What is a DHF?

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In this article you will learn tips and best practices for creating and maintaining your DHF (i.e., Design History File).

What is a DHF?

DHF is an acronym for design history file. The US FDA is the only country that specifically includes this in medical device regulations (i.e., 21 CFR 820.30j). Other countries simply require that you maintain records of design and development. The DHF is a file, virtual or physical, that includes all the records of your efforts to design and develop a medical device. You could create an index for a DHF that includes all of the most recent versions of the documents pertaining to the design of your device, but that is called a Device Master Record or DMR (i.e., 21 CFR 820.181). Another term for the DMR is “technical file” or “medical device file.” The FDA will be adopting the term “medical device file” as part of the Quality Management System Regulation (QMSR), and the definition for a DHF will become obsolete February 2, 2026.

Recommended DHF Contents 1024x577 What is a DHF?

What’s the difference between a DHF, DMR, and DHR?

The US FDA loves acronyms, but overuse of acronyms leads to confusion. The acronyms DHF, DMR, and DHR are the three most commonly confused acronyms in the medical device industry. One of the simplest solutions is to stop using acronyms and to rename each of these documents so that they are no so confusing. Instead of design history file, or DHF, start referring to this file as a record of new product development. That record consists of thousands of pages covering a year or more of design and development activity by your new product development team. Instead of device master record, or DMR, start referring to this as your medical device file or technical file. Clause 4.2.3 of ISO 13485:2016 is specific to this record. It is intended to be a living document that you will update each time you make a design change. Instead of device history record, or DHR, start referring to this as your batch record or lot record. This is a file containing all of the records, or cross-references to records associated with the manufacturing and inspection of a batch or lot of devices. The batch record or lot record will be reviewed for completeness, accuracy, and to ensure all inspection and testing passed. Often a release checklist is used to ensure consistency of this review, and the checklist will be signed and dated by the person that releases the batch or lot for distribution. For sterile products, this is done after sterilization and sterile product is quarantined until release.

Flow of Inspecting Design Controls 1024x181 What is a DHF?

Regulatory Requirements for a Design History File (DHF)

The requirements for a design history file (DHF) are found in 21 CFR 820.30(j):

“Each manufacturer shall establish and maintain a DHF for each type of device. The DHF shall contain or reference the records necessary to demonstrate that the design was developed in accordance with the approved design plan and the requirements of this part.”

 There is also a definition for a DHF found in 21 CFR 820.3(e):

“Design history file (DHF ) means a compilation of records which describes the design history of a finished device.”

The FDA provided an official interpretation of this requirement in the preamble when the QSR was published in 1996. That discussion of the requirement indicated that the DHF is intended to be a repository of the records required to demonstrate compliance with your design plan and your design control procedures. The discussion also indicates that the same DHF may be used for minor variations of a device such as size differences. Most manufacturers will organize the DHF in a binder and organize the binder chronologically to match a design project plan, however, most do not create a DHF template. Meeting minutes from each design meeting are typically included as an appendix to the DHF, while reviewed and approved documents such as the design plan, design inputs, design outputs and records of design reviews typically comprise the bulk of the DHF. Manufacturers also typically will conduct an internal auditor of active DHF binders in order to ensure that design projects are following the approved design plans.

Why you should never use a DHF template

The DHF is is intended to provide evidence of following an approved design plan, but the DHF consists of many records–not just one record. A DHF template could be created to follow a standardized design control process, but most manufacturers write a generic design procedure that allows and encourages the design team to customize the design plan to match the needs of each development project. Therefore, design plans may have different numbers of design reviews and very different testing activities prior to the start of the design transfer process and during design verification and validation.

For a device master record (DMR), I recommend creating a DMR Index using a template that is organized in accordance with an international standard to meet the needs of a DMR and a Technical File. The DMR is a living document that only shows the most current design outputs for a device while a DHF may require repeating various verification and validation testing if the initial design fails to meet acceptance criteria and a design change is required prior to the final design review and approval of commercial release. The need for including this variability eliminates the advantages of a template.

What is the purpose of the DHF?

The purpose of the DHF is to provide objective evidence that the design and development team followed design controls in order to develop a medical device. FDA inspectors review the DHF to make sure that the design process is effective by verifying that known hazards were identified, and appropriate design inputs (i.e., test requirements) were approved. The design specifications should demonstrate that risks were reduced as far as possible by implementing design solutions, protective measures, and by providing warnings and precautions of residual risks to users and patients. Verification of design inputs and validation of user needs comprise the bulk of your DHF in the form of testing protocols and reports. Inspectors will review your design transfer activities to ensure that the output of manufacturing consistently meets your design specifications. Design reviews meeting minutes will be sampled to verify that you included an independent reviewer and the design team completed all activities planned in your design plan. FDA inspectors will verify that your design team has adequate training on design controls and the relates processes. Finally, the FDA will look for justifications and updating of design documentation for the design changes your team made during the design process.

Where should you document design changes?

Product design changes that occur prior to the final design review and approval of commercial release are required for inclusion in the DHF. However, once a product is released the control over design changes should be tighter and regulatory submission of changes may be required. Therefore, I recommend documenting post-market design changes in the DMR Index for a device as part of the revision history. I treat the DMR Index as a controlled document and any post-market design changes are reflected in the revision history with a reference to the design change approval (e.g., ECN 123 – addition of UDI label to product labeling). The other advantage of this approach is that all post-market design changes that must be documented for a design dossier are summarized in the revision history of the DMR Index and the DMR Index will serve as a Technical File/Design Dossier.

Training Webinar

If you are interested in learning more about design history files, we recorded a DHF training webinar. The webinar explains how and when to create a design history file (DHF). After you create a design control procedure, you can show the recording of this webinar to your design and development team to ensure that design and development documentation is compliant and updates are efficiently maintained. We are in the process of updating this webinar and it will be hosted live in September.

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FDA User Fees for FY 2025 released on July 31, 2024

11 Comments / FDA / By / , ,

The FDA User Fees for FY 2025, October 1, 2024 – September 30, 2025, were released on Wednesday, July 31, 2024.

What are FDA User Fees?

At the very core of it, the FDA user fees fund the FDA Office of Device Evaluation (ODE) budget. Without these user fees, the FDA cannot begin reviewing a medical device submission. This includes 510k, PMA, and De Novo submissions. Before the FDA assigns a reviewer to your submission, you must pay the appropriate device user fee in full unless eligible for a waiver or exemption. If you pay the user fee by credit card, you must allow a few extra days for the user fee to clear. Otherwise, your submission will be placed on “User Fee Hold.” Small businesses may qualify for a reduced fee. The FDA announced the FY 2025 FDA User Fees on July 31, 2024. The FDA will announce the user fees for FY 2026 in a Federal Register notice next August 2025.

What are the FDA User Fees for FY 2025?

FY2025 User Fees 1024x544 FDA User Fees for FY 2025 released on July 31, 2024

How much did user fees increase for FY 2025?

The increase in FDA user fees from FY 2024 to FY 2025 was 11.8%, except the annual FDA Registration fee, which increased by 21.3% to $9,280. There are three components to the increase:

  1. Base Fee = a statutory base fee for each FDA user fee
  2. Standard Fee = an inflation-adjusted statutory base fee
  3. Adjusted Fee = adjusted fee to meet revenue target

The reason for each component for the user fees is described in the Federal Register.

When does the FY 2025 increase take effect?

Each year the new FDA user fees take effect on the 1st day of the FDA’s new fiscal year (i.e., October 1). You cannot pay the annual registration fee for FY 2025 until October 1, 2025, and the last day you can submit under the FY 2024 user fee pricing is Monday, September 30, 2023. For the submission to be accepted under the current fiscal year, the submission must be uploaded to the Customer Collaboration Portal (CCP) no later than 4:00 pm EDT on the 30th.

What do you do if you have already paid the FY 2024 price?

If you already paid the FY 2024, and your submission is received after 4:00 pm EDT on September 30, 2024, you must complete FDA Form 3914 for an FDA user fee payment transfer request. You will also need to pay the difference in user fees (i.e., 11.8%). If your submission is received before the FY 2024 user fee is transferred and you have paid the difference in user fees, your submission will be placed on a user fee hold. If you paid the FY 2024 user fee and are not ready to transfer your previously paid user fee to FY 2024 (and pay the difference), you can request an FDA user fee refund by filling in an online form.

What is the annual registration fee for FY 2025 due?

The annual establishment registration user fee can be paid any time between October 1 and December 31. If you pay late, there is no penalty, but your registration status will be inactive, and you cannot submit new device submissions or import products to the USA. If you are not yet distributing any devices in the USA, you are not required to have your establishment registered, and establishment registration is not required before submitting a new device submission. If you are not required to register yet, when you are paying the user fee for a new device submission on the Device Facility User Fee (DFUF) website, you will click the “Yes” button because there is no “N/A” option for the question below.

Click Yes 1024x200 FDA User Fees for FY 2025 released on July 31, 2024

Is the annual FDA registration fee prorated?

Annual registration payments are not prorated when you are paying in the middle or even near the end of the year for your initial registration. Therefore, you will need to consider if the revenues you expect to gain before the end of the current fiscal year are worth the registration cost. If you need any help with annual registration or you need a US Agent, we offer these consulting services.

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Classification recommendation written for a De Novo

1 Comment / De Novo / By / ,

This article explains how to write your classification recommendation for a De Novo Classification Request using a risk-based approach.

Classification Recommendation 1024x678 Classification recommendation written for a De Novo

“Automatic Class III Designation” does not mean that your device is a Class III device. That phrase means that the device is new, and therefore it will be automatically classified as Class III until a company submits a De Novo Classification Request. You and your company, not the FDA, should make the classification recommendation and propose the regulatory pathway for a new device. Submitting a 513g request is an option, but a 513g request involves paying the FDA money to write a classification recommendation. The FDA will always be more conservative in their assessment than the manufacturer.

Although no FDA guidance explains how to write a classification recommendation, companies have been writing these documents for years–for Technical Files. Most countries have risk-based classification rules, while the FDA’s product classification database is centered upon precedents and adjusted over time by historical trends of adverse events and recalls. Therefore, you should write a classification recommendation for the FDA that is focused on a documented risk assessment. Your approach will also need to be modified to include classification information for similar indications for use and technological characteristics that are already established in the US market.

Most Common Mistakes in Writing a Classification Rationale 

Many people mistakenly write a short classification rationale for a technical file, which simply states which classification rule applies and why. Although this approach is acceptable for a Declaration of Conformity, you must provide a comprehensive classification rationale in your technical file. First, you need to make sure that there is only one classification rule that applies. For example, classification rules fall into four general categories:

  1. Non-invasive Devices
  2. Invasive Devices
  3. Active Devices
  4. Special Rules

The software was haphazardly added to the active devices category until recently, and special rules were created to address emerging areas of interest and concern. Therefore, most active devices have a second rule that applies regarding the invasive nature of the device–or lack thereof. In order to write a comprehensive classification rationale, you need to review each classification rule and document your explanation for why it applies or does not apply to your device.

A Classification Recommendation Compares Indications for Use

The FDA does have classification rules, but the rules are not 13 numbered items in the Code of Federal Regulations (CFR). The FDA expects a risk assessment of comparing your device with existing devices on the US market. The basis of comparison should be: 1) the indications for use and 2) the technological characteristics. First, you should identify other devices that have similar indications for use. For example, a device intended for home use or over-the-counter (OTC) use represents a higher risk to patients and users than a device intended for prescription use only. Patients may fail to identify contraindications for a device properly, or the lack of formal medical training may result in use errors that would not occur when a physician uses the same device.

Other aspects of indications for use that impact the risk assessment are the part of the body where your device will be used and the duration of use. For example, implants are at higher risk than non-implants, because implants are in contact with the body for a much longer period of time. Implants can also expose the body to systemic risks, while a surface contacting device is likely only to have a localized effect. Degradation of implants also exposes the body to small particles, with more surface area, that can travel from one part of the body to another.

If your device is used for life support, the device will also be considered at higher risk than devices that are not required for life support. If your device is the only device used for diagnosis, this also represents a higher risk than a device that acts as an adjunct to other devices. Finally, if your device is an accessory to other devices that are high risk, your device may be considered a higher risk as well–especially if it controls the higher risk device.

In your analysis, you need to identify devices that are already on the US market that have similar indications for use. Usually, those devices will be Class II devices. However, if some of those devices are Class I or Class III, you will need to be more careful with how you differentiate your indications for use from those other devices.

A Classification Recommendation Compares Technological Characteristics

When comparing technological characteristics, the following aspects should be considered: 1) materials, 2) design, 3) energy source, and 4) other design features. For example, absorbable materials are generally considered at higher risk than devices that are not absorbable. Sterile devices are generally at higher risk than non-sterile devices because the failure of the sterilization process or the package integrity can result in serious infections and death. Devices that are electrically powered are usually considered at higher risk than devices that are not powered. Finally, software-controlled devices that provide feedback control are considered at higher risk than a device that does not have feedback control. Each technological characteristic also represents a different category of hazard. Hazard categories are listed in Table C1 of Annex C in ISO 14971:2019. These include chemical, biological, electrical, radiation, etc.

Once you have identified the Classification of other devices with similar indications for use and technological characteristics, you need to estimate the risks for each hazard identified. This involves more than just listing hazards and assigning scores for severity and probability for the occurrence of harm. Severity should consider the type of injuries, the number of injuries, and the duration of harm. Probability should consider the frequency of events (P1), and the probability of events resulting in injury (P2). These risk estimates also require clinical data.

Benefit-Risk Analysis

In the end, you prepare a benefit-risk analysis for your device. This is much more than a statement that the benefits outweigh the risks. You need to identify the clinical benefits of your device when compared to alternative treatments. You also need to analyze risks relative to alternative treatments. You will need to prepare this as a summary of risks–not a list of hazards. Ultimately, your benefits should be equivalent to the benefits of existing devices on the market or better, and the risks should be equivalent to existing devices on the market or less.

Examples of Classification Recommendation

Eight different medical devices are legally marketed in the USA for weight loss or weight management:

  1. Lap-Band Adjustable Gastric Banding System – Class III, PMA
  2. Maestro Rechargeable System – Class III, PMA
  3. ORBERA Intragastric Balloon System – Class III, PMA
  4. Obalon Balloon System – Class III, PMA
  5. TransPyloric Shuttle/TransPyloric Shuttle Delivery Device – Class III, PMA
  6. AspireAssist – Class III, PMA
  7. Sensor Monitored Alimentary Restriction Therapy (SMART) Device – Class II, De Novo
  8. Plenity – Class II, De Novo

The indications for use for these products are similar, but not identical. Plenity is indicated for patients with a BMI of 25 – 40 kg/m2. In comparison, ORBERA is indicated for patients with a BMI of 30-40 kg/m2, and AspireAssist is indicated for patients with a BMI of 35-55 kg/m2. All three of these indications have overlapping BMI ranges. However, the clinical benefits to a person with a BMI of 25 kg/m2 are not the same as the clinical benefits to a person with a BMI of 40 or 50 kg/m2. Therefore, these minor differences in BMI can have a significant impact on the benefit/risk analysis used for a De Novo approval decision and the Classification (i.e., Class II or Class III) determined by the FDA.

The only two weight management devices that received the approval of the De Novo Classification Request had very different technological characteristics from the other six devices. All six Class III, PMA devices, are implants, while the Class II devices are not implants. The risks associated with implants are much greater than with non-implants. The risk of implants breaking or leaking, and the difficulty in removing an implant, are just two of the considerations that must be evaluated in deciding whether an implantable device should be a Class II or Class III device.

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Are FDA pre-sub meetings a waste of time?

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This article reviews the top reasons why other companies feel requesting FDA pre-sub meetings is a waste of time but you can’t afford to.

Requesting 510k pre sub meeting is a waste of time 1024x448 Are FDA pre sub meetings a waste of time?

It only takes our consulting team a few hours to prepare an FDA pre-sub request using the new FDA PreSTAR. The FDA does not charge you a cent for submitting an FDA pre-sub, and a pre-sub should be part of every design plan. However, most companies are resistant to requesting FDA pre-sub meetings. In this article we review the top four reasons why companies resist submitting an FDA pre-sub request, and you will learn about the three options for the method of FDA feedback.

Our design is not finalized yet

The most common reason why people delay their request for an FDA pre-sub is that they are waiting until the design is complete. This rationale is flawed because the FDA can’t review data and the FDA can’t give you advice on the design of your device. The purpose of an FDA pre-sub is to “forge a better test plan.” The FDA prefers that you submit draft test protocols with specific questions. The ideal time to submit an FDA pre-sub request is 6-9 months before you approve your design outputs (i.e., design freeze). This timing should be shortly after you approve your design inputs (i.e., essential requirements for safety and performance, standards, and stakeholder requirements). Another reason for requesting a pre-sub early is that most companies need to submit a pre-sub supplement with a revised test plan. This is especially true for biocompatibility testing, non-clinical, benchtop performance testing plans, pre-clinical animal testing, human clinical studies, and human factors testing. The revised test plan includes protocol revisions based on the feedback from the original pre-sub.

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It’s too late to request FDA pre-sub meetings

If you are less than a week away from submitting to the FDA, it is too late. The FDA target for scheduling an FDA pre-sub meeting is 70-75 days from the date your request was submitted. That’s 10-11 weeks. Most companies tell me that they plan to submit to the FDA within weeks or a couple of months, but most of the companies take nine months or longer. For example, what if your device fails EMC testing, and you have to change the design and retest for both EMC and electrical safety at an NRTL? At best, you will have an 8-week delay. If you submit a request next week, and everything goes as planned, you can always withdraw your request for the pre-sub. If you encounter a delay for any reason, suddenly, it’s not too late.

We don’t want to be bound by what the FDA says in the FDA pre-sub meeting

FDA pre-sub meetings are “non-binding.” That means that the FDA can change its mind, but it also means you don’t have to do everything the FDA says in an FDA pre-sub meeting. If you don’t ask a question about testing requirements, that doesn’t mean that the FDA does not have any testing requirements. The FDA knows what previous companies have submitted for testing better than you do, and they may be in the process of evaluating draft guidance documents. If you ask questions, you will have better insights into what the FDA expects. The most important questions are related to your rationale for why a specific testing specimen represents the “worst-case” for one of your tests. Selecting the wrong testing specimen will result in you repeating that test. Understanding FDA expectations helps you write better rationales for testing or test avoidance. You also might learn about deadlines for the implementation of new testing requirements that you might be able to avoid. Finally, you can ask the FDA about possible testing options you are considering if the FDA denies your most optimistic testing plans.

There is already a guidance document for our device

Not all device classifications have a guidance document explaining what information should be submitted in an FDA pre-market submission. However, there are almost one hundred Special Controls Guidance Documents, and for new device regulations (i.e., De Novo applications) the FDA now incorporates the special controls directly in the new regulation. Therefore, there is a good chance that the FDA published special controls as part of the regulation for your device or as a guidance document. As part of the special controls, the FDA defines what performance testing is required for your device. If you already know what testing is required, then the value in requesting FDA pre-sub meetings is diminished. But at least three other key benefits remain.

First, you can verify that the predicate you plan to use for comparative testing is not going to be a problem. Although the FDA can’t tell you which predicate to pick, the FDA can tell you if there is a problem with the predicate you have selected. This is especially important if the product is not currently registered and listed, because you may not know if the device was withdrawn from the market after it was cleared.

Second, not all testing standards are prescriptive. Many tests have testing options that require a decision. Input from the FDA may be valuable in making choices between various performance testing options. Sometimes, you forgo testing and provide a rationale instead. FDA feedback on any rationale for not doing testing is critical to prevent delays and requests for additional information later.

Third, there are many different FDA representatives who participate in FDA pre-sub meetings. The lead reviewer will invite specialists and the branch chief to the meeting. Each of these specialists can answer questions during a pre-submission meeting that they are not able to answer during the actual review process. You also have the opportunity to get feedback from the branch chief–who has insight from all the previous devices that were cleared with your product classification. Your lead reviewer is not likely to be as experienced as the branch chief, and may only have been working at the FDA for months. Your request for the 510k pre-sub meeting will help an inexperienced lead reviewer as much as it will help your company.

Which method of FDA pre-sub feedback should you request?

The FDA offers three different options for the method of feedback in pre-sub request:

  1. a face-to-face meeting
  2. a conference call
  3. an email response

Pre submission meeting request feedback options Are FDA pre sub meetings a waste of time?

Feedback Option 1 – A Face-to-Face Meeting

Some executives believe that face-to-face meetings are critical in establishing relationships with people. However, you need to understand the culture of the people you are trying to build a relationship with. The FDA is an overworked bureaucracy, and government agencies have security concerns. When the FDA meets with visitors they must go to a different building and arrange for their guests to pass through security. This is more work and takes more time. To justify the extra work and time, you need a compelling reason why a face-to-face meeting with the FDA is necessary.

Traveling to the FDA will cost your team money and time that conference calls and emails will not. More importantly, you are limited to one hour for a pre-submission meeting. One hour is barely enough time to ask questions and listen to the answers. You only have minutes to introduce your company and your team and describe the product. There is no time for relationship building. The best way to impress the FDA is to 1) prepare thoroughly, 2) conduct an efficient meeting, and 3) ask smart questions.

There is one time when you should visit the FDA face-to-face–if you have a powerful demonstration and video just isn’t good enough.

Feedback Option 2 – Conference Call

Conference calls save you time and money, but conference calls also save the FDA time and effort. You won’t personally meet people from the agency, but you can communicate information prior to the meeting and you can provide videos of simulated use for your device. Conference calls do have the advantage of allowing you to mute the call for a moment and make a comment among your team members without the agency listening as well. Whenever you are discussing a performance testing plan or a clinical study protocol with the FDA, you will probably want a conference call to enable clarification questions. The image below is an example of a request for a teleconference as the method of feedback. The FDA will still send an email response to your questions within 70 days, and you will want to submit your presentation slide deck for the teleconference at least 48 hours before the teleconference.

Screenshot 2024 07 21 10.19.38 AM 1024x271 Are FDA pre sub meetings a waste of time?

Feedback option 3 – Email

Email responses from the FDA are highly underrated in value. When you specify an email response, you generally receive a response to your questions sooner. You also should receive more information, because each person from the agency is able to provide an hour of their time to write detailed feedback. In a conference call, you are speaking for part of the hour, and only one person from the FDA can speak at a time. Therefore, you almost always have less feedback during conference calls and face-to-face meetings. The primary downside to email as a feedback method is that it is not interactive. In the case of submission issue review (SIR) requests (i.e., a special type of FDA pre-sub request), the FDA will only give you the option of a teleconference or email feedback–not both. Due to the challenges of scheduling teleconference, sometimes an email response can be delivered sooner and might be your best choice for an SIR request.

Learning More about FDA Pre-sub Meetings

If you would like to learn more about how to prepare the format and contents of an FDA pre-sub request, we have a four-part webinar series that will teach you how to prepare a pre-submission meeting request using the new FDA PreSTAR template.Stop wasting time and register now Are FDA pre sub meetings a waste of time?

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De Novo pre IDE Meeting

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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.

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

8 Comments / ISO 14971:2019 (Risk Management) / By / ,

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.

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What is the FDA Breakthrough Device Designation?

5 Comments / De Novo, FDA / By /

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

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513g Request for Information

1 Comment / 513(g) / By

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.

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Packaging Complaint Investigation – Case Study

3 Comments / Complaint Handling / By

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.

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FDA eSTAR v5.0 – What’s new?

2 Comments / 510(k), eSTAR / By

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 »

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