A Risk Based Approach To 510(k) Cumulative Review For Medical Devices

510k Cumulative ReviewPlease enjoy this inaugural article in Innovatum’s new series containing timely content which is contributed by life sciences industry experts.  Guest blog contributors will be presenting topics pertaining to labeling, regulatory management, and compliance considerations. The following article was submitted by Joshua R. Dix Regulatory Affairs Specialist Baxter Healthcare, Suraj Ramachandran Regulatory Affairs Manager Baxter Healthcare, Darin Oppenheimer Director Global Regulatory Affairs Baxter Healthcare.

Risk Based 510(k) Cumulative Review

Joshua R. Dix, Suraj Ramachandran, Darin S. Oppenheimer
April 15, 2016

Close to twenty years ago the FDA provided the Medical Device Industry with a unique guidance detailing their current thinking regarding when a company should submit a 510(k) for a change to an existing device. While the agency went to great lengths to provide a framework to industry professionals for their assessment of individual changes specific to labeling, technology/performance and materials, a caveat found in the guidance has left many companies looking for answers nearly two decades later.

Collective Assessment of Changes?

In releasing the guidance and providing visual tools for the assessment of changes to a legally marketed device, the FDA inched closer to creating a general consensus amongst industry professionals. Though the information was documented in a minimalistic sense as part of both 21 CFR Part 807.81(a)(3)(i)and 21 CFR Part 807.81(a)(3)(ii), the industry now had concrete and documentable evidence to demonstrate their decision points while assessing the impact of individual changes. Still, portions of the guidance, specifically information detailed in the Assumptions/Axioms section found on page six of the document, produced further division amongst companies’ ability to address the impact of changes to regulatory filings in the United States.

The guidance was clear and concise when detailing the impact of an individual change. Simply put, the FDA did not want a single change to affect a medical device’s indications for use, or cause new issues of safety and efficacy without the company filing a new premarket notification. However, the FDA was now asking companies to consider a more holistic approach when determining impact to filings. As described in the guidance document, the agency was asking the industry to consider a cumulative methodology when assessing changes: “because many changes occur in the evolution of a device, each change must be assessed individually and collectively with other changes made since the last 510(k) clearance.”

In reference to this, the FDA provided no visual aids or expansive definition, only going as far to state “When the effect of any one change, considered together with all previous changes since the last 510(k) clearance, leads a manufacturer to decide it is legally required to submit a new 510(k), then a 510(k) incorporating all the changes should be submitted.” But the question remains: how? The subjectivity of such a statement has resulted in a variety of disparities. Because the guidance document provides no measureable criteria for what would constitute the filing of a new 510(k) through a cumulative assessment process, many industry professionals have relied instead on the criteria provided for individual assessments.

Individual Assessment vs. Cumulative Assessment

When grappling with the question of how to comply with the FDA’s current thinking regarding when a manufacturer should file a new 510(k) for a change to an existing medical device, industry professionals appear to be battling the same uphill climb they encountered upon the guidance’s initial release. How can a cumulative review of changes be done in a consistent and presentable manner? The answer many manufacturers have turned to in light of this challenge is one which keeps in mind the totality of the changes, but focuses instead on the Agency’s direct path for the assessment of individual changes. While many manufacturers may theorize the correct criteria for cumulative review is looking at all the changes as if they were being made at the same time, the question remains: how is the final decision made? Furthermore, will the conditions for the company’s ultimate decision to file or not to file be consistent and complete?

While it may be enough for a manufacturer to organize their reassessment of standalone revisions as a catalogued cumulative review, this approach does not overtly consider the more complex affects a change can have on the device holistically. It is imperative the manufacturer provide a fully justifiable criterion to demonstrate why they did or did not file at the conclusion of their process. The simplistic approach of attempting to determine whether the totality of product changes have significantly altered the devices performance or intended use may be defendable in some cases, but again is not consistent, nor is the final decision specific to cumulative review of the product. Again, it can be argued the final decision when using this criterion will most likely rest upon the impact of one change, not the cumulative impact to the device. If this is the case, and the manufacturer ultimately decides to file because of a significant change to the device, wouldn’t they have already filed when the product change was initially made?

The variability in this theory creates gaps and weakens the manufacturer’s defense of their process. Is it feasible a manufacturer could argue the impact of over a thousand product changes didn’t significantly alter the device? Arguably yes, but the Agency likely will not agree. But how do we bridge the gap and alter this process so it is both consistent and defendable?

Safety Assurance Cases and Risk Based Cumulative Review

One of the questions the FDA’s guidance on changes to an existing medical device asks assessors to consider while reviewing product changes is whether a modification will significantly impact the device’s safety and effectiveness Risk-based evidence, in the form of a Design Failure Mode Effects Analysis (DFMEA) or a Process Failure Mode Effects Analysis (PMFEA) may provide the assessor both an accurate baseline and the projected impact to patient risk based on an individual change, or multiple changes in same project. However, the same approach is not always readily available to assessors when considering the residual risk of multiple changes over the course of numerous engineering projects.

On December 2, 2014, the FDA released a final version of the Infusion Pumps Total Product Life Cycle Guidance. Most notably, this guidance solidified the agency’s current thinking around the use of Safety Assurance Cases as the framework for developing a device’s substantial equivalence to its predicate throughout the life cycle of the device, including residual risk of product changes. As described in section five of the guidance the agency states a Safety Assurance Case should be used to determine “whether a new, changed or modified infusion pump is substantially equivalent” to its predicate device.

Because Safety Assurance Cases are specific to medical devices, they provide a baseline for the complexities of modifications when assessed cumulatively. If revised, as suggested by the Agency, a Safety Assurance Case “will consider specified design requirements, associated hazards, design specifications and other design control documentation.” As such, the device’s Safety Assurance Case provides at measureable standard for the impact of cumulative changes on a cleared medical device. While assessment of incremental changes may help to measure impact to more clear changes such as the addition of a contraindication, or a change to the devices operating principles, the Safety Assurance Case risk approach goes beyond the simplistic and delivers a parallel assessment of both the impact to device as well as overall impact to the end user.

Medical Device Reporting (MDR)

Another important aspect of applying a risk-based approach to a product’s cumulative review is the inclusion of a manufacturer’s Medical Device Reporting (MDR) as a determining factor on whether a new 510(k) is necessary. The MDR regulation (21 CFR Part 803) is one of the postmarket surveillance tools the FDA uses to monitor device performance, detect potential device-related safety issues, and contribute to benefit-risk assessments of these products. When applied to a company’s risk profile, MDRs play a large role in determining both the Hazardous Situations documented in high-level risk documentation, for instance a Safety Assurance Case, as well as any resulting risk priority numbers applied to the device when the severities, occurrences and detections are considered.

As a company’s Medical Device Reporting plays an immeasurable role in how the safety and efficacy of a device is presented to the FDA, it is only reasonable to expect a company would consider reporting when formulating a decision during cumulative review. However, the practice of focusing solely on the “re-review” of individual changes can hamper a manufacturer’s ability to do so while completing this annual task. A change-centric approach may result in a company reviewing change documentation, but forgetting to determine how their reporting changed the patient risk of their product.  To mitigate this issue, Risk Based Cumulative Review does not focus solely on the content of a single change to the device, or a “re-review” of all device changes at a scheduled interval; instead the review incorporates device reporting through a parallel revision to the devices risk profile. During this review the manufacturer may ask itself the following questions when determining if the device has changed from its cleared version.

  • Does new information found through product surveillance alter the information documented in the device’s current risk profile?
  • Has the cumulative impact of product and process changes led to new hazardous situations?
  • Does the discovery of new hazardous situations impact the safety and efficacy of the device in a fashion which would significantly alter the residual risk of the device?
  • Has the cumulative impact of product and process changes led to new questions of the device’s safety and efficacy?

Because of the Agency’s heavy interest in a manufacturer’s Medical Device Reporting, it is essential for product owners to develop a linkage between the information collected during product surveillance and processes used to demonstrate the sustained safety and efficacy of their device. Specifically, creating a link between Medical Device Reporting, Risk Management, and 510(k) Cumulative Review allows a manufacturer to create holistic assurances of safety for their patients and a more refined process to assist in making important regulatory actions for their company.

Risk Based Cumulative Review

Twenty years ago the FDA stepped forward and provided medical device manufacturers with an opportunity to be proactive in their pursuit of compliance. While the release of the K97 Deciding When to Submit a 510(k) for a Change to an Existing Device, provided new challenges to industry, specifically how to create a consistent theory of cumulative review, advances in risk based engineering have delivered a potential method of closing the divide between the assessment of incremental changes and the holistic assessment of changes to a cleared medical device.

The proposed method does not attempt to dissuade manufacturers from reassessing individual changes made to the product as an opposing factor, rather encourages the reassessment as a starting point of cumulative review, keeping in mind Agency regulations and considerations may change during the cycle. With this in mind, any change to the device which would result in a significant change (one which could significantly affect the safety and effectiveness of the device) to the intended use statement, contraindications, control mechanism, operating principle, or energy type should still result in the submission of a 510(k) for the device as the guidance suggests, regardless of impact to the risk profile.

However, the original methodology is furthered as industry professionals are also asked to assess the cumulative changes impact to the device’s risk profile, or Safety Assurance Case. The assessor should view any significant increase in residual risk to patient as new questions of the safety and efficacy of the device. As a result a new 510(k) would then be filed as the cumulative review of changes has led to new questions regarding the devices safety and efficacy as it relates to substantial equivalence to the cleared medical device.

As medical device technology advances it is imperative both manufacturers and the agencies regulating their industry search for progressive ways to measure risk and ensure the safety of patients. A cumulative review process bearing in mind the impact to the residual risk of a device should provide manufacturers a straightforward starting point in developing more involved methods to measure the substantial equivalence of their cleared device during a review cycle. This patient-centric approach adds more control and provides more assurance of safety to both the end user and business interest of the manufacturer, creating a stronger and more trusting relationship with government agencies.

Author Bios:

Joshua Dix
Joshua Dix

Joshua R. Dix is a Regulatory Affairs Specialist with Baxter Healthcare. Centered in the Western New York area, Joshua is the Global Regulatory Lead for multiple product platforms with responsibilities including Regulatory Strategy, Submissions, Product CAPA, and Audits. With extensive experience in both Regulatory Affairs and Quality Systems, Joshua has worked diligently to bring multiple medical devices to market in over twenty different countries. Joshua holds a Bachelor’s degree in English from the State University of New York.

Suraj Ramachandran
Suraj Ramachandran

Suraj Ramachandran, MS is a Regulatory Affairs Manager at Baxter Healthcare. Based in the Chicago Area, Suraj is involved primarily with managing the infusion pump platform and supporting all new product development and lifecycle maintenance activities including regulatory submissions, design control, audits, and CAPA’s. Suraj has also led many development efforts regarding medical device software, intended for both domestic and international markets. Suraj holds an undergraduate degree in Biomedical Engineering as well as a Master’s degree in Biomedical Engineering from the University of Michigan. In addition, Suraj holds a RAC certification from the Regulatory Affairs Professional Society.

Darin Oppenheimer
Darin Oppenheimer

Darin Oppenheimer, MS is a Regulatory Affairs Director at Baxter Healthcare. Based in the Chicago Area, Darin is involved in many facets of the Product Development Lifecycle including regulatory submissions, due diligence, and active participation on industry trade organizations and standards committees. Darin leads a team of regulatory professionals focusing on electromechanical devices and software. His prior background as a Research and Development Scientist focused on pharmaceuticals and medical device diagnostic applications for biomarker and drug discovery. Darin’s undergraduate degree is in Molecular Biology from the University of Tampa. He also holds two Masters Degrees from Johns Hopkins University in Biotechnology and Regulatory Science as well as a graduate Certificate in Biotechnology Enterprise.


U.S. Food and Drug Administration K97 Deciding When to Submit a 510(k) for a Change to an Existing Device: Office of Device Evaluation: January 10th 1997
U.S. Food and Drug Administration. Infusion Pumps Total Product Lifecycle Device: Office of Device Evaluation and Center for Device and Radiological Health, December 2nd, 2014