A Regulatory Perspective: FDA Final Guidance for Design Changes Requiring new 510(k) Submissions

This article explores key elements of FDA's final guidance to the medical device industry for deciding when to submit a new 510(k) for medical device hardware and software design changes issued 25 October 2017. The author assesses the potential business impact and suggests what companies need to do to align with FDA's final guidance.

Introduction

In response to technological advancements, broadening medical knowledge and clinical use, medical device designs frequently evolve over time and the designs come in many forms. Design changes are often in response to industry pressures for increased customer satisfaction and device safety, maximized performance, manufacturability, and to achieve cost efficiencies.

Regulatory professionals within the medical device industry have many roles—one of which is the impact assessment of proposed design and labeling changes on medical devices that have previously received marketing clearance from the US Food and Drug Administration (FDA) or a pre-amendment to a device that is subject to 510(k) requirements. A new premarket notification (510(k) filing) on a medical device is required for "a significantly changed or modified design, components, method of manufacture or intended use" per US Federal Regulation 21 CFR 807.81 (a)(3).¹

Industry Outlook

Global medical device sales are estimated to increase by 6.4 percent annually from 2016 to 2020, reaching nearly €367 billion ($440 billion).² While the Americas are projected to remain the world's largest medical device market, the Asia-Pacific and Western Europe markets are expected to expand at a quicker pace over the next several years.³

In 2011, the medical device market in the EU accounted for one-third of the global market, with around €102 billion ($122.5 billion) in yearly revenue.⁴ The US is expected to continue to play a leading role in medical device R&D. After declining in 2009, R&D spending rebounded to $2.9 billion in 2010 and $7.3 billion in 2011. From 2013 to 2020, larger medical device companies are expected to increase their R&D budgets by approximately three percent, while the rest of the industry is expected to increase spending for this element by more than five percent.⁵

In the US, in order for a manufacturer to register and list a device as part of 21CFR Part 807, it requires the submission and clearance of a Premarket Notification 510(k) or the device cannot be commercially distributed legally. In an industry experiencing such growth, it is important for manufacturers to understand these 510(k) regulatory changes and implement revised Standard Operating Procedures (SOPs) to avoid misalignment with FDA further down the line as the device design evolves.

Design Changes and 510(k) Filing

In August 2016, FDA posted a revision of the guidance "Deciding When to Submit a 510(k) for a Change to an Existing Device" which superseded the version which was introduced in 1997.⁶ In the new draft guidance, FDA sought to address the lack of clarity and provide clear definition of key terms in highly subjective criteria that has given rise to differences in interpretation and application of the guidance by industry professionals, such as "could significantly affect the safety or effectiveness" and "major change or modification."

Medical device and healthcare organizations are at significant risk of repercussions if FDA and industry reach a conflicting 510(k) filing decision. When industry determines a new 510(k) filing is not necessary for a proposed design or labelling change, it documents the non-filling decision, but it is still subject to future review and scrutiny by FDA at future site inspections. An FDA investigator may disagree with a company's non-filing decision that has been made previously, which could result in the investigator citing the firm for failing to meet 21 CFR 807.81 and issuing an inspectional observation (Form 483). The organization can then be issued with a warning letter or product recall if they fail to adequately address the noted deficiency. Other areas of misalignment between FDA and industry regarding the 1997 guidance include:

• lack of current, pertinent examples⁷
• disconnect between the flowcharts and supporting text⁸
• lack of correlation to risk analysis
• absence of clear documentation expectations

With the issuance of final guidance documents in October 2017, FDA realized its commitments to Congress by "preserving the basic format and content of the original, 1997" guidance and remained consistent with the 2016 draft guidance. In the final guidance, FDA expanded on the guiding principles and labeling requirements and added more clarity and examples. The 10 new "guiding principles" have a significant impact on the process, decision and documentation required are summarized below in Table 1.

Table 1. Key Elements and Implications of Final 2017 Design Change Guidance Documents
Guiding Principle	Key Elements of Both 2017 Final Guidance Documents: Deciding When to Submit a 510(k) for a (Software) Change to an Existing Device	Impact
Principle #1	"Changes made with intent to significantly affect safety or effectiveness of a device, e.g., to improve clinical outcomes, in response to known risks, adverse events"	"Yes" answer = New 510(k)
Key	The word "significantly" relies on description, associated risk.
Principle #2	"Initial risk-based assessment"	"Yes" answer = New 510(k)
Key	Distinct terminology chosen by FDA to denote assessment of possible effects of the change on safety and effectiveness Broader scope by definition and includes positive and negative changes
Principle #3	"Unintended consequences of changes"	"Yes" answer = New 510(k)
Key	Scope of assessment to include unintended consequences
Principle #4	"Use of risk management"	Records must include risk assessment.
Key	directly links to Principle #1, ISO 14971 based, needs to include an effectiveness assessment
Principle #5	"The role of testing (verification and validation activities) in evaluating whether a change could significantly affect safety and effectiveness"	"Yes" answer = New 510(k)
Key	Introduces the need to consider a new 510(k) if unexpected results arise during verification and validation testing
Principle #6	"Evaluating simultaneous changes"	Records must include each change and aggregate.
Key	Assessment must include each change individually and as a total of all changes being made at the same time.
Principle #7	"Appropriate comparative device and cumulative effect of changes"	Records must include comparison.
Key	Recommend using a comparison table to illustrate differences in device "as cleared" and "as changed." Do not compare to predicate.
Principle #8	"Documentation requirement"	.Particularly important when no 510(k) decision is made.
Key	Emphasizes the expectation for records to correlate to the degree of changes and associated risk. Appendix B provides further explanation, recommendations and examples
Principle #9	"510(k) submissions for modified devices"	Avoids future retrospective "catch-up 510(k)" scenarios.
Key	If the decision requires submission of a new 510(k), describe all changes made, not just those triggering the need for a 510(k). Include any previous changes since device was cleared.
Principle #10	"Substantial equivalence determinations"	FDA holds final jurisdiction over SE.
Key	Submitting a new 510(k) per either guidance does not assure Substantial Equivalence (SE).

Device Modification Guidance: Key Changes

Labeling, Section A and the associated flowchart represents the most significant change between the final issue and 2016 draft guidance and increase the scope. The first question in A1 changed from a "substantive change to indications for use" to "a change to indications for use." FDA expanded and clarified that all indications for use changes are in scope, not just those deemed by the manufacturer as substantive.

The other significant change and increased scope is labeling section A4: "does the change affect the instructions for use" to "could the change affect instructions for use." FDA again opens the scope to include any possible affect of the change not those know to affect change.

Usability and over the counter clarification questions were also added. FDA increased the number of labeling examples in Appendix A from eight to 11 addressing industry comments and requests.

Sections B, C, D, and E remain primarily unchanged from the draft.

Final Software Guidance

The final software guidance primarily follows the 2016 draft with additional clarification and streamlined flowchart. FDA considers all software changes to be design changes by definition and added additional emphasis in the final guidance regarding what could significantly affect safety and effectiveness. Table 2 is an example flowchart for organizations to follow and specifies when a software change requires a new 510(k) submission. The following questions lead the assessor through the logic scheme to a defensible software change 510(k) filing decision. Note: question 3a and 3b both need to be answered.

Table 2. Key Elements and Implications of 2017 Final Software Change Guidance Document
Flowchart Questions	Key Elements and Implications of 2016 Draft Software Change Guidance Document	Impact
Question #1   (same as draft)	"Is the change made solely to strengthen cybersecurity and does not have any other impact on the software or device?"	Yes answer = 510(k) NOT required
Key	Clear criteria and reflects the increased need and FDA's interest in accommodating cybersecurity improvements
Question #2   (same as draft)	"Is the change made solely to return the system into specification of the most recently cleared device?"
Key	If changes to the software return it to the specifications cleared in the 510(k), a new 510(k) is not required.
Question #3a   (Draft #3 and #4)	"Does the change introduce a new risk or modify an existing risk that could result in significant harm and that is not effectively mitigated in the most recently cleared device?"	Yes answer = New 510(k) and records must include risk assessment
Key	If an existing risk is modified or a new risk is added that has an associated severity that is significant, a new 510(k) is required.
Question #3b   (Draft #5)	"Does the change create or necessitate a new risk control measure or a modification of an existing risk control measure for a hazardous situation that could result in significant harm?"
Key	New or changed risk control measures must be evaluated to determine if there is an effect on safety and efficacy. If the answer is yes, a new 510(k) is required.
Question #4   (Draft #6)	"Could the change significantly affect clinical functionality or performance specifications that are directly associated with the intended use of the device?"	Yes answer = New 510(k) and records must include comparison
Key	Addition or changes to clinical functionality or performance specifications will likely require a new 510(k).
Section VI	Additional Factors to Consider (same as draft)
Common SW Changes	The software must be assessed from the perspectives of "infrastructure, architecture, core algorithm, and reengineering" changes	Changes in these areas likely require a new 510(k)
Key	Consider impact on intended use, overall structure and software support system.
Common SW Changes	Changes to clarify requirements or that are cosmetic only in nature	Changes in these areas likely do not require a new 510(k)
Key	Changes could trigger need for new 510(k), assessment and documentation is the key.

Recommendations

FDA has clarified the significant role of risk management in the regulatory filing decision process. The burden is on industry to adopt and implement an effective risk-based change assessment process for its filing decisions. Several recommendations for updating existing regulatory filing decisions and processes related to design and intended use changes are provided below.

First, include an application/documentation of a risk-based assessment linked to your risk management process to substantiate your decisions.

It also is recommended that a comparison of the proposed changes against the cleared device be available and include current and aggregate changes since device clearance. Furthermore, software change assessment documentation must address the questions in Table 2.

It is recommended you look at your label review processes and the resultant documentation requirements and ensure they are robust and cover the full "new" scope of the guidance.

Key functional stakeholders should be able to provide expert input to address clinical, design and risk management considerations to ensure a fully comprehensive and error-proof decision process. It is advisable to do trial runs before implementing any changes. This is particularly important for smaller organizations or those with infrequent design changes.

Further considerations include the addition of a functional "swim lane" into the decision-process flowchart so there is full clarity on role responsibility and deliverables, and flexible forms/templates (similar to FDA's Appendix B) would ensure full process scalability.

Final Thoughts

To comply with the final guidance, revised procedures, associated documentation and implementation into the quality management system will require cross-functional planning and execution as well as an increase in the time and resources required. FDA anticipates that because the new guidance documents only add clarification and the impact of these new procedures on organizations is negligible. Whether this is true and if there is an increase in A510(k) submissions as a result of the change remains to be seen.

References

1. Title 21: Food and Drugs. Part 807-Establishment Registration and Device Listing for Manufacturers and Initial Importers of Devices. Subpart E-Premarket Notification Procedures. GPO website. http://www.ecfr.gov/cgi-bin/text-idx?SID=f35b20cdc0edc588fb4fb00139c86b60&mc=true&node=se21.8.807_181&rgn=div8. Accessed 14 March 2017.
2. https://www.trade.gov/topmarkets/pdf/Medical_Devices_Top_Markets_Report.pdf.
3. http://mercercapital.com/article/5-trends-to-watch-in-the-medical-device-industry-in-2016/.  
4. https://www.emergogroup.com/resources/market-europe.
5. The State of the US Medtech Industry, January 2015, Anchin, Block & Anchin.
6. Deciding When to Submit a 510(k) for a Change to an Existing Device K97-1 Memorandum and Guidance Issued 10 January 1997.
7. FDA's CDRH Webinar entitled: Deciding When to Submit a 510(k) for a Change to an Existing Device Draft Guidance for Industry and FDA Staff and Deciding When to Submit a 510(k) for a Software Change to an Existing Device Draft Guidance for Industry and FDA Staff. August 2016.
8. Inspection Observations. FDA website. https://www.fda.gov/ICECI/Inspections/ucm250720.htm. Accessed 14 March 2017.

About the Author

Jeff Ryberg is an active enterprise member of the Regulatory Affairs Professionals Society (RAPS) and holds the position of vice president, regulatory affairs and quality assurance, Danaher Business System Integration and Special Projects for Danaher Corporation. Ryberg has 30 years of experience in medical device quality and regulatory affairs and supports Danaher's diagnostics, life sciences, dental and water technologies businesses. He holds an MS in regulatory science from Johns Hopkins.

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Cite as: Ryberg, J. "A Regulatory Perspective: FDA Final Guidance for Design Changes Requiring new 510(k) Submissions." Regulatory Focus. February 2018. Regulatory Affairs Professionals Society.