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  4. Transcript: IDEs for Early Feasibility Medical Device Clinical Studies, Including First in Human (FIH) Studies
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Transcript: IDEs for Early Feasibility Medical Device Clinical Studies, Including First in Human (FIH) Studies


Moderator: Heather Howell
October 23, 2013
12:30 pm CT

Coordinator: Welcome and thank you for standing by. At this time all participants are in a listen-only mode. During the question-and-answer session, please press star 1 on your touch-tone phone. Today’s conference is being recorded. If you have any objections, you may disconnect at this time. Thank you and you may begin.

Heather Howell: Hello and welcome to today’s FDA Webinar to discuss the final guidance document titled IDEs for Early Feasibility Medical Device Clinical Studies Including First in Human.

Your presenters today are Andrew Farb and Dorothy Abel, both of the Office of Device Evaluations Division of Cardiovascular Devices. Following their presentation we will open the call to questions. Now I’ll turn the call over the Andrew Farb.

Andrew Farb: Good day, everyone. I’m happy to present a brief overview of the guidance on (inspecificational) device exemptions for early feasibility medical device clinical studies so to begin, there are clear opportunities associated with conducting early feasibility studies in the United States.

Performed in the United States, these studies allow for contact between investigators, developers, inventors and regulators in geographically closer locations and in more collaborative fashion.

We need to keep the patient in the center of our focus and when these studies are performed in the United States, they allow for access of promising new technology earlier in the device development process, in a more continuous fashion for early feasibility studies through clinical trials and then it expanded dissemination once beneficial devices are approved for use in the general population.

FDA’s goals in this effort are to provide the earliest and broadest patient access to beneficial medical devices and maintain or regain U.S. leadership in innovation but prevailing currents need to be recognized. Initial clinical testing of novel devices has been moving to non-U.S. sites.

Device innovation may follow overseas and we now know that some devices are being exclusively developed for non-U.S. (in country). There are real world consequences to these developments. There can be a palpable time lag in the availability of some beneficial medical devices for U.S. patients.

And there are real human costs associated with delaying access to new technology particularly in the context of limits of current available treatment options. What are some of the barriers to innovating in the United States?

There may be insufficient predictability of what information is needed to allow for the initiation of clinical studies. Data requirements may be difficult to identify when we’re dealing with increasingly complex devices when there are no established guidance or standards for innovative devices or no generally-accepted method for justifying data requirements.

There may be ineffective communication between (cedaration) industry and there can be poor quality data submissions that do not include or coherently describe relevant information.

In providing direction for this guidance, FDA recognizes the value of encouraging medical device innovation to address clinical needs and improve patient care. We are committed to improving U.S. patient access to new devices by strengthening and streamlining the clinical trial enterprise and we focus our efforts on promoting public health.

The (guardians) adopts a new framework, the core principle of which is the application of benefit-risk principles throughout regulatory decision-making. In this framework we keep the clinical context at the forefront.

By applying this framework, this allows our regulators to consider the totality of the benefit-risk profile for the device for example the disease condition and the limitations and risks associated with currently available (feasible) alternatives.

It also incorporates and understanding that patients tolerate risk differently and embraces their perspective on the potential benefits of new technology and also finally includes risk mitigation strategy when balancing risks and benefits.

With the early feasibility guidance, this was developed to facilitate the clinical evaluation of medical devices in the U.S. under the current IDE regulations using risk mitigation strategies that appropriately protect human subjects so what is an early feasibility study?

These are studies that involve a small number of subjects for devices intended for specific indications that may be early in its development typically before the device design has been finalized. The only feasibility study, however, does not necessarily involve the first clinical use of the device.

Guidance should be viewed as a regulatory toolkit that enables sponsors and regulators to think in new ways about device development, the appropriate evidence needed to move from bench to clinical study and the implementation of timely device and clinical protocol modification.

The key principle of the guidance is that approval of an early feasibility ID may be based on less not a clinical data, that is, for some new devices exhaustive non-clinical testing would not likely provide the information needed to further device development.

And in these cases early clinical use of the device in a limited number of subjects is needed to provide initial insights into clinical safety and device function, inform subsequent clinical and non-clinical testing and/or improve device performance through iteration before finalizing the design.

A guiding principle of the early feasibility study is a term we call just-in-time testing and this is a term that we borrowed and modified from industrial production. Just-in-time testing applies to the type and timing of non-clinical testing needed to justify study initiation.

It departs from the custom of expecting exhaustive non-clinical testing prior to any clinical use and it recognizes that comprehensive testing during the early phases of device development may add cost without important return.

Testing could have limited future applicability if the device is modified. Time-consuming non-informative testing delays access to the devices for patients who may have limited treatment alternatives. Just-in-time testing acknowledges that it may be acceptable to the first (sun) testing until the device design has been finalized for use in a pivotal study.

So there are other reasons why just-in-time testing is appropriate for early feasibility studies. The early feasibility study incorporates enhanced risk mitigation strategies and patient protection measures as compared to a pivotal study.

We expect that these patients will be highly selected and will receive individualized care and monitoring. Importantly the guidance does not recommend that sponsors prematurely initiate clinical testing when further useful and appropriate non-clinical testing can be performed through advances of device development.

So that an early feasibility study must be supported by an appropriate benefit-risk analysis including justification for the types and amounts of data needed to support study initiation.

How to put just-in-time testing into practice. This is best communicated through a device evaluation strategy which is submitted within the report or prior investigation that describes and justifies the appropriate testing to support initiation of the clinical study.

The device’s evaluation strategy provides the thinking behind the device development program and justifies what is sufficient rather than testing for the sake of testing.

The device evaluation strategy focuses on basic device functionality that is an expectation of acceptable clinical use and the device will function as intended and addresses the significant safety concerns such as biocompatibility, sterility and chemical compatibility and characterizes catastrophic failure modes and identifies associated risk mitigation approaches.

The device evaluation strategy presents a description of the device concept including the clinical contents for the device design and identifies device and procedure-related attributes necessary to obtain the desired performance, failure modes that might occur if each attribute is not achieved, how those failures could affect the device or the patient and what information is needed or available to evaluate the attribute or failure mode.

The second-most important principle of the guidance is the provision to facilitate changes in the device or the procedures during an early feasibility study. We know that experience and knowledge gained from the initial study subjects can guide device or protocol changes.

Rounds of regulatory submissions and review can delay the implementation of beneficial changes and impede study progress. Therefore, the early feasibility study guidance includes new approaches to facilitate timely device and clinical protocol modifications during the study.

There are three new approaches outlined in the guidance. First, more changes can be made through five-day notifications rather than requiring FDA approval. This is possible because many changes will not affect the interpretation of the results as the results do not depend on statistical analyses or (pooling) data among study subjects.

The second approach is a method we termed contingent approval. This involves approval of anticipated or proposed device changes that can be obtained contingent on the completion of an agreed-upon test plan and reporting the test data. After successful completion of the testing, the sponsor can begin to study the modified device without additional FDA action.

Finally interactive review which encourages communication between FDA and the sponsor within a 30-day review cycle to address deficiencies and is intended to facilitate timely approval of the ID.

What are the next steps after early feasibility study is completed? Subsequent clinical evaluation depends on the stability of the device design, the availability of data to justify the next study and the purpose of the clinical study so one alternative is expansion of the early feasibility study to additional patients for example if further device modifications are expected.

Alternatively, either a traditional feasibility study or a pivotal study may be proposed or a device design that is near final or final or a case where the early feasibility study data support the initial safety of the device and proof of principle and there are adequate non-clinical data available.

So what’s changed from the draft guidance to the finalized guidance that was recently published? We emphasize benefit-risk concepts throughout the document. We improved the report of private investigation section to clarify the information that will be useful to justify study initiation.

We added a design control section and included more guidance on drafting the informed consent form for the early feasibility study and finally we suggested pre-submission topics for discussion between the sponsor and the FDA.

We do recognize our current efforts and there are some remaining uncertainties. (Intramural) training programs are under development. We are hopeful based on the response we’ve received for the guidance in that many sponsors have committed to test the waters conducting early feasibility studies within the United States. There are some outstanding questions.

Will other sponsors step up to take the plunge? Is there sufficient value added for doing early feasibility studies within the United States and are non-regulatory clinical trial challenges surmountable?

Here are some references for questions and the Web address for the early feasibility study guidance. We look forward to working with you and answering questions you may have. Thank you.

Coordinator: Thank you.

Heather Howell: So we’ll take questions from the audience now.

Coordinator: Thank you. We will now begin the question-and-answer session. If you’d like to ask a question, please press star 1. You’ll be prompted to record your name. To withdraw your request, please press star 2. One moment, please, to see if we have any questions.

Dorothy Abel: Are we disconnected now?

Coordinator: We have a question from (Roya). Your line is now open.

(Roya): Hi. Our question is about the correlation between the design control and this ID feasibility studies. Is it a requirement that these feasibility studies are conducted within the design control structure or regulation?

Dorothy Abel: The answer to that is yes and we did include a design control section in the early feasibility guidance to give an idea of the type of information that would be appropriate at this phase of device development.

(Roya): Thank you.

Coordinator: Our next question comes from (Craig Combs). Your line is open.

(Craig Combs): Hi. I’m curious about the mechanism for the contingent approval and how will that be better than the typical 30-day supplement that we typically sent in?

Dorothy Abel: So the plan is that if you have an idea of potential modification in the future and you know how you would evaluate that, you can describe to us how you would do the evaluation and the outcomes that you would need in order to feel that it was appropriate to make the change and we would approve making the modification based on your plan.

So you’re actually getting an approval before you do the testing and it’s somewhat like we have with the shelf life testing currently where if design is you follow the protocol for shelf life and you get the results that you anticipate, you can change your shelf life time and your labeling without getting an additional approval from FDA.

So the benefit is you’re getting approval based on a plan and you don’t have to wait until you have all the testing completed.

(Craig Combs): Do you have some sort of timing in mind for how long it should take you to review these contingent plans?

Dorothy Abel: It would be the same as with any other IDE submission so that if you put in your proposals with your original IDE, you would get some sort of approval of those contingent plans within the 30 days of submitting your original or if you submit a supplement with the proposed changes, it would be an approval within the 30 days.

So you could be doing your testing while you’re waiting for the approval or, you know, you could be if you have a plan that you might want to make modification to a component with various modifications over time and doing the same testing and getting the same results would be necessary even though the piece would be different, you could get that done well in advance of actually making the modifications and doing the testing.

(Craig Combs): Terrific, thank you.

Coordinator: (Michael Linderman), your line is open.

(Michael Linderman): Oh hello. I didn’t do the studies before, just to maybe my question. How many (sale see) controls and how many patients you see in studies? I understand could be calculated from (par) analysis but practically can you give me some, you know, heads-up on how many of those people?

Andrew Farb: So the way we define these early feasibility studies is to point to a limited number of subjects, typically less than 10 to start. We’re medical devices and since we’re dealing with IDEs and significant risk devices, we usually don’t think about healthy controls and so that’s usually more of a drug question so I wasn’t quite sure what the context of the question was.

(Michael Linderman): Oh, in my case it’s strictly non-intrusive device, non-invasive at all so you answered my question with saying that less than 10 around 10 subjects would be good enough.

Andrew Farb: Well, that’s the general expectations. These would be limited investigations but then there are opportunities to expand to further feasibility work particularly if you’re anticipating making modifications to the device, more of the data support going through a larger type of trial like a larger feasibility study or even a pivotal trial to move forward to that framework.

(Michael Linderman): I see. How much the usually the study cost, roughly?

Dorothy Abel: I think the study would depend on the type of study and the type of device but that’s usually something that the sponsor would work out.

(Michael Linderman): Pardon, you’re breaking up.

Dorothy Abel: Yes, that’s not something that we would have any control over.

(Michael Linderman): I see, no, I understand. Thank you very much.

Andrew Farb: Could you repeat the question?

Coordinator: Our question comes from (Jason Brook). Your line is open.

(Jason Brook): Hi. I missed the first couple of slides so I apologize if you covered this but I realize that the guidance is meant for IDE significant risk studies. To what extent should a sponsor look to this for guidance related to non-significant risk studies if any at all?


Dorothy Abel: Mr. (Brook), did that address your question?

(Jason Brook): I’m sorry, I couldn’t hear the answer. I thought maybe you were thinking, sorry.

Dorothy Abel: Okay, can you hear me now?

(Jason Brook): Yes, that’s better.

Dorothy Abel: ...the IDE staff, non-significant risk studies whether they’re early feasibility or of any other type do not need to be submitted to FDA for review prior to beginning. They are submitted to the IRB which can make a final determination as to whether or not it’s significant risk or not.

If the IRB agrees that it’s a non-significant risk study, the you can just go ahead at that point with starting with a small number of patients or however many the IRB allots to you. Does that answer your question?

(Jason Brook): Yes, I’m comfortable with, you know, your answer. I guess the question is there’s a lot of really useful information in this guidance that could help sponsors in their effort to either make the determination of significant risk versus non-significant risk.

And if it is significant risk - sorry, non-significant risk - that this guidance could be helpful for both sponsors and the IRB to really kind of guide the obligations of the sponsor to ensure, you know, that there’s certain safety and design controls and things like that.

But I guess I’m just curious if there’s any information or anything here in this guidance that could be valuable for the non-significant risk side of things.

Dorothy Abel: This (current) release doesn’t delve into significant/non-significant risks. We do have a separate guidance with pretty much that in the title that’s available on the good clinical practice Website and that is entirely based on for significant and non-significant risk determination.

You can also submit a pre-submission to FDA for a study risk determination if you’re either the sponsor or IRB or not comfortable with that decision. There are some devices and studies we look at not only the device but the study and some of them fall into a gray area and FDA is very comfortable making the final decision.

(Jason Brook): Thank you very much.

Coordinator: (Anthony Ignotti), your line is open.

(Anthony Ignotti): Thank you. The structure of the submission for the early feasibility study is laid over the structure of a traditional IDE for the initial submission, is that correct, so we have to have a full traditional IDE submission with the additional elements that are identified in the early IDE or how’s the structure of the submission look?

Dorothy Abel: The structure would be the same and there isn’t additional information required. It’s just some guidance on how to address particular elements of an IDE application so you would always need a report (of par) investigation for example and this guidance gives you an idea of how to present the information to best make your case regarding justification of an early feasibility study.

(Anthony Ignotti): Okay, all right. Thank you.

Coordinator: (Louis Jimenez), your line is open.

(Louis Jimenez): Yes, thank you. I was wondering in your presentation you outlined that there’s going to be a risk-benefit consideration in that pre-clinical testing is always going to be required for early feasibility study.

I’m wondering if for example there’s long-term animal studies and there’s a need to start initial human testing if this would be an avenue or if the stance is always going to be complete the full pre-clinical kind of program on safety and compatibility and long-term assessment before being able to consider this type of study.

Andrew Farb: No, I think you really get to one of the focuses of the guidance and its intent and that is to provide the type of testing that is necessary to start a clinical trial and in some cases long-term studies might not be necessary to be completed at the time of the initial clinical test.

It’s really up to you to identify that the types of testing that are essential that are sufficient and provide a justification of why those tests are sufficient to provide the basic safety and information so that initial human testing can commence.

And then to make a justification of why certain tests that might complete the characterization of the device might be appropriately deferred for a later time point.

Dorothy Abel: You also implied that animal studies would always be necessary, is that what you meant?

(Louis Jimenez): Well, I thought that there was a comment in the presentation that stated that, that there’s always never going to be kind of a waiver on these but I guess from the answer now that there is kind of a balance that we have to hit in terms of not completing the full amount of testing but at least generating enough data to show comfort level with the risk ratio.

Dorothy Abel: Right.

(Louis Jimenez): And this might be a little aggressive but is there in general kind of a percent rule of thumb in terms of the standard pre-clinical testing if for example for a non-invasive material there will be 10 tests. Is getting 30% of them complete in your estimation a good enough to start potentially looking at this application or are we talking more like 80% of the tests ready to be able to start?

Dorothy Abel: It totally depends on the novelty of the technology and the intended use and, you know, it’s very much project-dependent so I would warn you that if you ask FDA we’re going to say 100% and what we’re trying to get away from here is to not have you come in and ask us what needs to be done.

But you would look at your device and what it needs to be able to do for the patient population you intend to enroll in your clinical studies and explain to us what information is appropriate and we work with you to figure that out to reach agreement on that.

For a device that we know exactly how the testing should be done and it’s been done for years and you just happen to have a new product or you’re new into the game, you’re probably going to have to do the testing that everyone else has had to do over the last 100 years.

But if it’s something really unique and we don’t know exactly how it should be tested, you know, we have the opportunity to work with you to figure out what makes sense.

Andrew Farb: Just getting back to your animal question, it may be that for a particular device an indication that the near-term testing may be sufficient to demonstrate acceptable safety and proof of concept or an expectation of proof of concept and you’ve reached an acceptable (chemo) dynamic or (histological) result, you may anticipate doing those longer-term animal studies but they may not be needed for the initial early feasibility study.

(Louis Jimenez): Thank you very much and this is my last question. With this data package, would it be required to be GLP pre-clinical testing?

Andrew Farb: So there’s no specific requirement for GLP. We encourage GLP work for all the animal testing but if the tests deviate from GLP, what we would want for you to provide is how those deviations - how the test is deviated for GLP - and why the testing you provide are still valid and so that we can look at them as objectively as possible.

(Louis Jimenez): Thank you very much.

Andrew Farb: There was a section on GLP in the guidance which might be helpful.

(Louis Jimenez): Thank you.

Coordinator: (Scott Derland), your line is open. Please check your mute button.

(Scott Derland): Sorry about that, can you hear me now?

Coordinator: Yes, we can hear you.

(Scott Derland): Okay, thank you. Yes, my question is on the back to the limited number of subjects. My question specifically is if this is a multi-site study that may have sites outside of the U.S., would those also be included in the consideration for the total number of subjects or is it only limited to sites within the U.S.?

Andrew Farb: So our jurisdiction ends at our borders.

(Scott Derland): Okay.

Andrew Farb: So you only - we would only be - referencing those subjects within the United States. However, within the context of our evaluation of the entire study, of course we would be interested in the entire clinical experience.

(Scott Derland): All right, very good. Thank you.

Coordinator: (Kathleen Venom), your line is open.

(Kathleen Venom): Hello. I just was wondering now that you’ve laid the groundwork with the new approaches for this particular situation, I was wondering if there’s any other applicability or any thought to expanding these approaches to other types of studies, for example I could see that the contingent approval would be ideal for a way to...

Dorothy Abel: I’m sorry, excuse me, Ms. (Venom), if you could speak up, we can’t hear your question.

(Kathleen Venom): Yes, okay, can you hear this better, is that better?

Dorothy Abel: More, if you could.

(Kathleen Venom): Okay, any better?

Dorothy Abel: There you go.

(Kathleen Venom): Okay, I think my phone is not the greatest here. Anyway, what I was saying is that now that you’ve laid the groundwork in this guidance with the new approaches, I’m wondering if there’s any applicability or any thought to expanding them to other types of studies?

One area that I think would be ideal would be when you’re doing a pivotal study and if you could use the contingent approval approach to negotiate a continued access, for example where you’re doing a lead study that requires many, many enrollments and also will continue to require many enrollments in a post-approval phase.

It would be nice to be able to keep the study centers enrolling and not have to start over again and I’m wondering if you could propose in your IDE application that you would like to have continue access assuming you’re contingent on a certain outcome of your study or certain amount of evidence.

I mean, would FDA consider, you know, applying this now that it’s been defined in one guidance to other areas?

Dorothy Abel: Yes, I think the contingent approval really isn’t intended to address expansion of studies whether you’re talking about continued access or moving into a pivotal study. The intent of that provision is to allow for modifications under the early feasibility study to make sure that you don’t have an interruption.

I hear what you’re saying. You want to make sure that we figure out ways to have a continuous enrollment from early feasibility to traditional or from early to pivotal or from pivotal to continued access and I think it’s reasonable to work with your review team to try to figure out how to make that as seamless as possible.

But at this point in time there aren’t any plans to come up with a new approach to doing what can already currently be done where you can come in before you’ve reached your limit and ask that you be able to expand based on the preliminary data that you have available to you so the short answer is no, there’s no plan to apply those options other ways at this point.

(Kathleen Venom): Okay, thank you.

Coordinator: (Amy), your line is open.

(Amy): Thank you. I was wondering if this program is also applicable in the case where you have a device on the market but you want to make changes to that device to pursue a different indication?

Andrew Farb: Yes, it is.

(Amy): Thank you.

Coordinator: (Mitchell Acres), your line is open.

(Mitchell Acres): Yes, thank you. I have a two-part question. The first part has to do with the sequence of the study. For example if you were to do an early feasibility study, can you then upon successful results jump to a pivotal study or you see this now as a three-part study series where you’d have the early feasibility, traditional feasibility followed by the final pivotal study?

Andrew Farb: So the answer is you can yes, jump to a pivotal study if your results are supportive of such and that you don’t plan to make any further modifications to the device or the procedure. The intent of the guidance is not to add steps and in fact we’ve made sure that we weren’t, that nothing here is required.

So the answer to jumping to pivotal or another feasibility or another early feasibility is all yes.

(Mitchell Acres): Okay, the second part is can you schedule a pre-IDE meeting going into the early feasibility study?

Andrew Farb: Yes.

(Mitchell Acres): Okay, thank you very much.

Coordinator: (John Allison), your line is now open.

(John Allison): Yes, my question is on your Slide 12 about just-in-time testing, the agency talked about acknowledging that some testing can be deferred and I wondered if you had some examples to help color that thought?

Dorothy Abel: So an example might be that you would do finite element analysis of your device to predict the fatigue properties of it but you would do the fatigue testing during your early feasibility study or maybe even during a feasibility study.

And I think another example may be that there are some testing that you do for characterization of a device and it may not be necessary to do the full characterization, the four corners testing for example of certain parameters but you may do that level of testing later on.

(John Allison): Okay, thank you.

Coordinator: Our next question comes from (Nancy Lowe). Your line is open.

(Nancy Lowe): Yes, thank you. From your presentation can you expand possibly on the non-regulatory clinical trial issues that you mentioned and possibly any other issues that were discovered in the pilot program?

Andrew Farb: Okay, so this gets to the idea that FDA is part of a larger clinical trial ecosystem and part of the success of this program will really depend on good quality submissions, good devices, good investigators, clinical study sites, cooperation from IRBs who understand the process.

I think we play a very important role in this clinical trial enterprise but that was the intent of this question. We’re hopeful that when we build this program from the ground up that it will be successful but time will tell.

(Nancy Lowe): Thank you.

Coordinator: (Maria), your line is open.

(Maria): Thank you so I understand that the conversation goes around the devices that do need the clinical trials and I wonder if for the devices Class 1 that do not need IDE submission or pre-market approval, how these new rules will change the commercialization or affect these kind of products, the products within this group?

Dorothy Abel: I’m sorry, could you please repeat the question and speak just a little louder, please?

(Maria): Okay, can you hear me now?

Dorothy Abel: Yes.

(Maria): Okay, I was saying that the conversation goes around pretty much about the devices that do need the clinical trials and I wonder for devices Class 1 that do not need the IDE submission or pre-market approval, how these new rules will affect these Class 1 devices?

Dorothy Abel: There’s no effect on the Class 1 devices because this guidance only applies to significant-risk devices that you would need an IDE submission in order to do a clinical evaluation.

(Maria): So what you’re telling me is that we don’t need to do anything regarding the Class 1 devices that do not need the IDE submission? Hello?

(Sheila): This is (Sheila). Unless you are doing some device modifications that would trip the limitation on your exempt device, no, you do not need to submit clinical data to FDA.

Dorothy Abel: Not even on the labeling of the (blodeces) or anything?

(Sheila): If your device is Class 1, it’s not affected by this guidance and the feasibility process.

(Maria): Okay, thank you very much.

Coordinator: (Ed Thomas), your line is open.

(Steve Meschino): Yes, this is (Steve Meschino). I had a question about the level of software documentation needed to support the submission. We have a - we believe we meet the requirements of the guidance document for an early feasibility study.

The device is an implantable device that has software and the software was developed to a software life cycle development process that may not meet all of the requirements of for example IC 62304 software development, the standard.

Is it acceptable to submit based on well, the question is what level of software development would be needed to support a submission of this type?

Dorothy Abel: You’d need to work with your review team to find out exactly what their expectation would be but some things that you can suggest to them would be for example if the risk of a software failure wouldn’t be catastrophic, you know, or if the tolerance for risk of the patient population would be such that even if the software failed and the device was completely ineffective, they would be more than willing to take the chance.

For example, if you have patients that are extremely limited in mobility so those are just examples and you certainly would want to use the pre-submission process to interact with the review team to help figure out what would be needed.

(Steve Meschino): Okay, thank you.

Coordinator: (Kim), your line is now open.

(Kim): Hi, my question’s regarding the applicability of this guidance document to in-vitro diagnostics and I guess in the realm of significant risks, in-vitro diagnostics and what I’m thinking of is in a companion diagnostics environment where a diagnostic would be used in treatment decisions potentially in Phase 1 Pharma studies?

(Sheila): This is (Sheila). If your device is determined to be significant risk which most of these are now as companion diagnostics because the results are being used to determine whether or not the patient gets a specific treatment, you could follow this process as well.

We strongly recommend for any of these that you come in for a pre-submission first. There is a draft guidance that’s available on our Website.

(Kim): Okay, all right, there wasn’t really any mention of in-vitro diagnostics and I know they’re a subset of devices so I just I wanted to see if I could clarify...

(Sheila): I’m sorry, can you speak up? We really can’t hear your question.

(Kim): Sure. Sorry. I just wanted to clarify because I note that in-vitro diagnostics are a subset of devices and there really wasn’t too much mention of any in-vitro diagnostics so I wanted to be sure.

(Sheila): Yes, if they meet the realm of significant risk then this guidance may apply.

Dorothy Abel: And we did work with people that regulate those devices in drafting the guidance document so it does talk about therapies and various things other than just implants which is what Andy and I know about so it is intended to cover other types of devices. There just may not be as much detail because it’s less common.

(Kim): Great, thank you.

Coordinator: And again as a reminder if you do have any questions or comments, please press star 1 and record your name. Again, please press star 1. We do have a question from (Roya). Your line is now open.

(Roya): Oh hi, thank you. Our question is about a non-significant device which doesn’t require an IDE and the question is would feasibility study be acceptable on a non-significant device that doesn’t follow the design controls and structure?

(Sheila): This is (Sheila). Were you planning on just submitting this as a marketing application, your results?

(Roya): In the end, yes.

(Sheila): If you need to have clinical data for this and it’s a non-significant risk study, you should go through your IRB. We would strongly recommend that you submit a pre-submission to make sure you’re collecting the correct data and that you do have in place the information that we need for your marketing application or that you will have it available by the time you submit your marketing application.

Dorothy Abel: Non-significant risk devices are outside the scope of this guidance and you know, as far as whether you need design controls for non-significant risk devices, we recommend that you talk to our small manufacturers assistance. The answer is yes, you need design controls.

(Roya): Thank you.

Dorothy Abel: We happen to have an expert sitting right here.

(Roya): Thank you so much.

Coordinator: (Alex Stile), your line is now open.

(Alex Stile): Yes, hello, thank you. We think these questions have already been answered but if you would just confirm if a sponsor should conduct an early feasibility study in a device that has PMA approval for another indication?

Andrew Farb: Yes, for new indications for approved device, the guidance can be applied.

(Alex Stile): And would you recommend a pre-submission meeting in this instance?

Andrew Farb: Yes.

(Alex Stile): Okay, thank you very much.

Coordinator: And our last question comes from (Enrita). Your line is now open.

(Enrita): Thank you. My question is does this guidance apply to first-in-humans HUD studies?

(Sheila): I’m sorry can you repeat the question please?

(Enrita): Sorry. I said does this guidance apply to first-in-human HUD studies?

(Sheila): If you’re - are you talking about - a study that will be used to support a submission for a humanitarian use product?

(Enrita): That’s correct.

(Sheila): Okay, then yes, it would.

(Enrita): It would, okay.

(Sheila): It would if the device or the study is significant risk, yes, it would apply.

(Enrita): It would apply, okay, thank you very much.

Coordinator: We have another question that came through from (Penny Cooder). Your line is now open.

(Penny Cooder): Hi. You may have just answered this question with the last caller but I didn’t quite hear the whole thing. My company is trying to obtain a humanitarian device exemption approval for a device. Are the requirements different for first-in-human studies as opposed to the humanitarian device exemption requirements?

(Sheila): They’re really two entirely different processes. First-in-human or an IDE is a clinical trial to obtain data for a marketing application. An HDE is a marketing application in which you would submit the data from your IDE.

(Penny Cooder): Okay, thank you.

(Sheila): Does that answer your question?

(Penny Cooder): Yes, it’s made it a little clearer. I think I just need to do some more research. Thank you.

(Sheila): Okay, there is an HDE guidance that’s available on FDA’s Website as well as this first-in-human guidance and information on IDEs in general.

Coordinator: (Mya Westbrook), your line is open.

(Mya Westbrook): Yes, thank you. I just wanted some clarification on changes to the protocol that you mentioned that could be done through either five-day notifications or through contingent approval. What types of protocol changes are typical examples like would changes to inclusion/exclusion criteria fall within that category?

Andrew Farb: It’s possible. They might as long as they, you know, don’t impact the usual rights, welfare and safety of individuals. Another example might be you’ve done your first six patients and you determine that the imaging that you performed on Day 3 wasn’t all that informative, it didn’t really help. You may present a use of the five-day notification to eliminate testing that may not be informative.

(Mya Westbrook): Okay, thank you very much and one last update to that so I believe you mentioned earlier that expansion of that feasibility should not be done through contingent approval. What is the fastest route to go from the initial early feasibility to expanding that cohort?

Andrew Farb: We’ll answer that question in a minute but I think (Sheila) had another comment on the first question.

(Mya Westbrook): Okay.

(Sheila): Regarding your first question, we also have a guidance on FDA’s Website regarding changes and modifications to a study.

Andrew Farb: So I think the best way forward in terms of expansion of the early feasibility study is that you’d come in and communicate with the review team where you are at with respect to your ongoing studies and why it’s appropriate at that point to either continue to ask for expansion for additional patients.

Under the early feasibility study either with the same device that you have to collect more information or if you have changes that you want to make to the device or procedure, apply those to the next cohort of individuals.

Alternatively, yes, we’ve discussed if the data and the device and procedures support a larger study, you would talk to the review team again about, you know, plans to go to a larger feasibility study or even a pivotal trial so I think the first step would be to communicate with the review team.

Dorothy Abel: But ultimately a 30-day supplement would be necessary.

(Mya Westbrook): Okay, thank you very much.

Coordinator: But if you do have any further questions, please press star 1 and record your name. We do have a question from (Mary Devore). Your line is now open.

(Mary Devore): Thank you. I just wanted to know if it’s possible your guidelines might apply to a combination device drug product?

Andrew Farb: Yes.

(Mary Devore): Thank you.

Andrew Farb: In those situations we would get consultations from our (Cedar) colleagues.

(Mary Devore): Thank you.

Coordinator: I show no further questions.

Heather Howell: So with no other questions, we want to thank you for the questions that you did provide today. This concludes our Webinar and for further questions please contact either Dorothy or Andrew at the contact information that was provided in the slide presentation.

And this presentation will be available on the CDRH learn Website along with a recording of this discussion within the next couple of days. Actually the presentation will be available today. The recording will probably be up with it on Monday so if you have any questions, please contact us and thank you very much.

Coordinator: This concludes today’s conference call. Thank you for participating. You may disconnect at this time.


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