Author name: Robert Packard

De Novo pre IDE Meeting

The article describes the most critical part of the preparation for a De Novo Classification Request, the De Novo pre IDE meeting.Pre Sub Timeline and Process Flow 1024x594 De Novo pre IDE Meeting

There are two critical differences between a De Novo classification request and a 510k submission. First, 510k clearance is based upon a substantial equivalence comparison of a device and a predicate device that is already marketed in the USA, while a De Novo classification is based upon a benefit-risk analysis of a device’s clinical benefits compared with the risk of harm to users and patients. Second, 510k clearance usually does not require clinical data to demonstrate safety and efficacy, while a De Novo classification request usually does require clinical data to demonstrate safety and efficacy. Therefore, it makes sense that the two most common challenges for innovative medical device companies are: 1) learning how to write a benefit-risk analysis, and 2) clinical study design. Success with both of these tasks can be significantly improved by requesting a De Novo pre IDE meeting with the FDA.

Benefit-risk analysis questions to ask during a De Novo pre IDE meeting

Most device companies are only familiar with substantial equivalence comparisons–not a benefit-risk analysis. The statement “the benefits outweigh the risks” is not a benefit-risk analysis. Medical device regulations have been changing toward an emphasis on benefit-risk anlysis. For example, the European MDD mentions benefit-risk analysis eight times, while Regulation (EU) 2017/745 mentions benefit-risk analysis 69 times. Despite the obvious increased emphasis on benefit-risk analysis in the new EU Regulations, ISO 14971:2019 only requires a benefit-risk analysis for unacceptable risks. The international standard also does not clearly explain how to perform a benefit-risk analysis. The best explanation for how to perform a benefit-risk analysis was provided in the FDA guidance, but now the ISO/TR 24971:2020 guidance includes detailed guidance in Clause 7.4.

In addition to reading ISO/TR 24971 and the FDA guidance, you will need to systematically identify all of the current alternative methods of treatment, diagnosis, or monitoring for your intended use. Therefore, you should ask in a pre-submission meeting if there are any additional devices or treatments that the FDA feels should be considered. You should review each of the alternative treatments for clinical studies that may help you in the design of your clinical study. You should carefully review the available clinical data for alternative treatments to help you quantify the risks and benefits associated with those treatments too. Finally, you should consider whether one or more of these alternative treatments might be a suitable control for your clinical study. Ideally, your clinical study design will show that the benefits of your device are greater, and the risks are less, but either may be enough for approval of your classification request. If you think the risks of your device are significantly less than alternative treatments, then ask the FDA about using this factor as an endpoint in your study design.

Clinical Study Design Considerations

Ideally, there is already a well-accepted clinical model for assessing efficacy for your desired indications. This means multiple, published, peer-reviewed journal articles. You might have a better method for evaluating subjects, but don’t propose that method instead of a “gold standard.” If you feel strongly that your method is more appropriate, propose both methods of evaluation. You also need multiple evaluators who can be objective. Randomization, blinding, and monitoring of clinical studies is critical to ensure an unbiased evaluation of clinical results. In general, it is difficult to design an unbiased post-market clinical follow-up (PMCF) study. A common deficiency identified by the FDA is that post-market study performed outside the United States (OUS) has selection bias and covariate imbalance.

You also need to design your study with realistic expectations. Murphy’s law is always active. That means, “things will go wrong in any given situation if you give them a chance.” Therefore, you must avoid optimism and devise methods for detecting errors quickly. This is why electronic data capture systems and eSource is preferred for data collection instead of the manual collection of data on paper case study forms. Not only does it reduce errors in data collection, but it also facilitates remote monitoring of clinical sites. This includes asking questions that are open-ended or quantitative–instead of Yes/No questions or qualitative evaluations that encourage subjectivity. You can always anticipate every mistake that will be made, and open-ended questions often capture essential data that would otherwise be lost. Asking the quantitative questions also will provide you with additional data you can analyze, which may reveal unexpected relationships or help you to explain unexpected results. To help facilitate the development of these questions, try asking yourself how you could detect an error for each data point you are collecting. Then add a detection mechanism to your data collection plan wherever and whenever you can.

Goals of De Novo pre IDE Meeting

A pre-IDE meeting is not typically your first pre-submission meeting with the FDA. Usually, your first pre-submission meeting is to verify that the FDA agrees that the regulatory pathway is a De Novo classification request rather than a 510k submission. Hopefully, you also were able to review your overall testing plan with the FDA during your first pre-submission meeting. You may have even reviewed a clinical synopsis with the FDA during your initial pre-submission meeting. During the pre-IDE meeting, your goal is to finalize your clinical study protocol. That doesn’t mean that the FDA should agree 100% with your draft protocol. You want positive and negative feedback on all aspects of your protocol before the IDE submission. During the IDE review, changes will be made.

The most important aspects of getting right before the IDE submission are the fundamentals. Most of our De Novo clients feel that a control group is not possible, because they think that test subjects will know when a sham device is used. However, trying to avoid a control group is nearly impossible. The most important factors for why a control group is needed are:

  • you need to minimize differences between experimental and control subjects, but you can’t do that if you are relying on data from other clinical studies
  • you also need to ensure that your evaluation methods are identical, which is nearly impossible when performed by different people, at different facilities, using slightly different protocols

Another area of weakness in most draft clinical protocols is the method of evaluation. Specifically:

  • Who is doing evaluations?
  • Which endpoints are important?
  • When are your endpoints?
  • What are your acceptance criteria?

The last area to consider in a pre-IDE meeting is your statistical plan. You need a statistical plan, but the statistical analysis seldom appears to be the reason for the rejection of clinical data. The reason is that changes can be made to your statistical analysis of data after the study is completed, but you can’t change the data once the study is over. The FDA is now accepting adaptive designs that allow the company to analyze data during the study to recalculate the ultimate sample size needed based upon actual data rather than initial assumptions.

What are the basic milestones in an FDA pre IDE meeting?

Once you have prepared your De Novo pre IDE meeting request and the FDA PreSTAR template indicates that the submission is complete, then you are ready to submit the PreSTAR to the FDA. There are 11 steps in the process for an FDA pre-submission meeting request (see flow chart above). The following is a brief summary of each milestone the process:

  1. Upload your completed FDA PreSTAR to the FDA Customer Collaboration Portal (CCP)
  2. Within seconds of uploading your file, you will receive an automated email acknowledging the uploading of the file to the CCP, but your real acknowledgement is a letter your receive by email the following day that has the Q-Sub number assigned to your request (i.e., QYYXXXX).
  3. A preliminary review of the PreSTAR used to be performed and a checklist was filled out, but with the use of the PreSTAR template the FDA is now only conducting a technical review. Once the technical review is completed, a lead reviewer is assigned and you will receive an email notifying you of who your reviewer is. This process usually is completed in 15 days.
  4. Once the FDA lead reviewer is assigned, the lead reviewer will ask subject matter experts to review and respond to each of the questions in the De Novo pre IDE meeting request. Pre-submissions are limited to a maximum of four topics, and therefore, there should only be a need for a four subject matter experts. The lead reviewer may be one of the subject matter experts. Typically the assistant director of the review panel (i.e., medical specialty) will also participate, and sometimes the director will also participate. This review process will occur from day 15 until day 70 of the pre-submission process. The lead reviewer will also contact you by email to coordinate a date and time for scheduling the pre-submission teleconference.
  5. Approximately five days before the scheduled De Novo pre IDE meeting teleconference, the FDA lead reviewer will provide a email response to your questions. The file name of the document sent by the lead reviewer will be in the following format: “QYYXXXX.Notification.EMFB.”
  6. Your team will need to review the FDA responses to each question and decide whether you want to ask any clarification questions. If you don’t have any clarification questions, you can cancel the FDA teleconference. A slide deck is not required for the teleconference, but if you decide to create a slide deck the FDA would like to receive it by email ~48 hours before the teleconference.
  7. For the De Novo pre IDE meeting teleconference, the FDA lead reviewer provides login information for a Microsoft Teams or Zoom teleconference in advance of the meeting. Attendees can login approximately 5 minutes before the start. The meeting begins with introductions, and then the company will present their slides and ask clarification questions. At the end of each slide, it is a good practice to ask if anyone from the company has additional questions, and then you should ask if the FDA have anything they would like to ask. We recommend alternating speakers for presentation of slides. This gives multiple people practice presenting to the FDA, it provides some variety of speakers, it increases engagement during meetings, and it allows people that are not speaking time to catch-up on their notes. The FDA will not permit recordings during the meeting. At the end of the meeting, you will want to leave approximately 5 minutes for summarizing any action items for your company or the FDA.
  8. After the teleconference most companies will conduct a debrief meeting without the FDA. Notes from each person will be shared with the person designated for creating draft meeting minutes. The minutes are intended to be only a summary of what was discussed–not a transcription. You have 15 calendar days to create the draft.
  9. Once the company agrees on a final draft of the meeting minutes you will prepare an FDA eCopy and upload it to the FDA CCP. If you created a slide deck, the slide deck should be included with the meeting minutes as a second document in the FDA eCopy. Lead reviewers will also sometimes request an MS Word version of the minutes be emailed directly to them to facilitate editing the minutes.
  10. Within seconds of uploading your FDA eCopy of the minutes, you will receive an automated email acknowledging the uploading of the FDA eCopy to the CCP. The document number assigned for meeting minutes is in the following format: QYYXXXX.A001.
  11. The FDA will take 30 days to review your draft meeting minutes. The minutes will be redlined by the FDA with what the FDA intended to say regarding your questions so it may differ from exactly what was said. You will receive an email with a letter attached. The filename of the letter will be: QYYXXXX.A001.Meeting Minutes.REVS. You can dispute the minutes if you disagree with the FDA’s redlines.

How to you use meeting minutes in your final De Novo application?

In your FDA eSTAR, you will need to attach a copy of the meeting minutes from any pre-submissions you had with the FDA. You will also need to provide a response memo indicating how you addressed any concerns or questions the FDA raised during those pre-submissions. Both documents will be attached to the eSTAR. We recommend using a tabular format and alternating between blue and black font to clearly separate the minutes from your responses.

Do you need more information about De Novo applications?

We created a cornerstone webpage that summarizes our content about De Novo applications. All of our webinars about De Novo applications and our De Novo templates can be purchased as part of our 510k Course Series. You can also learn a lot about clinical study design by purchasing Medical Device Academy’s Clinical Procedure (SYS-009). Finally, try searching the De Novo Reclassification Summaries for examples of how other companies designed their clinical studies to demonstrate safety and efficacy for a De Novo application.

De Novo pre IDE Meeting Read More »

Benefit-Risk Analysis – ISO 14971:2019, Clause 7.4

This article explains the requirements for a benefit-risk analysis as defined in ISO 14971:2019, Clause 7.4 and in the EU regulations.

benefit risk analsyis with scales 1009x1024 Benefit Risk Analysis   ISO 14971:2019, Clause 7.4

What is a benefit-risk analysis?

A benefit-risk analysis is one of the risk management activities explained in ISO 14971:2019. Specifically, this requirement is found in clause 7.4 of the medical device risk management standard. Originally, the requirement was described as “risk-benefit analysis” in the second edition of the medical device risk management standard. The US FDA revised their policies for novel devices (e.g., De Novo and PMA submissions) to emphasize that novel devices must demonstrate clinical benefits or they will not be approved. Therefore, the US FDA revised the wording to place the word “benefit” before the word “risk.” This approach and the revised wording was adopted by the committee that was drafting the third edition of the ISO 14971 standard. The wording was also adopted by 2012 European version of the standard, the EU MDR, and EU IVDR. In general, this risk management activity involves a semi-quantitative comparison of clinical benefits with risks of harm. The ISO 14971 standard indicates that if risks are unacceptable, a device can still be recommended for commercial release by a design team if the clinical benefits outweigh the risk of harm.

Is there discretion as to whether a benefit-risk analysis needs to take place?

The ISO 14971 Standard implies that a benefit-risk analysis is only required if the risks of harm exceed a threshold of acceptability. In the ISO/TIR 24971:2020 guidance, the committee clarified that acceptability of risk must be documented in a risk management policy (see Annex C2 for guidance and recommended content for a risk management policy). However, the EU MDR and IVDR regulations require that you perform a benefit-risk analysis for each individual risk and overall residual risk of a medical device. This is stated in Annex I, the General Safety and Performance Requirements. Therefore, if your company distributes devices only in the USA that are Class 1 or Class 2, and the submission type is not a De Novo or Humanitarian Device Exemption (HDE), then you are only required to perform a benefit-risk analysis if the risks of harm are unacceptable. If the device requires a De Novo application, and HDE, or a Class 3 PMA, then you are required to submit a benefit-risk analysis to the FDA in your premarket submission. For companies that distribute devices in Europe, the companies do not have discretion with regard to performing a benefit-risk analysis and they must include it in the risk management file. Since some of Medical Device Academy’s clients are seeking approval for a De Novo, HDE, or PMA, or the companies are distributing in the EU, our risk management procedure does not allow discretion regarding whether a benefit-risk analysis needs to be performed. The template we created for this is TMP-034 in SYS-010. 

As Low As Reasonably Practicable (ALARP)

Your company may have a risk management procedure which includes a matrix for severity and probability. The matrix is probably color-coded to identify red cells as unacceptable risks that require a benefit-risk analysis, yellow cells that are ALARP, and green cells that are acceptable. This practice was criticized in 2012 by the European Commission. “Acceptability” of risk is no longer permitted using the principles of “ALARP.”

Deviation 4 Benefit Risk Analysis   ISO 14971:2019, Clause 7.4

The EU regulations require that the analysis of benefit-risk ratios be performed for each risk and all residual risks—not just the risks you identify as unacceptable. However, the EU regulations also do not permit that financial considerations be used as part of the determination of risk acceptability. Financial considerations are implied in the ALARP principle. To clarify this, notes were added to ISO 14971:2019, the guidance on risk acceptability was moved to ISO/TIR 24971:2020, and the concept of ALARP was removed from the risk management standard and the guidance. Therefore, we recommend that your risk management policy reference the need for a benefit-risk analysis, regulatory requirements, the requirements of recognized medical device standards, and stakeholder requirements–not ALARP.

Integrating benefit-risk analysis into your design process

The best way to integrate benefit-risk considerations into your design process is by performing a clinical evaluation. In addition to using clinical literature, clinical study data, and post-market surveillance as inputs for your clinical evaluation, your company should also be using residual risks as inputs to the evaluation. The clinical evaluation should be used to assess the significance of these residual risks, and verify that there are not any risks identified in the clinical evaluation that were not considered in the risk analysis.

In order to document that your company has performed a benefit-risk analysis for each residual risk, you will need to reference the risk management report in the clinical evaluation and vice-versa. Both documents will need to provide traceability to each risk identified in the risk analysis, and conclusions of risk acceptability will need to be based upon the conclusions of the clinical evaluation.

Once your device is commercialized, you will need to update the clinical evaluation with adverse events and other post-market surveillance information. As part of updating clinical evaluations, you will need to determine the acceptability of the risk when weighed against the clinical benefits. These conclusions will then need to be updated in the risk management report—including any new or revised risks.

If you are interested in benefit-risk analysis training, we offer a benefit-risk analysis webinar as part of our 510(k) course series.

Benefit-Risk Analysis – ISO 14971:2019, Clause 7.4 Read More »

What is the FDA Breakthrough Device Designation?

The FDA Breakthrough Device Designation was created in 2015 to expedite device access for life-threatening and debilitating diseases.

What is the FDA Breakthrough Device Designation?

The FDA Breakthrough Device Designation is a formal identification by the US FDA that a device in development should be expedited for patient access because it has a reasonable chance of providing more effective treatment than the standard of care for the treatment or diagnosis of life-threatening or irreversibly debilitating human disease or conditions.

To be granted breakthrough status, your device must also meet at least one of the following four secondary criteria:

  1. Represents Breakthrough Technology
  2. No Approved or Cleared Alternatives Exist
  3. Offers Significant Advantages over Existing Approved or Cleared Alternatives
  4. Device Availability is in the Best Interest of Patients

Once the FDA has designated your device as a breakthrough device, all future communications with the FDA related to that device should be identified with the Q-sub reference number assigned to your breakthrough request. If you want more information, please schedule a call with us, or you can download the FDA guidance. We have helped multiple clients successfully receive breakthrough device designation.

What are the benefits of receiving the designation?

The breakthrough designation helps the FDA identify new technology to focus on to expedite access to novel devices that will save lives and treat debilitating diseases. It takes the FDA longer to review these devices because they may raise novel scientific and regulatory issues. Therefore, the FDA prioritizes 510k and De Novo submissions for breakthrough devices over other 510k and De Novo submissions, and the FDA’s senior management is involved in the review process. The average review time for the 32 breakthrough devices with 510k clearance was 152 days*. This may not seem like an expedited review, but the average review time for 510k cleared devices that require additional testing data is almost 270 days. The average review time for the twenty De Novo Classification Requests designated as breakthrough devices was 312 days*. This significantly improved compared to the average De Novo Decision timeline of 390 days for 2019-2023.

*Metrics updated on 10/31/2022 with data through 9/30/2022

Are there reimbursement benefits?

There have been multiple proposals to offer earlier reimbursement for Breakthrough Device Designation. Typically, CMS does not cover new technology for the first two years. Specifically, the Centers for Medicare and Medicaid Services (CMS) typically takes two years to establish qualification for public reimbursement coverage in the USA. In contrast, private insurers are inconsistent in their coverage because Medicare Administrative Contractor (MAC) is divided into 13 different US regions, each making independent coverage decisions case-by-case. Unfortunately, none of the proposed bills for immediate coverage through CMS have been approved.

Mechanisms of Expedited FDA Review

In addition to identifying breakthrough devices for priority review and involving the FDA’s senior management, the FDA also offers four other mechanisms for improving the review time. First, the FDA offers “Sprint discussions.” A “Sprint” discussion allows the FDA and the company to discuss a single topic and reach an agreement in a set period (e.g., 45 days). The FDA provides an example of a Sprint discussion, such as a pre-submission meeting. Still, the timeline is half the duration of the FDA’s target MDUFA V decision goals.

The second mechanism for improving the review time is a Data Development Plan (DDP). Using this mechanism, the FDA will work with the company to finalize the breakthrough device’s non-clinical and clinical testing plans. This may include starting clinical testing earlier while deferring certain non-clinical testing.

The third mechanism for improving the review time is the Clinical Protocol Agreement. In this scenario, the FDA will interactively review changes to clinical protocols rather than conducting a protocol acceptance review first. Therefore, the time required to review and approve a clinical protocol change is less, and the sponsor can complete their clinical studies in less time.

The fourth mechanism for improving the review time is a prioritized pre-submission review. If a company prefers to discuss multiple issues in one meeting rather than conducting Sprint discussions on single topics, then the FDA will prioritize pre-submission review. The prioritized pre-submission will be tracked as an interactive review with a shorter timeline than other pre-submission meeting requests.

How do you apply to the FDA for Breakthrough Device Designation?

To receive the designation, you must prepare a Breakthrough Device Designation request and submit it to the FDA Document Control Center (DCC) as an eCopy. The eCopy can be done via FedEx or through the new Customer Collaboration Portal (CCP) launched by the FDA in 2022. Your application could consist of a single document, but we recommend at least three documents: 1) a formal request outlining how your device meets the criteria for breakthrough designation, 2) a detailed device description, and 3) preliminary clinical data demonstrating the feasibility of your device delivering performance claimed in your request for designation. There are no user fees associated with the application for breakthrough designation, and you are not prevented from submitting other types of submissions in parallel with the breakthrough designation request, such as a pre-submission or investigational device exemption (IDE).

When should you apply to the FDA?

If the FDA denies an initial breakthrough designation request, the company may re-submit a request later. Therefore, companies should submit requests as soon as they can provide preliminary clinical data to demonstrate the feasibility of the device’s claimed performance. Therefore, a breakthrough designation request would typically be submitted after an Early Feasibility Study (EFS), which allows a maximum of ten clinical subjects.

Breakthrough Devices by FY 1 1024x555 What is the FDA Breakthrough Device Designation?

How many companies have received Breakthrough Device Designation from the FDA?

Since starting the Breakthrough Designation program in 2015, the FDA has granted 933 devices Breakthrough Device Designation*. CDRH, the device division of the FDA, granted 921, while CBER, the biologics division of the FDA, granted 12*. The breakthrough device designation, however, does not guarantee FDA market authorization. Only 95 of the breakthrough designations have resulted in market authorization so far. Four of the 95 devices were reviewed by CBER. Of the remaining 91 devices, 32 received 510k clearance, 30 De Novo Classification Requests were granted, and 31 PMAs were approved*. Given the number of submissions received yearly, only 10-15% of De Novo and PMA submissions are also Breakthrough Devices. In contrast, only about 0.1% of 510k submissions are also Breakthrough Devices. The data for breakthrough device designation is only reported through December 31, 2023, but the projected number of breakthrough designations for FY 2024 (ending September 30, 2024) is 232.

*Metrics updated on 4/14/2024 with data through 12/31/2024

**FY 2024 data is limited to one quarter

What is the FDA Breakthrough Device Designation? Read More »

513g Request for Information

Version 1.0 of the FDA PreSTAR template, released March 29th, now enables the use of the PreSTAR template for 513g requests for information.

Screenshot 2024 04 07 7.31.26 PM 1024x444 513g Request for Information

What is a 513g request?

A “513g” is a request for classification information from the FDA. The reference is to a Food, Drug & Cosmetic Act section. The purpose of the submission is to ask the FDA what product classification would be most appropriate for your device and what the appropriate regulatory pathway will be. The regulation requires the FDA to provide a written response within 60 days of receiving the 513g request. The submission also requires payment of an FDA user fee eligible for a small business discount.

Is it required to use the new FDA PreSTAR v1.0 template for a 513g request?

No, the FDA PreSTAR is not required to submit a 513g request for information. The FDA has not updated the 2019 guidance document yet, and the FDA continues to allow the use of an FDA eCopy for 513g submissions. However, the updated PreSTAR template simplifies the process of submitting a request for classification information.

What is the required content of a 513g request?

Page 15 of the FDA guidance for 513g requests specifies the following content:

  1. cover letter,
  2. description of the device,
  3. description of what the device is to be used for,
  4. any proposed labeling or promotional material for the device and, as applicable, any labeling or promotional material of a similar, legally marketed device, if available.

The guidance also details the minimum requirements for these four content requirements. The cover letter requirements specified in the guidance include “your specific question(s) concerning the class in which a device has been classified and/or the regulatory requirements applicable to a device.” When the PreSTAR is used for a pre-submission, there is a designated section at the end of the template for entering questions. However, v1.0 does not allow this option for a 513g. Therefore, questions must be added to the cover letter instead. The template Medical Device Academy created for a 513g includes the following default question:

Reason for the 513(g) Submission:

[Company Name] plans to submit a pre-market submission in 202x, and the company is requesting a decision from the FDA regarding the regulatory pathway for the subject device.

This section can be modified to include additional questions, depending on the specific reason for the 513g request.

Screenshot 2024 04 07 5.52.39 PM 513g Request for Information

When should a 513g request for information be submitted?

Usually, device companies ask me if I think they should submit a 513g or a pre-submission request to answer questions about the testing requirements. Often, the device has a known product classification code that requires a submission of 510(k). Sometimes, there will even be a Special Controls Guidance document available for the product classification. In these situations, a 513g is entirely unnecessary. I can understand the difficulties people experience when navigating the FDA product classification database because the database does not use modern natural language search algorithms like Google. However, a greater concern is that most companies ask this question after they have already started the development of their device and before they plan to initiate design verification testing. This is very late in the design process, and it is even a little late to conduct a pre-submission request. Your 513g submission should be during the beginning of your design project (i.e., during the concept or feasibility phases of design) to verify the proposed regulatory pathway.

How to prepare a 513g

For any device submission, including a 513g, you must prepare a detailed device description for the FDA. Many companies find this difficult. Therefore, we provide a template for the device description. In addition to the device description, we recommend including a copy of the draft labeling and instructions for use (IFU) with each device submission. A pre-submission does not require draft labeling, but a 513g classification request does to ensure the FDA understands your intended use for the device. Therefore, we provide templates for companies to prepare these drafts.

Screenshot 2024 04 07 9.42.55 PM 1024x573 513g Request for Information

Other Resources

If you need to submit a 513g request, you can learn more about FDA content requirements by watching our 513g submission webinar. You will also receive access to our 513g templates if you purchase the webinar bundle. We also provide the templates for the device description, draft label, and draft instructions for use (IFU) to new clients submitting a pre-submission meeting request, a 510k submission, or a De Novo Classification Request. In addition, there are six (6) other templates included with the 513g webinar bundle. Those templates are specifically required for De Novo submissions, and we recommend including them if you believe your device requires a De Novo submission.

513g Request for Information Read More »

Packaging Complaint Investigation – Case Study

This is part one of a case study on how to perform a packaging complaint investigation when packaging is found open by a customer.

Screenshot 2015 11 08 at 11.58.18 AM Packaging Complaint Investigation   Case Study

Overview of Packaging Complaint Investigation

This case study example involves a flexible, peelable pouch made of Tyvek and a clear plastic film. This is one of the most common types of packaging used for sterile medical devices. In parallel with the complaint investigation, containment measures and corrections are implemented immediately to prevent the complaint from becoming a more widespread problem. The investigation process utilizes a “Fishbone Diagram” to identify the root cause of the packaging malfunction. This is just one of several root cause analysis tools that you can use for complaint investigations, but it works particularly well for examples where something has gone wrong in production process controls, but we are not sure which process control has failed.

Description of the packaging malfunction

The first step of the complaint handling process (see SYS-018, Customer Feedback and Complaint Handling) is to record a description of the alleged quality issue. A distributor reported the incident that was reported. The distributor told customer service that two pouches in a box containing 24 sterile devices were found to have a seal that appeared to be delaminating. Unfortunately, the distributor was unable to provide a sample of the delaminated pouches or the lot number of the units. Packaging issues and labeling issues are typically two of the most common complaint categories for medical devices. Often the labeling issues are operator errors or a result of labeling mixups, while the packaging errors may be due to customers who accidentally ordered or opened the wrong size of the product. Therefore they may complain about packaging when there is nothing wrong. It is essential to be diligent in the investigation of each packaging complaint because if there is a legitimate packaging quality issue, then there may be a need for a product recall as part of your corrective action plan.

Initiation of the packaging complaint investigation

In your complaint record, you need to assign a person to investigate the complaint. The only acceptable reason for not initiating an investigation is when a similar incident was already investigated for another device in the same lot or a related lot (i.e., packaging raw material lot is the same and the problem is related to the material). If the complaint was already investigated, then the complaint record should cross-reference the previous complaint record.

The person assigned to investigate the complaint must be trained in complaint investigations and should be technically qualified to investigate the processes related to the complaint (e.g., packaging process validation). The investigator must record which records were reviewed as part of the investigation, and the investigation should be completed promptly in case regulatory reporting is required or remedial actions are needed. It is also necessary to demonstrate that complaints are processed in a consistent and timely manner (e.g., average days to complaint closure may be a quality objective). 

Regulatory reporting of packaging failures

We know everyone wants to avoid regulatory reporting because we are afraid that other customers will lose confidence in our product and bad publicity may impact sales. However, the consequences of failing to file medical device reports with the FDA are much worse. Even if an injury or death did not occur with a sterile medical device, the quality issue should still be reported as an MDR under 21 CFR 803 (see SYS-029, Medical Device Reporting) because a repeat incident could cause an infection that could result in sepsis and death. If you think that this is an extremely conservative approach, you might be surprised to learn that 251 MDRs were reported to the FDA in Q4 of 2023 for packaging issues. Of these reports, only one involved an actual injury, and the other 250 involved a device malfunction but no death or injury. The following event description and manufacturer’s narrative is an example:

Event Description

“It was reported by the sales rep in japan that during an unspecified surgical procedure on (b)(6) 2023 the rgdloop adjustable stnd device sterile package was not sealed and was unclean.Another like device was used to complete the procedure.There was an unknown delay in the procedure reported.There were no adverse patient consequences reported.No additional information was provided.”

Manufacturers Narrative

“This report is being submitted in pursuant to the provisions of 21 cfr, part 803.This report may be based on information which has not been able to investigate or verify prior to the required reporting date.This report does not reflect a conclusion by mitek or its employees that the report constitutes an admission that the device, mitek, or its employees caused or contributed to the potential event described in this report.If information is obtained that was not available for the initial medwatch, a follow-up medwatch will be filed as appropriate.Device was used for treatment, not diagnosis.If information is obtained that was not available for the initial medwatch, a follow-up medwatch will be filed as appropriate.H10 additional narrative: e3: reporter is a j&j sales representative.H4: the device manufacture date is unknown.Udi: (b)(4).”

Packaging complaint investigation when product IS NOT returned

What the narrative above does not elaborate on is what was the specific investigation details for “lot history reviewed.” One of the most useful tools for performing a packaging complaint investigation is the “Fishbone Diagram.” Other names include, “Ishikawa Diagram” and “Cause and Effect Diagram.” There are six parts (i.e., “6Ms”) to the diagram:

  1. materials,
  2. method,
  3. machine,
  4. “mother nature” or environment,
  5. “manpower” or people, and
  6. measurement.

What records can be investigated without the return of the product?

The following records could be reviewed and evaluated for potential root causes even if the customer does not return the packaging with the alleged malfunction:

  1. review the complaint log for other complaints with the same lot number and/or from a similar period, lot of raw materials, or packaging machine
  2. review the device history record for the lot to make sure that the number of units rejected as part of normal in-process and final inspection did not exceed pre-established thresholds for monitoring the sealing process
  3. if retains of the lot are available, these might be retested to verify that the testing results after real-time aging remain acceptable
  4. the maintenance and calibration records of the equipment for manufacture and testing may be reviewed to verify that no repairs were required and no equipment was identified as out-of-calibration

If all of the above fail to identify a potential cause for a packaging failure, then you might have a problem related to people or the environment. People include the people sealing the product package and the users. The environment consists of the temperature and humidity for storage of packaging raw materials, packaged products, sterilization conditions, storage conditions after sterilization, and shipping conditions–including any temporary extremes that might occur during transit.

In our case study, the product was not returned, and we did not have the lot numbers. Therefore, we may need to review distribution records to that distributor and/or the customer to narrow down the possible lots to one or more lots. Then we would need to perform the same type of review of lot history records for each potential lot. The best approach is to request a photo of the package labeling, including the UDI bar code, because that information will facilitate lot identification. Even if the product was discarded, often the UDI will be scanned into the patient’s electronic medical record (EMR) during surgery.

Conducting investigations when product IS returned

Sometimes you are fortunate enough to receive returned products. The product should be immediately segregated from your other products to prevent mixups and/or contamination. Normally the returned products are identified as non-conforming products and quarantined. After the quarantined product is evaluated for safety, the assigned investigator may inspect the packaging in a segregated area. Packaging investigations begin with visual inspection following ASTM F1886. If multiple packaging samples are available, or the packaging is large enough, the investigator may destructively test (i.e., ASTM F88) a 1” strip cut from the packaging seal to verify that the returned packaging meets the original specifications. If you kept retains of packaging with the same lot of flexible packaging, you may visually inspect and destructively test retains as well.

Next steps of the packaging complaint investigation

Once the root cause is identified for a packaging complaint, then you need to implement corrective actions to prevent a recurrence. Also, FDA Clause 21 CFR 820.100 and ISO 13485, Clause 8.5.3, require that you implement preventive actions to detect situations that might result in a potential packaging failure in the future and implement preventive measures so that similar packaging failures are not able to occur. If you are interested in learning more about conducting a root cause analysis, please read our blog on this topic: Effective Root Cause Analysis – Learn 4 Tools.

This article is the first half of the packaging complaint investigation case study. The second half of the two-part case study explains the necessary containment measures, corrections, corrective actions, and preventive actions to address the root cause of the packaging failure.

Additional packaging validation resources

There are many articles on the topic of package testing and package design for sterile medical devices. If you want to learn more, please register for our free webinar on packaging validation by Jan Gates.

Packaging Complaint Investigation – Case Study Read More »

FDA eSTAR v5.0 – What’s new?

This blog provides a deep dive into the newest version of the FDA eSTAR, version 5.0, released on December 6, 2023.

Why did the FDA release the new eSTAR version as v5.0 instead of v4.4?

A major version update consists of policy changes, regulatory changes, or major changes to the template and will be denoted by a major version number increment (e.g. 4.3 to 5.0). A minor version update will consist of other changes and will be denoted by a minor version number increment (e.g. 4.3 to 4.4). If there are policy or regulatory changes, a new major version of the eSTAR is made before the implementation date, and the previous version of the eSTAR is removed. In this case, enabling PMA content, updates to the international pilot of the eSTAR with Health Canada, and implementation of cybersecurity documentation requirements are considered major changes that trigger the need for a major version update (i.e., 5.0) instead of a minor version update (i.e., 4.4). These changes apply to the IVD eSTAR and the non-IVD eSTAR. If you are generally unfamiliar with the FDA eSTAR, please visit our 510k course page.

What is the deadline for using v5.0?

Version 4.3 of the FDA eSTAR, both the nIVD and IVD versions, will be removed from the FDA website on February 4, 2024. Any submissions that are submitted with an expired version of the eSTAR will be rejected. If you have already uploaded information to an older version of the template, you will need to scroll to the bottom of the eSTAR and export the data to an HTML file. Then you import the HTML file into the newer version of the eSTAR. Any attachments you made to the older version of the template will not be exported, and you will have to attach all of the attachments to the new template.

Import Export Function in FDA eSTAR 1024x423 FDA eSTAR v5.0   Whats new?

PMA content is enabled in the new FDA eSTAR

Previous versions of the FDA eSTAR included the functionality for premarket approval (PMA) submissions, but in version 5.0 the FDA finally enabled this functionality. 510k submissions have three types: 1) Traditional, 2) Abbreviated, and 3) Special. PMA submissions also have different types. There are two types of PMA submissions for a new device: traditional and modular. Unfortunately, the FDA eSTAR is not intended for PMAs using the modular approach. For Class 3 devices, the FDA has more stringent controls over changes than Class 1 and 2 devices. Therefore, a PMA supplement is required for the following types of changes to PMA-approved devices:

  • new indications for use;
  • labeling changes;
  • facility changes for manufacturing or packaging;
  • changes in manufacturing methods;
  • changes in quality control procedures;
  • changes in sterilization procedures;
  • changes in packaging;
  • changes in the performance or design specifications, and
  • extension of the expiration date.

There are several types of PMA supplements, but only three types of supplements can use the FDA eSTAR: 1) Panel-Track, 2) 180-Day, and 3) Real Time. To determine which type of PMA supplement you should use, the FDA published guidance for modifications to devices subject to the premarket approval process.

PMA Content

The following sections in the FDA eSTAR are specific to PMA submission content requirements:

  • Quality Management System Information
  • Facility Information
  • Post-Market Study (PMS) Plans
  • Attach an exclusion statement, or an Environmental Assessment Report in accordance with 21 CFR 814.20(b)(11)

Health Canada is conducting a pilot with the FDA eSTAR

Health Canada’s FDA eSTAR pilot is now full with a total of 10 participants (originally only 9 were planned). The pilot will test the use of eSTAR for applications submitted to Health Canada. The results of the pilot should be complete soon, and then we expect an extension of the pilot to a broader number of applicants. We heard rumors that the HC eSTAR was overly complicated. Hopefully, v5.0 is simplified.

Were there any changes to the EMC testing section?

EMC Labeling questions were consolidated into a single question instead of four because only one citation is usually provided in this section. A copy of the older version is provided below.

Additional ISO 18562 help text 1024x395 FDA eSTAR v5.0   Whats new? Old EMC Labeling Section 1024x506 FDA eSTAR v5.0   Whats new?

The updated version 5.0 is shown below and has only one question, but the help text was changed.

Pointing to help text box 1024x250 FDA eSTAR v5.0   Whats new?

Does the FDA eSTAR now require more cybersecurity documentation?

Bhoomika Joyappa updated our cybersecurity work instruction (WI-007) to address the updated FDA guidance for cybersecurity documentation. The revisions were completed earlier this month, and you can purchase the updated templates on our website. We have also been telling our subscribers to anticipate a significant revision to the FDA eSTAR cybersecurity requirements 300x71 FDA eSTAR v5.0   Whats new?template when this happens. The release of the updated eSTAR version took a little over two months, and the change resulted in a three-page section dedicated to cybersecurity documentation. The previous versions of the template included a requirement for documentation of cybersecurity risk management and a cybersecurity management plan/plan for continuing support. The following documents must be attached in this section if cybersecurity applies to your device:

  1. risk management – report (attach)
  2. risk management – threat model (attach)
  3. list of threat methodology (text box)
  4. verification that the threat model documentation includes (yes/no dropdown):
    1. global system view
    2. Multi-patient harm view
    3. Updateability/patchability view
    4. Security use case views
  5. cybersecurity risk assessment (attach)
  6. page numbers where methodology and acceptance criteria are documented (text box)
  7. verification that the risk assessment avoids using probability for the likelihood assessment and use exploitability instead (yes/no dropdown)
  8. software bill of materials or SBOM (attach)
  9. software level of support and end-of-support date for each software component (attach)
  10. operating system and version used (text box)
  11. safety and security assessment of vulnerabilities (attach)
  12. assessment of any unresolved anomalies (attach)
  13. data from monitoring cybersecurity metrics (attach)
  14. information about security controls (attach)
  15. page numbers where each security control is addressed (text box):
    1. Authentication controls
    2. Authorization controls
    3. Cryptography controls
    4. Code, data, and execution integrity controls
    5. Confidentiality controls
    6. Event detection and logging controls
    7. Resiliency and recovery controls
    8. Firmware and software update controls
  16. architecture views (attach)
  17. cybersecurity testing (attach)
  18. page numbers where cybersecurity labeling is provided (text box)

Sterility section changes include an updated question on EO residuals

In the sterility section of the FDA eSTAR there was a question about sterilant residues. Specifically, the question was “What are the maximum levels of sterilant residual that remain on the device?” The space provided for entering the information was small as well.

EO residue help text 1024x568 FDA eSTAR v5.0   Whats new?

Now the question is reworded to: “What are the maximum levels of sterilant residuals that remain on the device, and what is your explanation for why those levels are acceptable for the device type and the expected duration of patient contact?” No change was made to the help text for this question.

In addition to the changes in the sterility section regarding EO residuals, the FDA also modified the dropdown menu and the help text for pyrogenicity testing. There were options for “LAL” and “Rabbit Test” separately, but now these are combined into “LAL and Rabbit Pyrogen Test.” In addition, the following help text was added: “If you previously conducted rabbit testing on these materials, please either: 1) reference this testing according to the submission number in your attached Pyrogenicity documentation and specifically cite the attachment(s) and page number(s) where the testing is found in that submission, or 2) attach your previous test report.”

Pyrogenicity help text 1024x647 FDA eSTAR v5.0   Whats new?

What is the deadline for using v5.0?

Many clients say that they get an error message when they try to open the FDA eSTAR template. This is because they are opening the eSTAR from a PDF viewer instead of Adobe Acrobat Pro.

Please wait 1024x400 FDA eSTAR v5.0   Whats new?

Some people want to save money by using the free Adobe Acrobat Reader software instead, but this will not allow you to complete the eSTAR properly. Therefore, the FDA added a Popup message if Adobe Acrobat Reader is used.

How are devices with a breathing gas pathway evaluated for biocompatibility?

In the screen capture below, I have intentionally selected “Surface Device: Mucosal Membrane” as the type of tissue contact for a breathing gas pathway device because the device will have a mouthpiece placed in your mouth (i.e., mucosal membrane). This is a common mistake. In version 5.0 of the FDA eSTAR, the FDA clarifies that these devices should be evaluated as “externally communicating” and the tissue contact is “tissue/bone/dentin.” Specifically, the tissue contact is the lungs. For this reason, the FDA added the help text shown below in the JavaScript Window regarding the applicability of ISO 18562-1, -2, -3, and -4.

ISO 18562 references for biocompatibility 802x1024 FDA eSTAR v5.0   Whats new?

Additional questions and guidance will appear when you click on the individual blue boxes shown above. For the blue box labeled “Subacute/Subchronic,” you will find additional help text regarding the ISO 18562 standards. Similar help text is found when you click the blue box labeled “Acute Systemic & Pyrogenicity.”

Additional ISO 18562 help text 1024x395 FDA eSTAR v5.0   Whats new?

What is a cross-section change reminder?

One of the minor changes made in this FDA eSTAR version is the addition of “cross-section change reminders” to the help text in the device description section. This is not meant to help you avoid answering questions in your submission, because if you are missing a section of the submission because you answered “No” instead of “Yes” the FDA reviewer will identify this error during the Technical Review process. This will result in your submission being placed on hold and the review time clock will be reset to zero days when you resubmit with the corrections made. The screen capture below shows an example of one of these cross-section change reminders.

Cross section change reminder 1024x636 FDA eSTAR v5.0   Whats new?

What changes were made to the clinical testing section of the FDA eSTAR?

The clinical testing section will now display when using PDF-XChange Editor, but we recommend only using Adobe Acrobat Pro to edit the FDA eSTAR. This change is a bug fix, and it is specific to the nIVD eSTAR. The IVD eSTAR and the nIVD eSTAR both include a clinical testing section within the performance testing section, but the performance testing section is found in the FDA eSTAR before the electrical safety and EMC testing section, while the performance testing section is found after the electrical safety and EMC testing section. If your company is planning to submit clinical data in a future FDA submission, we have the following recommendations:

  • watch the CDRH Learn webinars on the topic of 21 CFR 812
  • conduct a pre-submission teleconference to ask questions about your clinical study protocol before IRB submission or ethics review board submission
  • before you submit the pre-sub meeting request, look at what general clinical information the FDA wants for a De Novo or PMA submission in the FDA eSTAR

FDA eSTAR clinical section 873x1024 FDA eSTAR v5.0   Whats new?

Note: The clinical section shown above is only found in the FDA eSTAR if you select a De Novo or PMA submission. If you submit a 510k submission with clinical data, the clinical section will be abbreviated as shown below.

FDA eSTAR clinical section for 510k 859x1024 FDA eSTAR v5.0   Whats new?

FDA eSTAR v5.0 – What’s new? Read More »

Complaints handling mistakes – Why?

Complaints handling mistakes, medical device reporting, and CAPA are the most common reasons for FDA 483 inspection observations, but why?complaints Complaints handling mistakes   Why?

Reasons for FDA 483s related to the CAPA process

You should already be well aware that deficiencies in the CAPA process, complaints handling, and medical device reporting are the three most common reasons why the FDA issues 483 inspection observations and Warning Letters in 2023. The most common reason for an FDA 483 inspection observation is related to the CAPA process (i.e., 336 observations citing 21 CFR 820.100). For the CAPA process, all 336 observations cited problems with inadequate procedures or inadequate records.

Reasons for complaints handling mistakes

The complaints handling process is the second most common reason for FDA 483 inspection observations (i.e., 276 observations citing 21 CFR 820.198). The complaints handling process has nine different reasons for 483 inspection observations (listed from most common to least common):

  1. Procedures for receiving, reviewing, and evaluating complaints by a formally designated unit have not been [adequately] established.  Specifically,*** 
  2. Complaints involving the possible failure of [a device] [labeling] [packaging] to meet any of its specifications were not [reviewed] [evaluated] [investigated] where necessary. Specifically, *** 
  3. Records of complaint investigations do not include required information.  Specifically, *** 
  4. Complaint files are not [adequately] maintained.  Specifically, *** 
  5. Not all complaints have been [adequately] reviewed and evaluated to determine whether an investigation is necessary. Specifically, ***
  6. Records for complaints where no investigation was made do not include required information.  Specifically, *** 
  7. Complaints representing events that are MDR reportable were not [promptly reviewed, evaluated, and investigated by a designated individual] [maintained in a separate portion of the complaint files] [clearly identified]. Specifically, ***
  8. Investigation records of MDR reportable complaints do not include required information.  Specifically, *** 
  9. Records of complaint investigations do not include required information, including any unique device identifier (UDI) or universal product code (UPC).  Specifically, ***

Reasons for FDA 483s related to Medical Device Reporting

There were 106 observations related to medical device reporting (i.e., 21 CFR 803) in 2023 thus far. There are 25 different reasons identified by the FDA for 483 inspection observations related to the Medical Device Reporting regulation. The majority o of the inspection observations were related to an inadequate or missing MDR procedure. However, there were also a number of inspection observations that were related to missing information in the MDR records. Therefore, we updated our Medical Device Reporting Procedure to include all of the required elements of the FDA’s MedWatch Form. We posted a blog about “Where to Focus your Medical Device Complaint Handling Training.” In that blog we answered questions from device manufacturers and consultants regarding the process of complaints handling investigation. The following section is a summary of my responses to those questions.

Complaints handling investigations

What criteria do you think should be used to determine whether a complaint should be investigated or not?

There is only one acceptable rationale for not investigating a complaint. If you don’t investigate complaints when required, then you might receive an FDA Form 483 observation worded like this…

21 CFR 820.198(c) – Complaints involving the possible failure of labeling to meet any of its specifications were not investigated where necessary. Specifically, a missing IFU was reported in customer complaints, but no investigation was conducted. The rationale documented in the complaint record was “the missing IFU presented no patient risk.”

A missing IFU is a “failure of labeling to meet any of its specifications.” Therefore, 21 CFR 820.198(c) requires you to conduct an investigation “unless such investigation has already been performed for a similar complaint, and another investigation is not necessary.” This is the only rationale that is acceptable for skipping your investigation. To ensure that no one forgets to investigate a complaint, make sure you include a space in your complaint handling form that is specifically labeled as “Summary of Complaint Investigation.” This space should also include an option to cross-reference to a previous complaint record where a similar investigation is already documented.

A missing IFU is also considered a misbranded product that requires correction (e.g., sending the customer a replacement IFU) or removal (i.e., recall). The FDA expects a Health and Hazard Evaluation (HHE) form to be included in your recall records, and the HHE should indicate the potential risk of a “delay in treatment.” This is the FDA’s conclusion in their evaluation of risk, and therefore your HHE must identify a delay in treatment as a patient risk too. The FDA also expects a CAPA to be initiated to prevent the recurrence of this type of labeling error. You can make a “risk-based” determination that reporting a specific recall to the FDA is not required as per 21 CFR 806.20. However, you need to maintain records of your determination not to report a recall. If you already received a Warning Letter, you should err on the side of reporting anyway.

Note: References to “recall” in the above paragraph are meant to include field corrections.

Intended Use

If a complaint consists of a medical device being used for something other than its intended use, is an MDR required for this user error?

The answer is yes. If you don’t report adverse events involving “user error,” then you might receive an FDA Form 483 observation worded like this…

21 CFR 803.17(a)(1) – The written MDR procedure does not include an internal system which provides for the timely and effective evaluation of events that may be subject to medical device reporting requirements.  Specifically, several incidents where a death or serious injury occurred were “caused by a user error,” and the procedure did not identify this as an event requiring Medical Device Reporting.

In 21 CFR 803.3, the FDA defines “caused or contributed” to include events occurring as a result of:

  1. Failure
  2. Malfunction
  3. Improper or inadequate design
  4. Manufacture
  5. Labeling, or
  6. User error

It is important to understand that the definition of complaints and the requirement to report adverse events should not be “risk-based.” The need for remediation and the need to report corrections and removals can be “risk-based,” but whether something is a complaint, and whether it is reportable should be “black-and-white.” For example, “Did the death or serious injury occur due to auser error’-including use other than the intended use?” If the answer is yes, then it is a complaint and reportable.

Incidents and Adverse Event Reporting

Do incidents that occurred outside the United States need to be reported to FDA?

The answer is yes. If you don’t report adverse events that occur outside the United States, then you might receive an FDA Form 483 observation worded like this…

21 CFR 820.50(a)(1) – An MDR report was not submitted within 30 days of receiving or otherwise becoming aware of information that reasonably suggests that a marketed device may have caused, or contributed to, a death or severe injury. Specifically, several instances were identified where the device caused or contributed to a death or serious injury, and the event was not reported to the Agency. The rationale documented in the complaint record was that the “event occurred outside the United States.”

This type of mistake is most likely due to a lack of training on 21 CFR 803–Medical Device Reporting. Some manufacturers that distribute products internationally are more familiar with the European Vigilance requirements as defined in Articles 87-89 of Regulation (EU) 2017/745. You can find additional guidance on vigilance reporting in our Vigilance Procedure or the applicable MDCG guidance. The European Medical Device Directive (i.e., MDD) only required vigilance reporting of incidents that occurred outside the Member States of the European Economic Area (EEA), Switzerland, and Turkey if the incident required implementation of field safety corrective actions. The EU MDR now requires reporting of incidents that occur outside of the EU if the device is also made available in the EU.

The FDA Part 803 requirements are worded differently. Part 803 does not indicate that the event had to occur in the United States. The MedWatch form (i.e., FDA Form 3500A) must be filed for events that occur in the United States and events occurring outside the USA if the devices are “similar” to devices marketed in the USA. Unfortunately, most device manufacturers are not aware of this requirement. Therefore, the FDA released a final guidance on Medical Device Reporting requirements on November 8, 2016. If you would like to learn more about Medical Device Reporting requirements, you can purchase our MDR procedure and webinar bundle. We will also be expanding our consulting services in January 2024 to include Medical Device Reporting for our clients.

Additional Resources on Complaints Handling

Medical Device Academy sells a complaints handling procedure, and a webinar on complaints handling. We will be updating the procedure during the holidays and hosting a new live complaints handling webinar on January 4, 2024. If you purchase the webinar, or you purchased the webinar in the past, you will receive an invitation to participate in the live webinar in January. If you purchase the complaints handling procedure, or you purchased the procedure in the past, you will receive the updated procedure, updated complaints handling form, and updated complaints log. You will also receive an invitation to the live webinar because we will be bundling the webinar with an updated procedure. We will also provide a discount code during the live webinar for people to upgrade their purchase of the webinar to include the purchase of the procedure. Customers who purchased one of our turnkey quality systems will also receive access to the live webinar.

Complaints handling mistakes – Why? Read More »

eSTAR Project Management

Using the new FDA eSTAR template also requires a new process for eSTAR project management to prepare your 510k and De Novo submissions.

Outline of ten (10) major changes resulting from the new FDA eSTAR template

As of October 1, 2023, all 510k and De Novo submissions to the FDA now require using the new FDA eSTAR template and the template must be uploaded to the FDA Customer Collaboration Portal (CCP). Yesterday the FDA published an updated guidance explaining the 510k electronic submission requirements, but there are ten (10) major changes to Medical Device Academy’s submission process resulting from the new eSTAR templates:

  1. We no longer need a table of contents.
  2. We no longer use the volume and document structure.
  3. We are no longer required to conform to sectioning or pagination of the entire submission.
  4. We no longer worry about the RTA screening or checklist (it doesn’t exist).
  5. We no longer bother creating an executive summary (it’s optional).
  6. We no longer have a section for Class 3 devices, because there are no Class 3 510(k) devices anymore.
  7. We no longer use FDA Form 3514, because that content is now incorporated into the eSTAR.
  8. We no longer create a Declaration of Conformity, because the eSTAR creates one automatically.
  9. We no longer recommend creating a 510(k) Summary, because the eSTAR creates one automatically
  10. We no longer use FedEx, because we can upload to FDA CCP electronically instead.

What is different in the 510k requirements?

Despite all the perceived changes to the FDA’s pre-market notification process (i.e., the 510k process), the format and content requirements have not changed much. The most significant recent change to the 510k process was the requirement to include cybersecurity testing.

Outline of eSTAR Project Management

There were 20 sections in a 510k submission. Medical Device Academy’s consulting team created a template for the documents to be included in each section. eSTAR project management is different because there are no section numbers to reference. To keep things clear, we recommend using one or two words at the beginning of each file name to define the section it belongs in. The words should match up with the bookmarks used by the FDA. However, you should be careful not to make the file names too long. Below is a list of all of the sections:

  • Administrative Information;
  • Device Description;
  • Predicates and Substantial Equivalence;
  • Benefits, Risks, and Mitigation Measures;
  • Labeling;
  • Reprocessing, Sterility, and Shelf-life;
  • Biocompatibility;
  • Software/Firmware and Cybersecurity/Interoperability
  • Software;
  • EMC, Wireless, Electrical, Mechanical, and Thermal Safety;
  • Performance Testing;
  • Quality Management; and
  • Administrative Documentation.

The Benefit, Risks, and Mitigation Measures Section only applies to De Novo Classification Requests. The Quality Management Section includes subsections for Quality Management System Information, Facility Information, Post-Market Studies, and References. However, only the References subsection will be visible in most submissions because the other three subsections are part of the Health Canada eSTAR pilot. Other sections and subsections will be abbreviated or hidden depending on the dropdown menu selections you select in the eSTAR. For example, the cybersecurity section will remain hidden if your device does not have wireless functionality or a removable storage drive.

Wireless Not Applicable 1024x252 eSTAR Project Management

A Table of Contents is no longer required for 510k submissions

510k submissions using the FDA eCopy format required a Table of Contents, and Medical Device Academy used the Table of Contents as a project management tool. Sometimes, we still use our Table of Contents template to communicate assignments and manage the 510k project. The sections of the Table of Contents would also be color-coded green, blue, yellow, and red to communicate the status of each section. FDA eSTAR project management uses a similar color coding process with colored bars on the side of the template to indicate if the section is incomplete, complete, or optional.

Color coding of eSTAR 1024x372 eSTAR Project Management

The eSTAR also has a verification section at the end of the template to help with eSTAR project management. The verification section lists each of the 13 major sections of an FDA eSTAR. When the sections are completed, the section’s name automatically moves from the right side of the verification section to the left side. During the past two years (2021 – 2023) of implementing the eSTAR template, I have slowly learned to rely only on the eSTAR to communicate the status of each section. To assign responsibilities for each section of the 510k submission, we still use the Table of Contents simple lists and project management tools like Asana. Using the eSTAR verification section to check on the status of each 510k section also increases our team’s proficiency with the eSTAR every time we use it.

Verification section 1024x379 eSTAR Project Management

Using Dropbox for eSTAR project management

PreSTAR templates for a Q-Sub meeting are approximately half the length (i.e., 15 pages instead of 30+ pages) of an eSTAR template, and the 510k submission requires far more attachments than a Q-Sub. Therefore, we can usually email a revised draft of the PreSTAR to a team member for review, but we can’t use email to share a nearly complete eSTAR with a team member. Therefore, Medical Device Academy uses Dropbox to share revisions of the eSTAR between team members. Some of our clients use One Drive or Google Drive to share revisions. We also create sub-folders for each type of testing. This keeps all of the documents and test reports for a section of the eSTAR in one place. For example, the software validation documentation will be organized in one sub-folder of the Dropbox folder for a 510k project.

When using FDA eCopies instead of the FDA eSTAR template, we used twenty subfolders labeled and organized by volume numbers 1-20. Some of those 20 sections are now obsolete (e.g., Class III Summary), and others (e.g., Indications for Use) are integrated directly into the eSTAR template. Therefore, a team may only need 8-10 sub-folders to organize the documents and test reports for a 510k project. We typically do not attach these documents and test reports until the very end of the submission preparation because if the FDA releases a new version of the eSTAR, the attachments will not export from an older version of the eSTAR to the new version.

Coordination of team collaboration is critical to successful eSTAR project management

In the past, Medical Device Academy always used a volume and document structure to organize an FDA eCopy because this facilitated multiple team members simultaneously working on the same 510k submission–even from different countries. Many clients will use SharePoint or Google Docs to facilitate simultaneous collaboration by multiple users. Unfortunately, the eSTAR cannot be edited by two users simultaneously because it is a secure template that can only be edited in Adobe Acrobat Pro. Therefore, the team must communicate when the eSTAR template is being updated and track revisions. For communication, we use a combination of instant messenger apps (e.g., Slack or Whatsapp) and email, while revisions are tracked by adding the initials and date of the editor to the file name (e.g., nIVD 4.3 rvp 12-5-2023.pdf).

Importance of peer reviews

Each section of the FDA eSTAR must be completed before the submission can be uploaded to the Customer Collaboration Portal (CCP). If the FDA eSTAR is incomplete, the CCP will identify the file as incomplete. You will not be able to upload the file. If questions in the eSTAR are incorrectly answered, then sections that should be completed may not be activated because of how the questions were answered. Below are two examples of how the eSTAR questions can be incorrectly answered.

  • Example 1 – One of the helpful resource features of the FDA eSTAR is that many fields are populated with a dropdown menu of answers. One example is found in the Classification section of the eSTAR. This section requires the submitter to identify the device’s classification by answering three questions: 1) review panel, 2) classification regulation, and 3) the three-letter product code. Each of these fields uses a dropdown menu to populate the field, and the dropdown options for questions two and three depend on answers to the previous question. However, if you manually type the product code into the field for the third question, then the eSTAR will not identify any applicable special controls guidance documents for your device. Unless you are already aware of an applicable special controls guidance document, you will answer questions in the eSTAR about special controls with “N/A.” The eSTAR will only identify a special controls guidance document for your device if you select a product code from the dropdown menu, but the FDA reviewer knows which special controls guidance documents are applicable. This is why the FDA performs a technical screening of the eSTAR before the substantive review begins.

Classification Section 1024x612 eSTAR Project Management

  • Example 2 – If you indicate the cumulative duration of contact for an externally communicating device < 24 hours, the eSTAR template will expect you to evaluate the following biocompatibility endpoints:  cytotoxicity, sensitization, irritation, systemic toxicity, and pyrogenicity.

24 hour duration of contact 1024x118 eSTAR Project Management

However, if you indicate the cumulative duration of contact is  < 30 days, the eSTAR template will be populated with additional biocompatibility endpoints. The eSTAR doesn’t know what the cumulative duration of use is, but the FDA reviewer will. This is why the FDA performs a technical screening of the eSTAR before the substantive review begins.

30 day duration of contact 1024x152 eSTAR Project Management

To make sure that all of the sections of your submission are complete, it’s helpful to have a second person review all of the answers to make sure that everything was completed correctly. Even experienced consultants who prepare 510k submissions every week can make a mistake and incorrectly answer a question in one of the eSTAR fields. Therefore, you shouldn’t skip this critical QC check.

Additional 510k Training

The 510k book, “How to Prepare Your 510k in 100 Days,” was completed in 2017, but the book is only available as part of our 510k course series consisting of 58+ webinars. Please visit the webinar page to purchase individual webinars.

eSTAR Project Management Read More »

510k Electronic Submission Guidance for FDA 510k Submissions

This is an overview of the updated 510k electronic submission guidance document that the FDA released on October 2, 2023.

What’s included in the 510k electronic submission guidance?

As with any FDA guidance, there is an introduction and background regarding the reason for the updated guidance document (i.e., eSTAR guidance). At the very beginning of the document (i.e., page 3) the reference to the RTA Guidance was deleted, because there is no longer an RTA screening process with the implementation of the FDA eSTAR templates. The updated guidance explains on page 6 that “The CDRH Portal will automatically verify that the eSTAR is complete, and therefore we do not expect to receive incomplete 510(k) eSTARs.” In the scope section, the FDA specifies that this document is specific to 510k submissions using the eSTAR template. The document also explains that CBER conducted a pilot with the eSTAR template in June 2022 and now the FDA eSTAR template must be used in conjunction with the CDRH Portal for submission of a 510k to CBER. The FDA has plans to release a similar De Novo submission guidance for using the eSTAR template, but this has not happened in the year since the FDA announced the intention to do so. In the “Significant Terminology” section of the guidance (i.e., Section IV), the FDA provides definitions for each of the different types of submissions: eCopy, eSubmitter, etc. In the “Current Electronic Submission Template Structure, Format, and Use” section of the guidance (i.e., Section V), the FDA modified the term used for the company that is applying for 510k clearance from “Submitter” to “Applicant,” because sometimes a regulatory consultant or 3rd party reviewer is submitting the 510k on behalf of the applicant. On page 12 of the updated guidance, the FDA added “Withdrawal requests” to the list of 510k submissions/information that is exempt from the 510k electronic submission requirements. In the next to last section of the electronic submission guidance, the FDA provides a table outlining all of the sections of the new eSTAR template. The table is reproduced later in this article. If you are interested in a tutorial on completing each section outlined in the table, we recommend purchasing Medical Device Academy’s 510(k) Course. The last section of the eSTAR guidance indicates the timing for compliance with the updated guidance (i.e., October 1, 2023).

Revisions to the FDA eSubmissions Guidance 10 2 2023 1024x620 510k Electronic Submission Guidance for FDA 510k Submissions

What is the deadline for compliance with the guidance?

The deadline has now passed. The new eSTAR template must be used for all 510k and De Novo submissions as of October 1, 2023. You must upload the new FDA eSTAR submissions using the CDRH Portal. You will need to request an account using a registration hyperlink.

What’s missing from this 510k submission guidance?

The updated 510k electronic submission guidance does not provide information regarding the receipt date for electronic submissions made through the new customer collaboration portal (CCP) created by CDRH. The image below is a screen capture of the current CCP upload webpage. It includes the following statement, “Send your submission before 16:00 ET on a business day for us to process it the same day.” This statement was added sometime in August or September, but the FDA has not released a detailed explanation. This statement makes it clear that the FDA is not promising to process a submission the “same day” if the submission is received after 4:00 p.m. ET. However, “processed” does not have the same meaning as “receipt date.”

Another element missing from this updated guidance is a reference to human factors documentation. For any devices that have a user interface that is different from the predicate device, and for software devices, the FDA requires documentation of your human factors process to make sure that differences in the user interface do not result in new or different risks when compared to the predicate device. The 2016 FDA guidance for human factors has not been updated, but FDA reviewers continue to issue deficiencies related to the objective evidence provided in a 510k for human factors validation.

CCP screen capture 1024x619 510k Electronic Submission Guidance for FDA 510k Submissions

The FDA must be consistent in the wording for “Hours for Receipt of Submission” because this affects submissions at the end of the fiscal year, but it also affects any submissions with a deadline for response to an RTA Hold, AI Response, and IDE submissions. The CDER and CBER divisions of the FDA address the need for defining the date of receipt in a guidance document specific to this topic, “Providing Regulatory Submissions in Electronic Format–Receipt Date.” Below is a screen capture copied from page 4 of the guidance.

Electronic Submission 510k Electronic Submission Guidance for FDA 510k Submissions

Another element missing from this new guidance is a reference to human factors documentation. For any devices that have a user interface that is different from the predicate device, and for software devices, the FDA requires documentation of your human factors process to make sure that differences in the user interface do not result in new or different risks when compared to the predicate device. The 2016 FDA guidance for human factors has not been updated, but FDA reviewers continue to issue deficiencies related to the objective evidence provided in a 510k for human factors validation.

What are the new sections for a 510k submission?

In 2019, the FDA released a guidance document on the “Format of Traditional and Abbreviated 510(k)s.” That guidance outlines the 20 sections of a traditional 510k submission that have been used for decades. However, the new 510k electronic submission guidance has no numbering for the sections of the eSTAR template, and there are 22 sections instead of 20 sections. Several of the new sections are elements of the current FDA submission cover sheet (i.e., FDA Form 3514), and some sections exist in the 2019 guidance that were eliminated, such as: “Class III Summary and Certification.” Therefore, Medical Device Academy is recreating 100% of our 510k training webinars to explain how our 510k templates are used with the 510k eSTAR template and how to fill in the PDF form. To prevent confusion between the two formats, we are using letters for each section in the eSTAR template instead of numbers (i.e., A-V instead of 1-20). Table 1 from the new eSTAR guidance is reproduced below for your information.

Information Requested Description
A Submission Type Identification of key information that may be useful to FDA in the initial processing and review of the 510(k) submission, including content from current Form FDA 3514, Section A.
B Cover Letter / Letters of Reference Attach a cover letter and any documents that refer to other submissions.
C Submitter Information Information on submitter and correspondent, if applicable, consistent with content from current Form FDA 3514, Sections B and C.
D Pre-Submission Correspondence & Previous Regulator Interaction Information on prior submissions for the same device included in the current submission, such as submission numbers for a prior not substantially equivalent (NSE) determination, prior deleted or withdrawn 510(k), Q-Submission, Investigational Device Exemption (IDE) application, premarket approval (PMA) application, humanitarian device exemption (HDE) application, or De Novo classification request.
E Consensus Standards Identification of voluntary consensus standard(s) used, if applicable. This includes both FDA-recognized and nonrecognized consensus standards.
F Device Description Identification of listing number if listed with FDA.Descriptive information for the device, including a description of the technological characteristics of the device including materials, design, energy source, and other device features, as defined in section 513(i)(1)(B) of the FD&C Act and 21 CFR 807.100(b)(2)(ii)(A). Descriptive information also includes a description of the principle of operation for achieving the intended effect and the proposed conditions of use, such as surgical technique for implants; anatomical location of use; user interface; how the device interacts with other devices; and/or how the device interacts with the patient.

Information on whether the device is intended to be marketed with accessories.

Identification of any applicable device-specific guidance document(s) or special controls for the device type as provided in a special controls document (or alternative measures identified that provide at least an equivalent assurance of safety and effectiveness) or in a device-specific classification regulation, and/or performance standards. See “The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)].

G Proposed Indications for Use (Form FDA 3881) Identification of the proposed indications for use of the device. The term indications for use, as defined in 21 CFR 814.20(b)(3)(i), describes the disease or condition the device will diagnose, treat, prevent, cure, or mitigate, including a description of the patient population for which the device is intended.
H Classification Identification of the classification regulation number that seems most appropriate for the subject device, as applicable.
I Predicates and Substantial Equivalence Identification of a predicate device (e.g., 510(k) number, De Novo number, reclassified PMA number, classification regulation reference, if exempt and limitations to exemption are exceeded, or statement that the predicate is a preamendments device).The submission should include a comparison of the predicate and subject device and a discussion why any differences between the subject and predicate do not impact safety and effectiveness [see section 513(i)(1)(A) of the FD&C Act and 21 CFR 807.87(f)]. A reference device should also be included in the discussion, if applicable. See “The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)].
J Design/Special Controls, Risks to Health, and Mitigation Measures Applicable to Special 510(k) submissions only.Identification of the device changes and the risk analysis method(s) used to assess the impact of the change(s) on the device and the results of the analysis.

Risk control measures to mitigate identified risks (e.g., labeling, verification). See “The Special 510(k) Program.

K Labeling Submission of proposed labeling in sufficient detail to satisfy the requirements of 21 CFR 807.87(e). Generally, if the device is an in vitro diagnostic device, the labeling must also satisfy the requirements of 21 CFR 809.10. Additionally, the term “labeling” generally includes the device label, instructions for use, and any patient labeling. See “Guidance on Medical Device Patient Labeling.
L Reprocessing Information for assessing the reprocessing validation and labeling, if applicable. See “Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling.
M Sterility Information on sterility and validation methods, if applicable. See “Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile.
N Shelf Life Summary of methods used to establish that device performance is maintained for the entirety of the proposed shelf-life (e.g., mechanical properties, coating integrity, pH, osmolality), if applicable.
O Biocompatibility Information on the biocompatibility assessment of patient contacting materials, if applicable. See “Use of International Standard ISO 10993-1, ‘Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process.’”
P Software/Firmware Submission of applicable software documentation, if applicable. See “Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices.
Q Cybersecurity/Interoperability Submission of applicable information regarding the assessment of cybersecurity, if applicable. See “Content for Premarket Submissions for Management of Cybersecurity in Medical Devices” and “Design Considerations and Premarket Submission Recommendations for Interoperable Medical Devices.
R Electromagnetic Compatibility (EMC), Electrical, Mechanical, Wireless and Thermal Safety Submission of the EMC, Electrical, Mechanical, Wireless and Thermal Safety testing for your device or summarize why testing is not needed. See “Electromagnetic Compatibility (EMC) of Medical Devices” and “Radio Frequency Wireless Technology in Medical Devices.
S Performance Testing For non-in vitro diagnostic devices: Provide information on the non-clinical and clinical test reports submitted, referenced, or relied on in the 510(k) for a determination of substantial equivalence. See “Recommended Content and Format of NonClinical Bench Performance Testing Information in Premarket Submissions.”For in vitro diagnostic devices: Provide analytical performance, comparison studies, reference range/expected values, and clinical study information.
T References Inclusion of any literature references, if applicable.
U Administrative Documentation Inclusion of additional administrative forms applicable to the submission, including but not limited to a general summary of submission/executive summary (recommended), a Truthful and Accuracy Statement, and a 510(k) Summary or statement.
V Amendment/Additional Information (AI) response Inclusion of responses to Additional Information requests.

Important information in the eSTAR guidance

In Table 1 above, there are 14 hyperlinks to various FDA guidance documents. These links are extremely helpful when you have questions about a specific question. Unfortunately, the 510k electronic submission guidance document will quickly become out-of-date as guidance documents are updated and made obsolete. In particular, one of the A-list final guidance documents that was planned for FY 2023 was the FDA cybersecurity guidance. The updated cybersecurity guidance was finally released last week.

510k Electronic Submission Guidance for FDA 510k Submissions Read More »

Predicate selection guidance proposes controversial additions

The FDA released a new draft 510k predicate selection guidance on September 7, but the draft guidance proposes controversial additions.

Draft Guidance on Predicate Selection Best Practices 1024x664 Predicate selection guidance proposes controversial additions
Download the Draft FDA Predicate Selection Guidance

On September 7, 2023, a draft predicate selection guidance document was released by the FDA. Normally the release of a new draft of FDA guidance documents is anticipated and there is an obvious need for the draft. This new draft, however, appears to include some controversial additions that I feel should be removed from the guidance. This specific guidance was developed to help submitters use best practices in selecting a predicate. There is some useful advice regarding the need to review the FDA database for evidence of use-related and design-related safety issues associated with a potential predicate that is being considered. Unfortunately, the last section of the guidance suggests some controversial recommendations that I strongly disagree with.

Please submit comments to the FDA regarding this draft guidance

This guidance is a draft. Your comments and feedback to the FDA will have an impact on FDA policy. We are preparing a redlined draft of the guidance with specific comments and recommended changes. We will make the comments and feedback available for download from our website on our predicate selection webinar page. We are also creating a download button for the original draft in Word (.docx) format, and sharing the FDA instructions for how to respond.

Section 1 – Introduction to the guidance

The FDA indicates that this new draft predicate selection guidance document was created to provide recommendations to implement four (4) best practices when selecting a predicate device to support a 510k submission. This first objective is something that our consulting firm recommended in a training webinar. The guidance indicates that the guidance was also created by the FDA in an attempt to improve the predictability, consistency, and transparency of the 510k pre-market review process. This second objective is not accomplished by the draft guidance and needs to be modified before the guidance is released as a final guidance.

Section 2 – Background

This section of the guidance is divided into two parts: A) The 510k Process, and B) 510k Modernization.

A. The 510k Process

The FDA released a Substantial Equivalence guidance document that explains how to demonstrate substantial equivalence. The guidance document includes a new decision tree that summarizes each of the six questions that 510k reviewers are required to answer in the process of evaluating your 510k submission for substantial equivalence. The evidence of substantial equivalence must be summarized in the Predicates and Substantial Equivalence section of the FDA eSTAR template in your 510k submission, and the guidance document reviews the content that should be provided.

Substantial equivalence is evaluated against a predicate device or multiple predicates. To be considered substantially equivalent, the subject device of your 510k submission must have the same intended use AND the same technological characteristics as the predicate device. Therefore, you cannot use two different predicates if one predicate has the same intended use (but different technological characteristics), and the second predicate has the same technological characteristics (but a different intended use). That’s called a “split predicate,” and that term is defined in the guidance This does not prohibit you from using a secondary predicate, but you must meet the requirements of this guidance document to receive 510k clearance. The guidance document reviews five examples of multiple predicates being used correctly to demonstrate substantial equivalence.

B. 510k Modernization

The second part of this section refers to the FDA’s Safety Action Plan issued in April 2018. The announcement of the Safety Action Plan is connected with the FDA’s announcement of actions to modernize the 510k process as well. The goals of the FDA Safety Action Plan consist of:

  1. Establish a robust medical device patient safety net in the United States
  2. Explore regulatory options to streamline and modernize timely implementation of postmarket mitigations
  3. Spur innovation towards safer medical devices
  4. Advance medical device cybersecurity
  5. Integrate the Center for Devices and Radiological Health’s (CDRH’s) premarket and postmarket offices and activities to advance the use of a TPLC approach to device safety 

Examples of modernization efforts include the following:

  • Conversion of the remaining Class 3 devices that were designated for the 510k clearance pathway to the PMA approval process instead
  • Use of objective performance standards when bringing new technology to the market
  • Use of more modern predicate devices (i.e., < 10 years old)

In this draft predicate selection guidance, the FDA states that feedback submitted to the docket in 2019 has persuaded the FDA to acknowledge that focusing only on modern predicate devices may not result in optimal safety and effectiveness. Therefore, the FDA is now proposing the approach of encouraging best practices in predicate selection. In addition, the draft guidance proposes increased transparency by identifying the characteristics of technological characteristics used to support a 510k submission.

The FDA did not mention an increased emphasis on risk analysis or risk management in the guidance, but the FDA is modernizing the quality system regulations (i.e., 21 CFR 820) to incorporate ISO 13485:2016 by reference. Since ISO 13485:2016 requires the application of a risk-based approach to all processes, the application of a risk-based approach will also impact the 510k process in multiple ways, such as design controls, supplier controls, process validation, post-market surveillance, and corrective actions. 

Section 3 – Scope of the predicate selection guidance

The draft predicate selection guidance indicates that the scope of the guidance is to be used in conjunction with the FDA’s 510k program guidance. The scope is also not intended to change to applicable statutory or regulatory standards. 

Section 4 – How to use the FDA’s predicate selection guidance

The FDA’s intended use of the predicate selection guidance is to provide submitters with a tool to help them during the predicate selection process. This guidance suggests a specific process for predicate selection. First, the submitter should identify all of the possible legally marketed devices that also have similar indications for use. Second, the submitter should exclude any devices with different technological characteristics if the differences raise new or different issues of risk. The remaining sub-group is referred to in the guidance as “valid predicate device(s).” The third, and final, step of the selection process is to use the four (4) best practices for predicate selection proposed in the guidance. The diagram below provides a visual depiction of the terminology introduced in this guidance.

Visual diagram of terminology in predicate selection guidance 1024x438 Predicate selection guidance proposes controversial additions

Section 5 – Best Practices (for predicate selection)

The FDA predicate selection guidance has four (4) best practices recommended for submitters to use when narrowing their list of valid predicate devices to a final potential predicate(s). Prior to using these best practices, you need to create a list of legally marketed devices that could be potential predicates. The following FDA Databases are the most common sources for generating a list of legally marketed devices:

  • Registration & Listing Database
    • Trade names of similar devices (i.e., proprietary name)
    • Manufacturer(s) of similar devices (i.e., owner operator name)
  • 510k Database
    • 510k number of similar devices
    • Applicant Name (i.e., owner operator name) of similar devices
    • Device Name (i.e., trade name) of similar device
  • Device Classification Database
    • Device classification name of similar devices
    • Product Code of similar devices
    • Regulation Number of similar devices

Our team usually uses the Basil Systems Regulatory Database to perform our searches. Basil Systems uses data downloaded directly from the FDA, but the software gives us four advantages over the FDA public databases:

  1. The search engine uses a natural-language algorithm rather than a Boolean search.
  2. The database is much faster than the FDA databases.
  3. The results include analytics regarding the review timelines and a “predicate tree.”
  4. Basil Systems also has a post-market surveillance database that includes all of the FDA adverse events and recall data, but it also includes access to data from Health Canada and the Australian TGA.

A. Predicate devices cleared using well-established methods

Some 510k submissions use the same methods used by a predicate device that was used for their substantial equivalence comparison, while other devices use well-established methods. The reason for this may have been that the 510k submission preceded the release of an FDA product-specific, special controls guidance document. In other cases, the FDA may not have recognized an international standard for the device classification. You can search for recognized international standards associated with a specific device classification by using the FDA’s recognized consensus standards database. An example is provided below.

How to search for FLL recognized standards 1024x712 Predicate selection guidance proposes controversial additions

FLL recognized standards 1024x577 Predicate selection guidance proposes controversial additions

New 510k submissions should always use the methods identified in FDA guidance documents and refer to recognized international standards instead of copying the methods used to support older 510k submissions that predate the current FDA guidance or recognized standards. The problem with the FDA’s proposed approach is that the FDA is implying that a device that was not tested to the current FDA guidance or recognized standards is inherently not as safe or effective as another device that was tested to the current FDA guidance or recognized standards. This inference may not be true. Therefore, even though this may be a consideration, it is not appropriate to require manufacturers to include this as a predicate selection criterion. The FDA is already taking this into account by requiring companies to comply with the current FDA guidance and recognized standards for device description, labeling, non-clinical performance testing, and other performance testing. An example of how the FDA PreSTAR automatically notifies you of the appropriate FDA special controls guidance for a product classification is provided below.

Screen capture of PreSTAR classification section 1024x792 Predicate selection guidance proposes controversial additions

B. Predicate devices meet or exceed expected safety and performance

This best practice identified in the FDA predicate selection guidance recommends that you search through three different FDA databases to identify any reported injury, deaths, or malfunctions of the predicate device. Those three databases are:

  1. MAUDE Database
  2. MDR Database
  3. MedSun Database

All of these databases are helpful, but there are also problems associated with each database. In general, adverse events are underreported, and a more thorough review of post-market surveillance review is needed to accurately assess the safety and performance of any device. The MAUDE data represents reports of adverse events involving medical devices and it is updated weekly. The data consists of all voluntary reports since June 1993, user facility reports since 1991, distributor reports since 1993, and manufacturer reports since August 1996. The MDR Data is no longer updated, but the MDR database allows you to search the CDRH database information on medical devices that may have malfunctioned or caused a death or serious injury during the years 1992 through 1996. Medical Product Safety Network (MedSun) is an adverse event reporting program launched in 2002 by CDRH. The primary goal for MedSun is to work collaboratively with the clinical community to identify, understand, and solve problems with the use of medical devices. The FDA predicate selection guidance, however, does not mention the Total Product Life Cycle (TPLC) database which is a more efficient way to search all of the FDA databases–including the recall database and the 510k database.

The biggest problem with this best practice as a basis for selecting a predicate is that the number of adverse events depends upon the number of devices used each year. For a small manufacturer, the number of adverse events will be very small because there are very few devices in use. For a larger manufacturer, the number of adverse events will be larger–even though it may represent less than 0.1% of sales. Finally, not all companies report adverse events when they are required to, while some companies may over-report adverse events. None of these possibilities is taken into consideration in the FDA’s draft predicate selection guidance.

C. Predicate devices without unmitigated use-related or design-related safety issues

For the third best practice, the FDA predicate selection guidance recommends that submitters search the Medical Device Safety database and CBER Safety & Availability (Biologics) database to identify any “emerging signals” that may indicate a new causal association between a device and an adverse event(s). As with all of the FDA database searches, this information is useful as an input to the design process, because it helps to identify known hazards associated with similar devices. However, a more thorough review of post-market surveillance review is needed to accurately assess the safety and performance of any device–including searching databases from other countries where similar devices are marketed.

D. Predicate devices without an associated design-related recall

For the fourth best practice, the FDA predicate selection guidance recommends that submitters search the FDA recalls database. As stated above, the TPLC database includes this information for each product classification. Of the four best practices recommended by the FDA, any predicate device that was to a design-related recall is unlikely to be accepted by the FDA as a suitable predicate device. Therefore, this search should be conducted during the design planning phase or while design inputs are being identified. If you are unable to identify another predicate device that was not the subject of a design-related recall, then you should request a pre-submission meeting with the FDA and provide a justification for the use of the predicate device that was recalled. Your justification will need to include an explanation of the risk controls that were implemented to prevent a similar malfunction or use error with your device. Often recalls result from quality problems associated with a supplier that did not make a product to specifications or some other non-conformity associated with the assembly, test, packaging, or labeling of a device. None of these problems should automatically exclude the use of a predicate because they are not specific to the design.

Section 6 – Improving Transparency

This section of the FDA predicate selection guidance contains the most controversial recommendations. The FDA is proposing that the 510k summary in 510k submissions should include a narrative explaining their selection of the predicate device(s) used to support the 510k clearance. This would be a new requirement for the completion of a 510k summary because that information is not currently included in 510k summaries. The new FDA eSTAR has the ability to automatically generate a 510k summary as part of the submission (see example below), but the 510k summary generated by the eSTAR does not include a section for including a narrative explaining the reasons for predicate selection.

Sections of the 510k summary that are automatically populated in the eSTAR 1024x544 Predicate selection guidance proposes controversial additions

The FDA added this section to the draft guidance with the goals of improving the predictability, consistency, and transparency of the 510k pre-market review process. However, the proposed addition of a narrative explaining the reasons for predicate selection is not the best way to achieve those goals. Transparency is best achieved by eliminating the option of a 510k statement (i.e., 21 CFR 807.93). Currently, the 510k process allows for submitters to provide a 510k statement or a 510k summary. The 510k statement prevents the public from gaining access to any of the information that would be provided in a 510k summary. Therefore, if the narrative explaining the reasons for predicate selection is going to be required in a 510k submission, that new requirement should be added to the substantial equivalence section of the eSTAR instead of only including it in the 510k summary. If the 510k statement is eliminated as an option for submitters, then all submitters will be required to provide a 510k summary and the explanation for the predicate selection can be copied from a text box in the substantial equivalence section.

The FDA eSTAR ensures consistency of the 510k submission contents and format, and tracking of FDA performance has improved the consistency of the FDA 510k review process. Adding an explanation for predicate selection will not impact either of these goals for improving the 510k process. In addition, companies do not select predicates only for the reasons indicated in this FDA predicate selection guidance. One of the most common reasons for selecting a predicate is the cost of purchasing samples of predicate devices for side-by-side performance testing. This only relates to cost, not safety or performance, and forcing companies to purchase more expensive devices for testing would not align with the least burdensome approach. Another flaw in this proposed additional information to be included in the 510k summary is that there is a huge variation in the number of predicates that can be selected for different product classifications. For example, 319 devices were cleared in the past 10 years for the FLL product classification (i.e., clinical electronic thermometer), while 35 devices were cleared in the past 10 years for the LCX product classification (i.e., pregnancy test). Therefore, the approach to selecting a predicate for these two product classifications would be significantly different due to the number of valid predicates to choose from. This makes it very difficult to create a predictable or consistent process for predicate selection across all product classifications. There may also be confidential, strategic reasons for predicate selection that would not be appropriate for a 510k summary.

Section 7 – Examples

The FDA predicate selection guidance provides three examples. In each example, the FDA is suggesting that the submitter should provide a table that lists the valid predicate devices and compare those devices in a table using the four best practices as criteria for the final selection. The FDA is positioning this as providing more transparency to the public, but this information presented in the way the FDA is presenting it would not be useful to the public. This is creating more documentation for companies to submit to the FDA without making devices safer or improving efficacy. This approach would be a change in the required content of a 510k summary and introduce post-market data as criteria for 510k clearance. This is a significant deviation from the current FDA policy.

Example 1 from predicate selection guidance

In this example, the submitter included a table in their 510k submission, along with their rationale for selecting one of the four potential predicates as the predicate device used to support their 510k submission. This example is the most concerning because the summary doesn’t have any details regarding the volume of sales for the potential predicates being evaluated. The number of adverse events and recalls is usually correlated with the volume of sales. The proposed table doesn’t account for this information.

Example 2 from predicate selection guidance

In this example, the submitter was only able to identify one potential, valid predicate device. The submitter provided a table showing that the predicate did not present concerns for three of the four best practices, but the predicate was the subject of a design-related recall. The submitter also explained the measures taken to reduce the risk of those safety concerns in the subject device. As stated above, using the occurrence of a recall as the basis for excluding a predicate is not necessarily appropriate. Most recalls are initiated due to reasons other than the design. Therefore, you need to make sure that the reason for the recall is design-related rather than a quality system compliance issue or a vendor quality issue.

Example 3 from predicate selection guidance

In this example, the submitter identified two potential, valid predicate devices. No safety concerns were identified using any of the four best practices, but the two potential devices have different market histories. One device has 15 years of history, and the second device has three years of history. The submitter chose the device with 15 years of history because the subject device had a longer regulatory history. The problem with this approach is that years since clearance is not an indication of regulatory history. A device can be cleared in 2008, but it might not be launched commercially until several years later. In addition, the number of devices used may be quite small for a small company. In contrast, if the product with three years since the 510k clearance is distributed by a major medical device company, there may be thousands of devices in use every year. 

Medical Device Academy’s recommendations for predicate selection

The following information consists of recommendations our consulting firm provides to clients regarding predicate selection.

Try to use only one predicate (i.e., a primary predicate)

Once you have narrowed down a list of predicates, we generally recommend only using one of the options as a primary predicate and avoiding the use of a second predicate unless absolutely necessary. If you are unsure of whether a second predicate or reference device is needed, this is an excellent question to ask the FDA during a pre-submission teleconference under the topic of “regulatory strategy” (see image below). In your PreSTAR you can ask the following question, “[Your company name] is proposing to use [primary predicate] as a primary predicate. A) Does the FDA have any concerns with the predicate selection? B) Does the FDA feel that a secondary predicate or reference device is needed?”

PreSTAR Topic Selection 1024x330 Predicate selection guidance proposes controversial additions

When and how to use multiple predicates

Recently a client questioned me about the use of a secondary predicate in a 510k submission that I was preparing. They were under the impression that only one predicate was allowed for a 510k submission because the FDA considers the two predicate devices to be a “split predicate.” The video provided above explains the definition of a “split predicate,” and the definition refers to more than the use of two predicates. For many of the 510k submissions, we prepared and obtained clearance for used secondary predicates. An even more common strategy is to use a second device as a reference device. The second device may only have technological characteristics in common with the subject device, but the methods of safety and performance testing used can be adopted as objective performance standards for your 510k submission.

When you are trying to use multiple predicate devices to demonstrate substantial equivalence to your subject device in a 510k submission, you have three options for the correct use of multiple predicate devices:

  1. Two predicates with different technological characteristics, but the same intended use.
  2. A device with more than one intended use.
  3. A device with more than one indication under the same intended use.

If you use “option 1”, then your subject device must have the technological characteristics of both predicate devices. For example, your device has Bluetooth capability, and it uses infrared technology to measure temperature, while one of the two predicates has Bluetooth but uses a thermistor, and the other predicate uses infrared measurement but does not have Bluetooth.

If you use “option 2”, you are combining the features of two different devices into one device. For example, one predicate device is used to measure temperature, and the other predicate device is used to measure blood pressure. Your device, however, can perform both functions. You might have chosen another multi-parameter monitor on the market as your predicate, however, you may not be able to do that if none of the multi-parameter monitors have the same combination of intended uses and technological characteristics. This scenario is quite common when a new technology is introduced for monitoring, and none of the multi-parameter monitors are using the new technology yet.

If you use “option 3”, you need to be careful that the ability of your subject device to be used for a second indication does not compromise the performance of the device for the first indication. For example, bone fixation plates are designed for the fixation of bone fractures. If the first indication is for long bones, and the second indication is for small bones in the wrist, the size and strength of the bone fixation plate may not be adequate for long bones, or the device may be too large for the wrist.

Predicate selection guidance proposes controversial additions Read More »

Scroll to Top