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Classification Recommendation – How to write one for a De Novo request

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   How to write one for a De Novo request

“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 E1 of Annex E in ISO 14971:2007. 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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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 IDE Meeting Timeline 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) designing a clinical study. 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. The European MDD requires a benefit/risk analysis (mentioned eight times), while Regulation (EU) 2017/745 mentions benefit/risk 69 times. Despite the obvious increased emphasis on benefit/risk analysis in the new EU Regulations, the new ISO 14971 standard that is expected to be released next month still does not require a benefit/risk analysis for all risks as required by the regulations. 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 is provided in the FDA guidance.

In addition to reading that 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.

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 510(k) 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 my De Novo clients feel that a control group is not possible, because they think that test subjects will know when a sham 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.

Other De Novo Classification Request Resources

On Thursday, October 17, we presented a live webinar showing medical device companies on how to avoid a stunning disaster. Click here to access the webinar recording. We recorded another webinar about the preparation De Novo Classification Requests that you can download from our website. I wrote a blog about De Novo classification requests. You can also learn a lot about how to Design your own De Novo clinical study by reviewing the Decision Summaries published by the FDA for each De Novo in the list of De Novo classification requests. Finally, the FDA pre-sub guidance 2019 is an invaluable resource for preparing any pre IDE meeting request.

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De Novo Application – If there is no 510(k) predicate

There are four differences between a De Novo application and a 510k submission, and they do not include time or money.

De Novo Pathway 300x169 De Novo Application   If there is no 510(k) predicate

De Novo Application – If there is no 510(k) predicate

The best regulatory experts plan regulatory submissions months before the performance testing is completed, and often the strategic regulatory pathway is determined before the design of the device even begins. If your design team is developing innovative technology, you may have difficulty finding a predicate device that is substantially equivalent to your device. If you have not completed a De Novo application before, where do you start?

History of the De Novo

Historically, a De Novo application required that your device be submitted through the 510k process first. If the FDA determined that your device was not substantially equivalent to the predicate you chose, then you received a “Not Substantially Equivalent” (NSE) letter from the FDA. Once you receive an NSE letter, you have three options: 1) select a different predicate and re-submit, 2) re-submit the device through the Pre-Market Approval (PMA) process, or 3) submit the device through the De Novo application process. You were not allowed to submit a De Novo application until you received an NSE letter.

The De Novo application process was revised on July 9, 2012 to allow manufacturers to submit a De Novo application without a preceding 510k submission. This was done because there are many products that are technologically equivalent to a predicate device, but the indications for use are quite different. For example, many in vitro diagnostic (IVD) products are indicated for the diagnosis of new viruses, but the device uses technology equivalent to another IVD product the manufacturer already makes. For this reason, most of the first 100+ De Novo application approvals were for IVD products.

Draft Guidance Document

The De Novo application process still (updated September 6, 2017) does not have an approved final guidance document. For now, there is only a draft guidance document. However, with the new fees being charged for De Novo applications as part of MDUFA IV for FY 2018 FDA user fees, you can expect that a final guidance document with an application checklist will be expedited.

Pre-Sub Meetings Prior to a De Novo Application

Pre-sub meetings are generally recommended by the FDA for manufacturers that intend to submit a De Novo application without a prior 510k submission and subsequent NSE letter. If the device is a Class II, a  pre-sub meeting allows the manufacturer to request input from the FDA,  regarding performance testing and special controls. The draft De Novo guidance document specifically recommends following the existing content guidelines for a pre-sub meeting request, but the guidance also recommends including the following elements in the pre-sub meeting request:

  1. Proposed product classification (i.e., Class I, Class II exempt, or Class II)
  2. Details of efforts previously taken in order to identify a predicate
  3. Risks and Risk/Benefit Analysis
  4. Proposed Performance Testing and/or Special Controls

Before you submit a pre-submission request for a potential De Novo application, you should consider the following questions. First, is your device suitable for a De Novo application (see point #2 above)? Second, when is the ideal time for you to submit your application? At least 90 days before your design freeze is needed if the meeting request is going to have any impact on the performance testing plans. Third, what questions do you want the FDA to answer regarding data requirements? Sometimes providing some preliminary data can help you persuade the FDA to accept less total data for approval of the final application. Finally, you may want to consider preparing a draft Special Controls Guidance for the FDA to review as a supplement to your pre-submission meeting. 

A De Novo for Class I and Class II Exempt Devices?

Most manufacturers mistakenly assume that De Novo applications are only for devices that are Class II and will require a 510k submission for future product submissions in the same classification. However, the regulations require that the application cover letter include both a “Classification Summary” and a “Classification Recommendation.” The recommendation for classification may be for Class I, Class II exempt, or Class II non-exempt. If you recommend that the FDA classify the device as Class II exempt, then the recommendation must include a justification for why premarket notification is not required.

Regardless of which classification is recommended, the justification for classification needs to be based upon a risk/benefit analysis. Class I and Class II exempt classifications are likely to be recommended more in the future for many of the standalone software products that are being developed by manufacturers because those software devices generally have a low risk. Existing product classifications may be used, but if the indications for use are not substantially equivalent to a predicate the manufacturers will submit a 510k and receive NSE letters. For the companies that are claiming substantial equivalence to products that already have a product classification that is exempt from premarket notification, manufacturers will continue to register and list products under existing classification codes until the FDA intervenes–even if the indications for use are not equivalent.

How to Modify Your 510k Templates

Twenty sections comprise a 510k submission, but regulatory experts typically use templates for each section in order to streamline the process of preparing a new device submission. For a De Novo application, a large percentage of the sections required for a 510k submission are the same. The draft guidance identifies one unique section of a De Novo: the cover letter (i.e., Attachment II in the De Novo guidance). However, there are three sections of a 510k submission that also need to be eliminated for a De Novo application:

  1. Section 1: User Fee Cover Sheet, because De Novo applications do not require a user fee
  2. Section 5: 510k Summary or 510k Statement is not required, because this is not a 510k submission
  3. Section 12: Substantial Equivalence Comparison, because a De Novo does not claim equivalence to a predicate

Do you need help submitting your De Novo Classification Request?

If you need help with the validation of your FDA eCopy, we offer an FDA eCopy print and ship service for $99/eCopy. We will also be updating this webinar in 2022 to explain how to use the new FDA eSTAR template for De Novo Classification Requests.

New De Novo Webinar

Companies developing devices with truly innovative technologies frequently have difficulty identifying suitable predicate devices. The best regulatory experts plan in advance for these regulatory submissions by honing their knowledge of the De Novo application process. On Thursday, January 28th we recorded a webinar sharing our tips and templates for De Novo applications. Click here to learn more about the webinar.

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