a design change is an improvement and won’t negatively impact patients. Device firms should be ruthless in their risk evaluations. If there is a new risk that was not present in the cleared design, a new 510(k) is needed even if there is a way to mitigate that risk.
Single Changes vs. Many Changes
Evaluating device changes can be challenging, as it often entails assessing multiple modifications that have occurred over time. Any design changes must be evaluated both individually and as a whole. Consider the following hypothetical example: A company has crafted three letters to file to justify three revision changes between an FDA-cleared device (Revision 1) and its current commercially distributed version (Revision 4). Each letter to file compares the new revision to the previous change, but such assessments will not endear the FDA to the revised product. Why? The new revision must be compared to the original change (Revision 1). To win the FDA’s blessing, the new and (hopefully) improved device must still resemble the original upon comparison. The best advice I can give to anyone seeking substantial equivalence for a device is this: Review the FDA guidance document, work through the flow chart, and determine whether the product changes are “significant.”
Labeling changes include any changes to a device’s printed wording, whether it be the product label or instructions for use. Indications for use are a critical part of labeling and changes in indications for use should be done very carefully. The indications for use form is one of the official documents submitted to the FDA as part of the clearance process, so changing this wording should not be done lightly. A wording change made for readability and clarity needs no documentation but a change in indications to describe a new disease or patient population warrants a new 510(k). Some smaller companies I have worked with that lack a robust regulatory review process have changed the product labeling Indications for Use statement to align with their own desired marketing claims. Big mistake.
Other labeling changes include contraindications, warnings, and precautions. An addition or deletion of a contraindication needs a new 510(k), but a change in warnings or precautions is less clear. Typically, after product launch, a change in product warnings or precautions is driven by post-market feedback. If this is the case, it means the original risk assessment on the device either missed or underestimated the likelihood of a risk. Thus, a new 510(k) should be submitted. Conversely, a letter to file can be submitted for changes to product label warnings or precautions if those modifications help clarify wording.
Technology, Engineering, or Performance Change
Technological changes that improve device performance specifications must be carefully assessed to determine the best method for meeting FDA regulations. Engineering changes involving dimensional alterations, for example, may be justifiable with a letter to file if the device risk profile remains unchanged. A 1 mm change in shaft length, after all, is probably not as critical as the 1 mm reduction of a device’s cannulated shaft. The sponsor must determine whether the change creates a new worst-case testing situation or is simply a change to a non-critical feature for manufacturability. Additionally, if the product cleared by the FDA was available in lengths of X to Z, then the addition of a length Y (in between the bookends) is likely a letter to file.
For devices containing circuit boards and firmware, changes are nearly impossible to avoid due to the frequency of component obsolescence. A letter to file would be appropriate for devices with minor circuit board changes whose functionality and safety testing results are equivalent to those found in the original device. Similarly, a battery change (from a 3 Volt to a 9 Volt lithium) can be justified with internal documentation supported by testing to show the device operates the same as the original. However, if the power source changes from a wall plug to a battery, the change in energy source would most likely merit a new 510(k).
Technology changes involving sterilization can be very complicated. If the sterility assurance level is lowered or there is a change in the way the device is provided (sterile vs. non-sterile), a new 510(k) is necessary. If there is a justifiable change in sterility, the manufacturer should carefully assess the impact of the sterilization change on the material of the device. Polymers are sensitive to various sterilization methods, so a change in sterilization methods could conceivably impact a product’s material performance and/or biocompatibility (due to residuals). Other commonly accepted letter to file changes include a change to packaging or expiration dates, as long as the methods were previously described in the 510(k).
Obviously, changes in materials must be assessed for both performance and biocompatibility impacts. If the device will function the same with the material change, the new biocompatibility concerns must be identified. If the biocompatibility risk assessment does not identify any concerns, but the material is very different than what was cleared in the original 510(k), the sponsor should identify one of its own cleared devices for similar intended use to justify the material change.
Change is inevitable and making a defendable decision regarding a letter to file versus a new 510(k) is critical for audits that assess a manufacturer’s control of device changes. In my opinion, testing is one of the most critical components of a sound letter to file. When making technology changes, it is important to repeat applicable testing as part of the overall validation activities. Validation testing that generates any unexpected results could indicate a potential unintended consequence of the change.
Orthopedic companies that have written a letter to file detailing their thought process but are still unsure about their chosen method for proving substantial equivalence should probably file a 510(k).
They’ll be glad they did when an FDA auditor pays them a visit.
Linda Braddon, Ph.D., is president and CEO of Secure BioMed Evaluations. She works with emerging and established companies to prove regulatory, quality, and technical support to both the medical device and biologics industries. Dr. Braddon has a bachelor of science degree in engineering from Mercer University along with a master of science degree and a Ph.D. in mechanical engineering with a specialization in bioengineering. Her 20 years of experience includes extensive work in orthopedics, dental implants, ophthalmology, respiratory, urology, hydrogels, dura mater substitutes, wound coverings, orthotic devices, and antimicrobial agents.