Is the Pre-Submission process worth the time and effort?

The last in a series of blogs about informal, pre-submission contact with FDA.  Visit our website for the previous six.

Med_D6A1047The Pre-Sub process can be time-consuming (Pre-Sub; see FDA guidance here). You may wonder if it’s worth it. We discussed some of the reasons for having a Pre-Sub (or not having one) in a previous post, but let’s look at those again:

  • Is the device new (to you) or FDA?
  • How well do guidance documents, recognized consensus standards, or 510(k)/PMA summaries apply?
  • Where are you in the development cycle?
  • How expensive is it to be wrong?

Those are the “hard” questions to ask before you decide, but there are a few more “soft” reasons for asking for a Pre-Sub:

  • It is a valuable opportunity to make a good first impression.
  • It is a great way to sort out major issues in a non-adversarial manner.
  • It is a great way to educate FDA on your new device, technology, or test.

This last one is especially important. You may have 100% confidence in your development program. But if FDA has never seen this type of device before, it is helpful if they are exposed to it proactively. The back-and-forth of the Pre-Sub program gives you time to explain your device before your formal submission, when table upon table of data arrive at their doorstep unannounced.

MED believes it is important to integrate your engineering and regulatory strategies from the very beginning of the medical device development process, if possible, or at least as early in the process as you can. The Pre-Submission (Pre-Sub) process is a perfect opportunity to present both your engineering strategy and your regulatory strategy to FDA early in the process and ensure that everyone is in agreement.

We all have the same goal: to help patients by providing innovative and safe medical devices. Keeping this common goal in mind during our interactions will help us to focus on the supporting data and risk mitigation tools that support that goal. We can also develop trust and foster meaningful relationships with the agency in the process.

To have a more thorough discussion or to answer any questions you may have regarding the Pre-Sub process or tips on how to effectively communicate with FDA, please contact MED Institute via our website at

What happens once I submit a Pre-Submission? (Part 3: After the meeting)

The sixth in a series of blogs about informal, pre-submission contact with FDA. See here, here, here, here, and here for the previous five.

MED Inst, Med,  regulatory science, regulatory dataYou have sent FDA a Pre-Submission (Pre-Sub; see FDA guidance here) to get answers to questions you want to know well before your formal submission (e.g., an IDE or 510(k)). You have received comments from FDA, and met with them to discuss them. What’s next?

Minutes: Within 15 calendar days of the teleconference or in-person meeting, you will draft meeting minutes and submit them to FDA. FDA will review and edit the meeting minutes, if necessary, within 30 days of receipt. The final version will become the final record of the meeting or teleconference 15 calendar days after you receive FDA’s edits. If you disagree with FDA’s edits, you can submit an amendment and FDA will discuss them with you.

Don’t try to capture everything that was said, just important agreements (or disagreements) and action items. The process may seem tedious, but it is often a good opportunity to get further clarification on FDA’s thinking and to clear up any misunderstanding.

Issues needing further discussion: As mentioned in a previous post, you only have 60 minutes, so you may not have time to discuss some of the lesser points of disagreement. Many of these can be handled with supplements to the original Pre-Sub. Talk to your lead reviewer about how to structure the discussion.

FDA’s commitment: In the Pre-Sub guidance, FDA has committed to standing by their feedback, with the following conditions: information in the formal submission is consistent with the Pre-Sub interaction, the data in the subsequent submission do not raise new important issues, and no material issues have arisen since the time of their feedback, e.g., new scientific findings about risks.

It is not unreasonable to be wary of this commitment, especially the caveat about “new scientific findings”. If there is a long gap between the meeting and the final submission, consider whether you will need to double-back with FDA.

Future submissions: All of your work will go to waste if you don’t remind FDA what was agreed upon when your formal submission (e.g., IDE, 510(k), PMA) is submitted. Those formal submissions should include a copy your questions, FDA’s comments, the meeting minutes, detailed responses to each of FDA’s comments, and cross-reference to the same information in the main body of the submission.

For instance, suppose your Pre-Sub asked a question about the types of bench tests to be conducted. FDA responded that they agreed to the test matrix, but they wanted you to do two more tests. The meeting minutes reflect that you agreed to the first additional test, but not the second one. In this case, the appendix to the formal submission should include your original question, a clear statement that FDA agreed to it with reservations, and (1) a reference to the location of the agreed-upon tests in the main body, and (2) a well-supported justification about why the remaining test was unnecessary.

For more information, please visit our website at

Next time: Is the Pre-Sub Process worth the time and effort?

What happens once I submit a Pre-Submission? (Part 2: The meeting)

The fifth in a series of blogs about informal, pre-submission contact with FDA.  See here, here, here, and here for the previous four.

MED Inst, Med,

You have sent FDA a Pre-Submission (Pre-Sub; see FDA guidance here) to get answers to questions you want to know well before your formal submission (e.g., an IDE or 510(k)). For instance, your clinical study involves novel technology and/or methods to assess effectiveness and you want FDA’s buy-in before you go too far down the road. You are convinced of the methods, but you know they are new to FDA, so you want to explain them in a face-to-face setting and make sure they understand them. A few other questions have come up too, so you will cover them.

The meeting will only last 60 minutes, so you will need to focus your efforts on key points of confusion or disagreement. Here are some key points to consider:

  • The guidance recommends that your formal presentation be limited to one-third of the allotted meeting time. We think even less is better. Can you say what you need to say in 10 minutes? The meeting is intended for discussion. If you spend too much time in your initial presentation, you will hear less of what they are thinking. We often use the format of “Here is our question; here is your response; here are our thoughts on your response; let’s discuss;” for each question that was raised.
  • Do not spend time repeating previous information. Do not talk about your company; talk about the device only to briefly remind people of it and bring up any features that may be the subject of their questions and comments.
  • Rehearse the presentation and the meeting dynamics before the meeting. Who is in charge of introductions? Who gives the formal presentation? Who manages the meeting flow and fields questions? To whom does the meeting manager turn when they can’t answer a question? To whom does the fielder redirect for various types of questions? What sort of questions will FDA raise?  Who answers them and how? Who takes minutes? If you are bringing outside experts, make sure they understand what you expect of them.
  • However, do not over-rehearse. Your manner should be relaxed, not antagonistic or stiff, but still keep your eye on the goal of getting to a mutually satisfying resolution. With only 60 minutes, you do not have time for getting sidetracked.
  • Always start with thanking FDA for their comments. If you have points of agreement with FDA’s comments (e.g., you are willing to increase the sample size or use the animal model they suggested), then let them know that right away.
  • “Why” is always a good question for these types of meetings. You want to understand why FDA said what they said. So just politely ask them. Once they have explained, you may find yourself in agreement with them! Or you can propose a different solution and/or explain in more depth why you took your original position.
  • Do not bring new data into the discussion or, if you do so, be careful about how and when you do it. The guidance states that, in most cases, FDA will only be able to respond to the questions or issues that were included in your meeting request or background information, not on new information presented during the meeting. If you do bring up new information, it’s best to couch it with the caveat, “We know this is new information, but we think it is relevant…” and then try not to force an immediate response.

Should you have this meeting over the phone or in person? As you can see from the list above, much of this is far more effective when everyone can see each other. Conversations are more spontaneous and relaxed. People are less likely to speak over one another or wait overly long as can often happen on a conference call.

Here is a second reason to have your meeting in person.  The written comments are the collective opinion of FDA. But when you meet with them in person, you may be exposed to a diversity of opinions and viewpoints within the Agency. Several times, we have come to realize that a particular FDA team member was driving what seemed to be an unreasonable request. When the entire team is assembled and we’ve had an opportunity to explain things further, FDA’s opinion changed.

We are happy to help at any stage along the way, including preparing for the meeting, but it is best for all to be involved from the very beginning. For more information, please visit our website at

Next time:  After the Pre-Submission meeting.

What happens once I submit a Pre-Submission? (Part 1: Before the meeting)

The fourth in a series of blogs about informal, pre-submission contact with FDA.  See here, here, and here for the first three.


You have sent FDA a Pre-Submission (Pre-Sub; see FDA guidance here) to get answers to specific questions well before your formal submission (e.g., an IDE or 510(k)). For instance, your technology is very new to the medical device world and you want to make sure that FDA agrees with your testing plan. What happens next?

  1. Initial acceptance review; setting the date. FDA will perform an “acceptance review” within 15 calendar days of receipt to make sure all the required elements of a Pre-Sub have been included in your submission. After that, they will contact you about setting a date and time for the in-person meeting or phone call.
  2. FDA internal review. The meeting typically occurs about 90 days after receipt of the Pre-Sub, with a commitment to provide you written feedback a few days before the meeting. FDA will create a team to review the matter, discuss your questions, and finalize their comments. You may get a phone call or email along the way, asking for clarification. As the meeting date approaches, it is advisable to reconfirm the date and time as well as FDA’s proposed list of attendees. Make sure that your expertise matches theirs. If they are including an engineer or statistician, make sure you have one too.
  3. FDA’s written feedback. FDA will answer your questions and provide you with additional comments. Those additional comments are as valuable as the answers to your questions. If the feedback is all positive, you may decide to cancel the meeting, but in our experience there are always more questions to be discussed.
  4. Before your meeting with FDA. The guidance states that FDA wants your presentation slides at least two business days before the meeting, but since you will have just received FDA’s comments, you will probably spend most of your time sorting out how you want to respond,so don’t feel an obligation to send the slides.

In our experience, the time between receiving FDA’s comments and preparing for the meeting is usually very intense. You have received feedback on your questions. You have likely received extra feedback. Some of it is clear, some of it is not, some of it is adverse, and some of it is supportive. Your meeting will last only 60 minutes. What topics do you cover?

It helps to remember that the Pre-Sub program is a process. You may need to come back later, perhaps via email, to discuss some of the minor points. MED Institute has considerable experience with Pre-Sub meetings. We are happy to help at any stage along the way.

For more information, please visit our website at

Next time:  The Pre-Submission meeting.

What is involved when submitting a Pre-Submission?

The third in a series of blogs about informal, pre-submission contact with FDA. See here and here for the first two.

You have decided to ask FDA a question or questions that you want answered well before your formal submission (e.g., an IDE or 510(k)), so that you can save valuable time and money in the long run. For instance, you want to know if you’re doing the right large animal study or have the correct sample size for your expensive bench test.

RegulatoryThe Pre-Submission (Pre-Sub) program (see FDA guidance here) describes the contents of the submission you need to write  to get your questions answered. It is a long guidance, but not too hard to understand, especially if you have a specific product in mind. We’ll use this blog to cover some strategy and tactics we’ve learned over the years about what should go in the submission itself.

  • Cover Letter: This is fairly boilerplate. Introduce yourself, ask for the meeting, propose at least 3 dates to meet or talk, state who is attending, and who from FDA you want to attend. FDA typically limits the meetings to 60 minutes, so if you have a great deal to discuss, you can always plan on more than one Pre-Sub interaction; for example, the first to discuss non-clinical testing and the second to discuss a clinical protocol.
  • Device Description and Indications for Use: The “Goldilocks” principle applies here. Not too much, not too little. Write enough so that FDA can understand the questions you are asking, but don’t provide unnecessary detail.
  • Previous discussions or submissions; Overview of product development: Keep it brief. FDA doesn’t need to know the details.
  • The background for the question you are asking: This is the key section of the submission and, again, the Goldilocks principle applies. You want to give them enough background to understand the questions you are asking and the information that supports your proposed or desired answer. Answer possible objections, but don’t add details that aren’t relevant or else FDA may misunderstand your position.
  • Specific questions: Figuring out which questions to ask and how to ask them can be a challenge. Don’t ask, “What should I do?” Instead ask, “Do you agree with this approach?”
  • Method for feedback (writing only, meeting, phone): We strongly encourage you to meet with FDA in person at least once. It helps them feel comfortable with you. It helps you understand them better.

There is so much more to writing a Pre-Sub than these brief highlights. Each Pre- Sub has its unique challenges and all of them must be written carefully. We would be happy to be a sounding board, coach you through the process, write the submission for you, and/or coordinate the meeting.

For more information, please contact MED Institute via our website at

Next time:  What happens once I submit a Pre-Submission?

When should you take advantage of the Pre-Submission program?

The second in a series of blogs about informal, pre-submission contact with FDA. See here for the first one.

The Pre-Submission (Pre-Sub) program (see FDA guidance here) can save manufacturers and sponsors valuable time and money in the long run, when you want to learn FDA’s thoughts before your formal submission (e.g., IDE, 510(k)). The program provides free consultation with FDA and is designed to support successful clearance or approval of your medical device. A Pre-Sub is appropriate when FDA’s feedback on specific questions is necessary to guide product development and/or application preparation. But should you use it? Some factors to consider:

  • Is the device new (to you or FDA)?
  • How well do guidance documents, recognized consensus standards, or 510(k)/PMA summaries apply?
  • Where are you in the development cycle?
  • How expensive is it to be wrong?

MED Inst, Med,  regulatory science, regulatory dataIf you are developing a truly novel device or planning to expand the indication of a currently marketed device, consider taking advantage of the Pre-Sub program. Make sure you meet with FDA early enough in your medical device development cycle to get their feedback in time to make a difference (usually, you have to wait 90 days), but don’t meet with FDA without considering the potential answers to the questions you are going to ask. If you approach FDA empty-handed without a well thought out plan, you could end up having FDA drive your project, rather than you.

Many people avoid informal contact with FDA because they are afraid that, whatever they propose to FDA, the Agency will always ask for more.  However, waiting until you have completed your testing and submitted to FDA could be costly.  If you did the wrong test, no amount of favorable data will change FDA’s mind. The fundamental question is: Do you want to find out now about those extra requirements or do you want to find out when you get your first deficiency letter?

To have a more thorough discussion or to answer any questions you may have regarding the Pre-Sub process, please contact MED Institute via our website at

Next time: What is involved when submitting a Pre-Submission?

What do I do if I want talk to FDA before I send in a submission?

The first in a series of blogs about informal, pre-submission contact with FDA.

You are working on your submission – perhaps your first one. You have read all the guidance documents you can; you have attended several courses. But now you have a specific question on your product, your submission; a question that no guidance can answer. What do you do? Here are two simple options:

  1. Call or email the Premarket Programs Branch at the Division of Industry and Consumer Education (currently: 800-638-2041 or and ask your question. They are trained to answer all sorts of questions, but if the question is too specific (and yours probably is), they may direct you to the branch chief for your device.
  2. Contact the branch chief. FDA’s Office of Device Evaluation is split into divisions and then into branches. If they don’t tell you who the branch chief is or you want to contact the branch chief first, you can find the lists of branches and their chiefs here:

Look for the various “branches” under the Office of Device Evaluation or the Office of In Vitro Diagnostics and Radiological Device headings, find your best match, and send an e-mail or call the listed person.

But, if your question is very technical or you’re asking something that will require them to commit to a position (e.g., whether a certain test from a guidance document applies to your device) be prepared for this answer: “I can’t answer that via e-mail or phone. Send us a Pre-Sub.”

MED Inst, Med,  regulatory science, regulatory data

The Pre-Sub program

A Pre-Sub is a voluntary, written request from an applicant for informal feedback from FDA to be provided in the form of a written response or, if the applicant chooses, a meeting or teleconference. The Pre-Sub guidance includes a mechanism for getting informal feedback from FDA on a multitude of planned medical device submission types:

  • Premarket Approval (PMA) application
  • Premarket Notification (510(k)) Submission
  • Investigational Device Exemption (IDE) application
  • Humanitarian Device Exemption (HDE) application
  • Evaluation of Automatic Class III Designations (de novo petition)

There are other informal meetings referenced in the guidance, such as “Informational Meetings”. All of these written requests fall within the same organizational structure and are collectively referred to as Q-Submissions, or “Q-Subs” after the “Q-number” that is assigned to each request.

There are no user fees associated with a Pre-Sub. The process is intended to provide applicants with the opportunity to obtain targeted FDA feedback in response to specific questions. Some examples of targeted questions that are appropriate to ask during a Pre-Sub meeting are:

  • Do you agree with our test matrix?
  • Here is our risk analysis, do you agree that we’ve captured everything?
  • Does the FDA agree with the use of the proposed alternative test method, which is different than the normally recognized standard?
  • Are the proposed clinical trial design and selected control group appropriate?
  • Can you give us your input on our primary endpoint and hypothesis for our clinical study?

We frequently stress the importance and the value of involving regulatory strategy experts early and often during the development of a new medical device. A regulatory strategy for a novel medical device will often include a Pre-Sub meeting to address a specific area of concern. These early interactions can smooth the preparation of the subsequent submission, minimize deficiency questions that can draw out the approval process, and foster collegial relationships with the regulators. MED has a long history of successfully navigating these types of interactions with the FDA.

For more information, please visit our website at

Next time: When should you take advantage of the Pre-Submission program?

The medical device product lifecycle is challenging. We can help you through all of the steps!

MED recently exhibited at MD&M West in Anaheim, CA. We were so excited to begin the trade show season with our new booth! The new graphic illustrates that we can help you get your product through the medical device product lifecycle. MED supports entrepreneurs, consultants, developers, and manufacturers of medical products through the entire product life cycle; from initial concept through product approval to post market needs. With experience in medical device testing, clinical evaluation, data analysis, and global regulatory submission preparation, our team knows what it takes to guide a product through all the complex steps required for market approval. Visit our website to learn more.

Visit us next in booth #936 at ADM Cleveland March 29-30

west 10x20 booth

Uncertainty Analysis is an Important Part of Validation

“Testing” is a term that covers a vast range of activities. Not every test is a measurement; some are visual inspections or can be qualified with nominal descriptions such as “pass or fail” or “hot or cold”. However, for tests that either are measurements or include measurements, understanding the uncertainty of those measurements is important to interpreting resulting data. An important component of test method validation is an uncertainty analysis that systematically assesses the factors influencing the measurement.

Instruments and the process of calibration to reference standards are not perfect. Neither is the person performing the test, the environment, or the test method itself. Therefore, every measurement has some uncertainty associated with it. The use of recognized standard procedures reduces many potential sources of measurement uncertainty, however even when the method is standardized, the uncertainty of the method should be understood.


A measurement is a function of all the input quantities that affect the measurement. For example, for the measurement of volume there might be three measurements (length, width, height). The uncertainty in the volume measurement can be determined by calculating and combining each measurement uncertainty along with the uncertainty associated with other factors (e.g., temperature or hydration).

Measurement uncertainty is a statistical estimate of experimental error. Thus, when estimating the uncertainty of a measurement, uncertainty components which are of importance in the given situation should be taken into account using appropriate statistics.

When a test method validation includes an uncertainty analysis to systematically assess the factors influencing the measurement, use of the test method for inappropriate applications can be avoided. The test method may also be improved, controlled, or monitored in areas of high uncertainty, ultimately building more confidence into the associated results.

For more information, please visit our website at




The Goals of Test Method Validation

Test method validation is a documented process that is used to confirm that the procedure to be employed for a specific test is suitable for its intended purpose. The validation of a test method by a laboratory should be a planned activity. Validation plans should be updated as development proceeds. The plan should include a description of the method and describe the various validation activities.

When planning a test method validation, consider the scope of the test method and the associated risk (link to previous blog) before the necessary validation activities are selected. The scope of the method is defined in terms of the method’s purpose and the breadth of medical devices that the method is intended for. The range and accuracy of the test method should be adequate for the test method’s intended purpose. The activities selected should be a balance between the rigor needed for a credible validation, breadth of applicability of the test method, and associated effort.

A validation should establish that the test method has: image-2

  • Accuracy within the needed range
  • Repeatability
  • Reproducibility
  • Robustness

A test method that has adequate accuracy will have instruments that are calibrated to reference standards and will have compared well to other methods or compared well in an inter-laboratory study.

A test method that is repeatable will yield successive measurements in close agreement under tightly controlled conditions within the same laboratory.

A test method that is reproducible will yield measurements in close agreement from different laboratories or within the same laboratory over a longer period of time.

A test method that is robust will demonstrate minimal sensitivity to external factors, such as operator skill or changes in ambient conditions.

Validated test methods, used appropriately, provide data that can be relied upon to make important decisions related to the verification and validation of medical devices with confidence.

To have a more thorough discussion or to answer any questions you may have regarding the test method validation process please contact MED Institute via our website at