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 http://www.medinstitute.com.

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 http://www.medinstitute.com.

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 DICE@fda.hhs.gov) 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 http://www.medinstitute.com.

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  medinstitute.com.




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 http://www.medinstitute.com

Why do I need test method validation and what level of rigor is necessary?

The medical device industry has long understood the requirements related to process and software validation, however, US FDA Title 21 Code of Federal Regulations Part 820 Quality System Regulations does not have explicit requirements related to test method validation. Despite the lack of requirements, the FDA does have expectations around test method validation and has issued 483s and warning letters for insufficient method validation activities. Test methods that have not been validated yield a risk of the method being inadequate for evaluating medical devices and can lead to failed clinical devices, market recall and patient harm. Thus, to satisfy FDA expectations and avoid the pitfalls of using an inadequate test method, test methods used to produce data in support of regulatory filings or the manufacture of medical devices for human use need to be validated.


21 CFR 820.3 states: Validation means confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled. 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.  Test method validation gives an overall understanding of uncertainty of the method. A validated method provides confidence that the method is appropriate and that the data generated are reliable and repeatable.

Incorporate Risk

When establishing test method validation activities, first consider the purpose and risk associated with the test. ISO 17025 states: The validation shall be as extensive as is necessary to meet the needs of the given application or field of application. The extent of validation activities required for a given method is driven by its intended purpose and closely related to the risk of patient harm. For example, a test for conformity of appearance may not require the same level of validation activities as a durability test replicating the clinical usage of the device.


The level of validation should be commensurate with the risk associated with the test method being wrong.

Test method developers should determine the risk associated with the test method by evaluating the severity of potential harm and the probability that the harm occurs. With the purpose of the method and the associated risk assessed, the validation activities and level of rigor needed may be planned.

As an example, consider a test method to measure the length of medical device that is 100 cm +/- 1 cm long. The severity and probability associated with the device length being incorrect is low. Thus when planning the test method validation activities associated with a metal ruler, uncertainty determination including accuracy, resolution and repeatability is needed. However determination of the uncertainty related to the thermal expansion of a metal ruler isn’t likely warranted.

A deeper look at validation activities including uncertainty determination will be covered in future blog posts.

For more information, please visit our website at http://www.medinstitute.com

MedTech Policy Forum


On September 20th Justin Renfrow, Director of Business Operations, participated in the 2016 MedTech Policy Forum. This was a joint effort between the Indiana Medical Device Manufacturers Council (IMDMC) and the Indiana Health Industry Forum (IHIF). Justin participated on a panel with Paul Moses, Purdue Research Foundation, and Kyle Hultgren, Imagine Medical Devices. The panel was chaired by Brooke Beier, Assistant Director for Business Development for Purdue’s Office of Technology Commercialization. The panel focused on the collaborative efforts needed to take a medical device to market. Participants discussed success stories and a few of the lessons learned along the way. In regards to the event, Justin stated, “IMDMC does an excellent job connecting thought leaders from around the state to share their experiences and to collaborate. I’m always proud to be involved.”

To learn more about how MED can help you, visit our website.

4th Annual Purdue Research Park Kickball Tournament

Last month, MED Institute participated on the ‘Too Many Cooks in the Kitchen’ Kickball team as part of the 4th annual Purdue Research Park Kickball Tournament. 3 other Cook companies participated on the team: Cook Advanced Technologies, Cook Research Incorporated and Cook Regentec. In total, the team played in 4 games throughout the evening scoring a total of 52 runs over the course of the evening! We held our opponents to only 6! This is the second year that the Cook team has won the kickball championship game. It’s really great that so many Cook companies can come together as one for events like this. We are excited and proud to take home the trophy for the second year in a row!


What Should You Do When a Testing Standard Doesn’t Exist? Part 6: Overcoming Standard Committee Stalemate

In part five of this series, we discussed forming an industry consortium as another means to develop a test method. In this part, we’ll discuss what you can do when the standards community disagrees with your proposed method. omtec-6-image

One course of action available to you is to promote awareness of test methodology by publication in peer-reviewed journals. The development of a publication portfolio can help to validate the methods you have developed and will allow industry peers to confirm your practices. This can help everyone come to a consensus on the best way to move forward.

This concludes our series on what you should do when a testing standard doesn’t exist. To continue the discussion or to answer any questions you may have, please contact MED Institute via our website at http://www.medinstitute.com

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