Training and Continuing Education

FDA Decisions for Investigational Device Exemption (IDE) Clinical Investigations - Transcript

NWX-HHS FDA

Moderator: Heather Howell
July 2, 2013
4:15 pm CT

Coordinator:

Welcome and thank you for standing by. At this time all participants are in a listen-only mode. If you would like to ask a question during the question and answer session, please press star 1 on your touchtone phone.

Today's conference is being recorded if you have any objections you may disconnect at this time. I will now turn the call over to Ashley Boam.

Ashley Boam:

Thank you and good morning and thank you for joining us. I apologize we've had some technical difficulties sharing the slides with you through Adobe. As the Operator has previously announced these slides are available on our Web site at the following link, www.fda.gov/downloads/training/cdrhlearn/ucm359296.pdf. That link was also in the announcement that you received by email about this audio conference as the location where the slides will be posted. So you may follow that link directly from that email. We will call out the number of the slide that we are on so that you can keep track with the presentation today.

So again, I'm Ashley Boam and I'm the Associate Director for Guidance and Regulations within the Office of Device Evaluation in CDRH and I am joined by my colleague Owen Faris who is the Deputy Director of the Division of Cardiovascular Devices also within the Office of Device Evaluations.

Moving to slide 2 this is an overview of our presentation today. First, we'll start by outlining how this guidance really fits within an overall FDA strategic party related to streamlining clinical trials.

We'll speak briefly about what is the guidance and what is the draft guidance. We'll give some background on investigational device exemption study and then we'll move more specifically into this draft guidance.

We'll talk about changes that came with legislation passed almost one year ago and then what has changed in this draft guidance as a result. We'll walk through decisions for IDEs and how that's addressed within this guidance document and the other information that would be communicated in FDA's decision letters for IDEs and then finally we'll walk you through a proposed new process called the pre-decisional IDE process.

So on slide 3 you may have reviewed our strategic priorities that FDA and CDRH have posted on our Web site. One of those strategic parties is to improve patient access for American patients to new devices by strengthening and streamlining the clinical trial enterprise.

As part of that, this draft guidance includes processes that would allow more efficient study enrollment to reduce time and cost associated with conduct of clinical trials, provide more transparency into FDA's decision-making process and improves predictability of those processes and also introduces additional communications to further improve transparency of our decision-making to study sponsors and other stakeholders. Now a couple of words about FDA guidance documents, our guidance documents explain the agencies current thinking on a topic but do not establish legally enforced full responsibilities.

What's in an FDA guidance document should be viewed only as a recommendation unless there's a specific citation to a regulation or a statutory requirement.

Further, a draft guidance is a preliminary guidance document upon which FDA is seeking comments from the public and other interested stakeholders. When finalized the guidance will represent our current thinking on that topic.

Today we'll be talking about investigational device exemptions, which are established in Section 520G of the Food, Drug and Cosmetic Act and in the regulations at part 812 of the CFR.

Okay, approval of an IDE is required for U.S. human clinical studies of significant risk device and the IDE basically exempts the sponsor from certain provisions of the Food, Drug and Cosmetic Act including the requirement for a marketing application before introducing the device into interstate commerce and compliance with full good manufacturing practices.

The IDE regulations include requirements for informed consent, labeling, record keeping and reporting by both sponsors and study investigators among others.

Finally, initiation of a study under an IDE also requires approval by the institutional review board. At this time I'll turn the microphone over to my colleague Owen Faris.

Owen Faris: Good morning, so now we're moving onto slide 6 of the presentation and I'm going to start by giving a little bit of a history of how we got to where we are today.

So originally, this guidance was published in draft on November 10, 2011. The main purpose of the guidance was to explain each of FDA's possible decisions with regard to IDEs, specifically approval, approval with conditions and disapproval.

The guidance provided some examples of reasons that could support IDE disapproval or approval with conditions and we also explained a new term now known as staged approval, which allows some studies to begin while those issues are addressed concurrently.

Moving onto slide 7, so after the draft went out towards the end of 2011 and the comment period ended there was some changes implemented in the law that impacted several elements of the Food, Drug and Cosmetic Act and some of these changes impacted some elements of the guidance.

So specifically today we're talking about Section 601 of the legislation notice FDASIA, which amended the disapproval criteria for IDEs and I'll read some elements of those changes.
FDA now shall not disapprove an IDE for one of three different reasons. First, we may not disapprove an IDE if the investigation may not support a substantial equivalence or de novo classification determination or approval of a device.

If the investigation may not meet a requirement, including a data requirement related to the approval or clearance of a device or if an additional or different, investigation may be necessary to support clearance or approval of a device.

Moving to slide 8, so what this means is that an IDE cannot be disapproved on the basis of FDA's belief that the study is inadequate to support a future PMA, 510K, HDE, or De novo classification. I do note that the standards for market approval or clearance have not changed.

Moving to slide 9, so in response to changes in the law under (FDASIA) FDA developed a working group to develop and accomplish several goals. First, was to develop IDE decision policy and how we would interpret the new changes to the law in terms of implementation.

Second was to modify IDE decision letter templates. Third was to consider other mechanisms to encourage sponsors to work with FDA to develop pivotal trials that are appropriately designed to support marketing applications and fourth was to reissue the draft guidance for public comment.

I'm going to walk through these in more detail. So moving to slide 10 we're now going to move into the specifics of the guidance itself and what has changed in the reissued draft guidance.

First, explanations for the reasons for which FDA may disapprove an IDE have been changed to directly address the changes in the law. Second, information that would be communicated in FDA's decision letters has been modified. Specifically we've added a section called study design considerations, which we're going to discuss in detail in the following slides. Thirdly, there's a proposal for a new voluntary comprehensive interactive review process to assist in the development of appropriately designed cohort studies.

We're terming this process the pre-decisional IDE, this is being introduced in this guidance for comment and we will be discussing that in detail today as well.

So slide 11, now we are going to get into the meat of the guidance itself. Again similar to the original draft we are going to talk about three main decisions that can be made with regard to IDEs.

Approval and within approval we'll talk about approval of the full study cohort or approval of a staged approval, which is approval of a smaller cohort initially.

Approval with conditions and again within an approval with conditions it is either approval with conditions of the full study cohort or a staged approval with conditions and lastly we'll talk about disapproval.

So slide 12, we're talking about approval decisions. So what does an approval mean for an IDE? It means that FDA does not have any remaining questions that must be addressed prior to enrollment of the approved number of subjects. The study is approved for a specified number of enrolled subjects and investigational centers and the study may be initiated upon IRB approval.

Moving to slide 13, now we're moving to approval with conditions. So what does that mean? It means that FDA has determined that despite some outstanding issues the information provided is sufficient to justify human clinical evaluation of the device and the proposed study design is acceptable with regard to the protection of study subjects.

Resolution of the outstanding issues is not required prior to initiation of enrollment in the study with the exception of certain issues related to the informed consent document, which must be correct prior to enrollment and the sponsor may begin the study upon receipt of IRB approval on the condition that within 45 days from the date of FDA's decision letter the sponsor submits information addressing the issues identified in FDA's letter.

Slide 14, so what are some examples of typical conditions that one would see in an approval with conditions letter. Here are some examples, requests for additional information or data involving non-clinical testing issues that do not need to be resolved prior to study initiation.

Late stage follow-up procedures and assessments that relate to the care study subjects but because they occur late in the study will likely be addressed prior to subjects reaching that point in the study and minor issues related to the informed consent document that must be corrected before the study starts but can be reviewed by FDA after study initiation.

Study design related issues that don't impact the protection of study subjects should not be communicated as conditions and we're going to talk about that in more detail later.

So with either full approval or approval with conditions we have something called staged approval. So approval or approval with conditions is granted in this case while certain outstanding questions are answered concurrently with the enrollment of a limited number of subjects.

If the benefit risk profile is sufficiently favorable to justify an enrollment of a portion of the study subjects a staged clinical investigation allows initiation of a study while providing additional mitigation of risk by limiting exposure of the device to a smaller subject population and the sponsor would be permitted to expand the enrollment once an IDE supplement contained the necessary additional information is submitted to FDA and found to be acceptable.

Slide 16, so staged approval or staged approval with conditions may be appropriate in a couple of different scenarios. It may be appropriate when additional clinical confirmation of the safety profile or the potential for benefit is obtained by reviewing initial data from subjects enrolled early in the clinical investigation before enrolling the entire subject cohort.

Also it could be appropriate when additional non-clinical testing is needed to more fully characterize device performance to adequately evaluate the potential for risks of the device before permitting testing of the entire subject cohort and it's conducted concurrently with early enrollment in the clinical investigation.

There are some particular considerations for total studies that I do want to point out. Now we're on slide 17. If one is considering staged approval for a pivotal study meaning a study that is intended to support future marketing application successful support of a marketing application, staged approval is not really expected until the full plan cohort of subjects is studied.

Also a stage pivotal study should only be considered if the additional information that is requested is not expected to result in changes to important elements of the clinical investigation such as end points, sample size, stopping rules or device design.

If we're still at the stage where we're asking questions about how to develop end point sample size, stopping rules or device design then really in our opinions we're really talking about feasibility study and we're not really ready to design a typical study.

Moving onto slide 18, some additional considerations for pivotal studies. FDA determined that new feasibility data are needed prior to approval of the proposed pivotal IDE in order to allow for a comprehensive examination of the study outcomes related to the device safety profile in a small group of subjects prior to exposing a large group of subjects to the risk for the study.

So whereas staged approval is generally to answer some very specific isolated questions FDA may feel that a more comprehensive review is needed and that feasibility data would be better, would serve that purpose more optimally.

Lastly, the data requested by FDA should not inappropriately un-line any of the relevant stakeholders including the sponsor, investigators or study management personnel to critical study data.

Moving to slide 19, we're now talking about disapproval an IDE. In disapproval the sponsor may not initiate the clinical investigation until the sponsor submits an amendment to the IDE to respond to the deficiencies identified in FDA's letter and subsequently receives a new letter from FDA granting approval or approval with conditions.
Slide 20, so again we're going back now to the FDASIA Section 601 modifications to the law that impacted very significantly the criteria for disapproval that were articulated in the previous draft guidance and now have been modified in this new draft guidance.

So it is important to note that the standards for protection of study subjects remain unchanged. Issues regarding the study design that are not related to protecting study subjects are not the basis for disapproval or approval with conditions.

Slide 21, we're going to now start walking through the criteria that are the basis for disapproval. So consistent with 21 CFR 812.30 Part B and Section 520G of the Food, Drug and Cosmetic Act, FDA may disapprove an IDE for any of the following reasons.

First, there has been a failure to comply with any requirement of 21 CFR Part 812 or Section 520G of the Food, Drug and Cosmetic Act. Any other applicable regulation or statute or any condition of approval and posed by an IRB or FDA.

Next, the application or report contains and untrue statement of material fact or amiss material information required by 21 CFR Part 812. Next, the sponsor fails to respond to a request for additional information within the time prescribed by FDA.

Next, moving on to slide 22, there is reason to believe that risks to the subjects are not outweighed by the anticipated benefits to the subjects and the importance of the knowledge to be gained such as for example the investigational plan contains elements that would expose subjects to unacceptable probable risks or fails to adequately protect steady subjects from probably risks.

Next, the informed consent requires changes to adequately inform subjects of the study and must be reviewed by FDA prior to study initiation. Again, there are circumstances where changes that are needed to the informed consent are appropriate for approval with conditions. Those are generally minor changes that FDA believes can be implemented before FDA's review.

Next, the investigation as proposed is scientifically unsound because it does not pose a reasonable scientific question or the investigation does not include the collection of data or information related to the scientific question.

And we'll note that scientifically unsound in this case does not include concerns that relate to the study design in terms of it not being adequate to support a marketing application.
Moving onto slide 23, additional reasons for disapproval. There is reason to believe that the device as used is ineffective such as the available data suggests that the device is ineffective or no information has been provided to suggest that the device as used may result in patient benefit and the generation of knowledge adequate to justify the risks of the study.

Next, it is otherwise unreasonable to begin or to continue the investigation owing to the way in which the device is used or the inadequacy of the report of prior investigations or the investigational plan, the methods, facilities and controls used for the manufacturing, processing, packaging, storage and where appropriate installation of the device or monitoring and review of the investigation.

Such as the data and information provided are insufficient to adequately characterize the safety profile of the device such that the human and clinical investigation is not considered reasonable.

And I just want to note as noted here in the slides that the guidance itself goes into quite a bit more detail regarding these reasons. This is really just a high-level overview.
So now we're going to move into the IDE decision letter itself and there have been some notable changes in the IDE decision letters and we're going to walk through some of those with some specific language that you'll be seeing in those letters.

So here on slide 24 I will call out some of the specific changes. We now note whether a study is considered by FDA and the sponsor to be feasibility versus a pivotal study.
We clarify the meaning of an FDA approval, we clarify what it means to be approved with conditions, we clarify whether FDA believes that the study design is appropriate to support the study goals, for example future pivotal study or future marketing application.

We communicate important suggested modifications regarding study design now communicated as study design considerations and we describe the staged approval option in more detail.
I do want to note moving to slide 25 that we are specifically asking for comment during this comment period on our proposal to communicate important study design considerations in our decision letters.

Moving to slide 26 I'm now presenting some specific text that is quoted from our current letters for IDE approval. So I'm going to read some specific sections that are in these letters now.
So, one example is the first bullet FDA has reviewed your IDE application to conduct a either feasibility or pivotal study for a significant risk device. Later in the letter quote, "FDA has determined that you have provided sufficient data to support the initiation of a human study” end quote.

This means that there are no subject protection concerns that preclude initiation of the investigation, your application is therefore approved. Essentially, we are defining what it means to be approved.

And then for pivotal studies one of the following is communicated either: A, FDA believes that the study designed provided in your submission is adequate and may support a future marketing approval or clearance if it is successfully executed and meets its stated end points without raising unforeseen safety concerns or B, although the proposed study meets the regulatory requirements of Section 520G4 of the Food, Drug and Cosmetic Act, FDA believes that additional modifications as outlined in the study designs consideration section below are needed for your study design to support a marketing approval or clearance.

So essentially the study would be approved and then either FDA would say that we have agreement with the study design or we would point out changes that we believe are needed in order for the study design to support the goals of the study.

Moving to slide 27, additional text that is in the IDE approval letter. Please note that approval of an IDE application does not ensure that the results of this investigation will provide reasonable assurance of safety effectiveness of your device or assured determination of clearance approval for your pre-market submission.

And then if there are study design considerations if FDA does have important recommendations for improvements to the study design in order for the study to support its marketing goals this additional text will precede the study designs consideration quote "FDA believes that additional modifications are needed in order for your study design to support marketing approval or clearance. We recommend but do not require that you modify your study to address the following issues."

Moving to slide 28, here are some examples of typical study design considerations. First example, primary and important secondary end points including study success criteria, randomization control and blinding issues, follow up duration and assessments.

Statistical plan issues including sample size and power, missing data handling, type 1 error control, interim analyses in stopping rules, poolability, case report forms if not related to subject protection, enrollment criteria if not related to subject protection, core labs and independent adjudication committees again if not related to subject protection.

If these issues are related to subject protection there would be deficiencies in the letter either under a disapproval or an approval with conditions.

Moving to slide 29, some additional text that is now in the approval with conditions letters. So quote, "FDA has reviewed your IDE application to conduct a either feasibility or pivotal study for a significant risk device that is similar to the approval letter."

Next quote, "While FDA identified some outstanding issues in your application FDA has determined that you have provided sufficient data to support initiation of a human clinical study. This means there are no subject protection concerns that preclude initiation of the investigation. Your application is therefore approved with conditions, you may begin your investigation."

Later in the letter, disapproval is being granted on the condition that within 45 days from the date of this letter you submit information correcting the following issues. And then similar to an approval letter study design considerations would be included if appropriate.

Slide 30 is future considerations. Future considerations are intended to provide helpful advice to sponsors regarding important elements of the future application that the IDE may not specifically address.

So the language that would precede the future consideration section in the letter would be quote "You should also give serious consideration to the following, which FDA considers important for the support of a future submission."

Some examples of future considerations include, known limitations of the IDE clinical investigation with regard to supporting certain claims of indications. And specific non-clinical testing that while not necessary to support approval of the IDE will be needed to support the marketing application.

And similar to the study design considerations FDA is specifically seeking input on whether future considerations should be communicated in FDA's decision letters or in a separate communication to the sponsor.

For slide 31 I'll now turn it back over to (Ashley Boam).

(Ashley Boam): As Owen just described the focus of Section 601 of FDASIA and the changes it implemented to the act really focused on moving FDA's approval and disapproval decisions away from study design issues and focusing them more on device safety and subject safety considerations.

However, that being said, FDA still believes it's quite important to work with study sponsors to do the best that we can to develop studies that will support future marketing applications.
And so with that in mind we spent some time within our working group to try to think about how we could better get to what we could both FDA and the industry sponsor think about as the right study to support those future goals.

And so with that in mind we've developed a proposed program called the proposed pre-decisional IDE process. And so on slide 31 we describe a little bit about this.

It's a voluntary approach and I want to make that very clear this is a voluntary program that we are proposing here. And the idea is to enable sponsors to obtain timely feedback from FDA review staff on what is essentially a near final IDE application.

But with the opportunity for a mid-cycle interaction with that review team to promote a clear understanding and quicker resolution of major issues with device or subject safety, which could lead to a disapproval as well as study design issues.

The idea is for an interactive and comprehensive pre-review if you will of an IDE so that sponsors will be able to anticipate our concerns and submit a formal IDE that addresses those concerns.

Our hope is that this process could result in faster approval of IDE submissions that can both be initiated but also are for studies that may support market approval or clearance.

Due to resource constraints at least initially eligibility for this process would be limited to those pivotal studies, which in IDE is required and while I'll go through some more of the steps of this proposed process today there is certainly more detail in the draft guidance.

So on slide 32 I've mentioned we are limiting this to certain studies and certain sponsors. So first it's for those sponsors who are proposing a pivotal IDE study that would require an IDE.
So this means that at this time this program would not be for non-significant risk studies or studies that are intended to be conducted wholly outside of the United States.

It's also intended for sponsors that have completed the non-clinical testing typically needed to support an IDE for that device type. And for those sponsors who wish to interact with FDA about the clinical study design prior to submission of a formal IDE.

So on slide 33 there are differences between this proposed program and the existing pre-submission, which is previously known as the pre-IDE process. So unlike a pre-submission a pre-decisional IDE would need to be a complete submission as would be expected for a formal original IDE submission.

It would also need to include what’s termed a device evaluation strategy. A term that was first introduced in the draft early feasibility studies guidance but we believe has important application here.

And that device evaluation strategy is intended to address the risks of the device as well as the mitigations that are in place in terms of the testing and evaluations of device in addition to certain elements of the protocol.

And this providing this device evaluation strategy is intended to provide FDA and our review staff with a more complete picture of how the study sponsor has concluded that sufficient information has really been gathered to support initiation of human clinical trial.

Another important difference between a pre-submission and a pre-decisional IDE is that a pre-decisional IDE would receive a comprehensive review by FDA. So not just protocol's but the actual data provided from the test done according to those protocols.

And this process would result in a complete list in FDA's deficiencies to the sponsor and include this FDA sponsor interaction as part of the process.

So on the next slide, slide 34 there is an overview in bullet format of this proposed process. And then on slide 35 you'll see a flowchart that also covers this process.

So the first step in this process is that the sponsor would submit a pre-decisional IDE to our document control center and FDA will take five days or less to screen the information for completeness.

So is this a pivotal study, is this a study that would require an IDE and are the tests and other information complete? We would not accept for this program a pre-decisional IDE where the sponsor says, well I'm part of the way through this animal study and I've completed some portion of the bench test that would ordinarily be required to support an IDE.

This is really intended to be a complete review so the application needs to be completed as well. So if the pre-decisional IDE is accepted within those five days then FDA would proceed to an in depth review and that would take approximately 30 days as a regular IDE review does.

And it would be conducted in the same depth that a traditional IDE review for which that would occur. At the end of that 30 days FDA would provide communication to the sponsor of all significant deficiencies via email.

And within 15 days of that FDA would be prepared to meet or over teleconference at the sponsors preference with the study sponsor. An important aspect of this is that the study sponsor would really drive the agenda for that meeting.

So the study sponsor could ask FDA to be prepared to discuss all of the significant concerns identified or perhaps only want to discuss one or two particularly important or issues that raise concern for the sponsor.

Following that meeting or teleconference FDA would provide a full list of all and include significant and even any minor deficiencies or concerns within 15 days following that meeting or teleconference.

So if you're following along with the math at this point the total number of days in this process to this point would be approximately 65. There are a couple of possible next steps that would happen after this.

So once FDA has provided the full written feedback the sponsor has the option to take that feedback, incorporate any changes that are necessary and then submit the formal IDE and that would follow the normal FDA IDE review process.

Another option would be that if the submission raised a few issues at the initial review that such that the IDE if it had been submitted as a formal IDE the submission could have been conditionally approved.

The sponsor has the option to request that FDA convert the pre-decisional IDE to a formal IDE and FDA would issue it's decision letter within 15 days. So there is a shorter version if the sponsor feels that the concerns FDA has raised would not have precluded an approval or approval with condition.

If on the other hand FDA's feedback has raised a number of issues for which the pre-decisional IDE sponsor finds it would be helpful to engage in further interaction with FDA the sponsor has the option to submit a focused response to certain of those issues for which they would want additional feedback.

If they submit those within 30 days FDA could provide comments by email or if FDA believes that further interaction would be helpful we can repeat the process of going through the complete review and having another FDA sponsor interaction through a meeting or a teleconference.

If the pre-decisional IDE sponsor wants additional feedback but takes more than 30 days to come back to the agency that should then come to us as a traditional pre-submission. As I mentioned the draft guidance includes more details about the process as I've described it today.

So moving to slide 36, we do believe there are a number of potential advantages of this type of program. It would provide an opportunity to get FDA's comprehensive feedback outside of a formal deficiency letter, which if there were subject safety or other device safety concerns could have been a disapproval letter.

It would also provide the ability to interact directly with the review team very quickly after receiving that feedback. FDA has also made the commitment in the guidance document to stand behind our feedback that we give as part of this process unless something changes between the pre-decisional IDE and the formal IDE submission.

So if you go through this process you should be sure of getting the same answer for the same information submitted in the pre-decisional IDE and then in your subsequent formal IDE.

We also believe this process would provide an improved likelihood of receiving what we might call a clean letter. So a letter that not only says you're approved to start your study but also states clearly that FDA is in agreement with your study as being adequate to support a marketing application.

And we believe this may help to eliminate many of the challenges that have been reported to us with sponsors working with IRBs and third-party payers regarding the current IDE letters that they received.

And ultimately we hoped that this type of program will lead to more well designed trials that result in better quality marketing applications that then really leads to quicker patient access to safe and effective devices, which is part of our strategic priority.

There are some considerations as part of this process however. There is some additional time to the process as I mentioned to go through the feedback loop and to get FDA's complete feedback following the meeting, it's about a 65-day process.

And then the submission of the formal IDE would add another 30 days to that. However, if going through this process results in a clean letter on the first round of the IDE submission this actually may take less time than going through multiple rounds of approvals with condition or an initial disapproval decision followed by rounds of approvals with conditions.

There are additional resource implications for FDA, we believe however if the the subsequent IDE that's submitted identifies that the majority of that submission is identical to the pre-decisional IDE and only points out where there are the new information that addresses the issues we raised as part of that process our review of that formal original IDE could be much more efficient.

As I mentioned there are differences between this process and the existing pre-submission process and further we don't review this as a replacement for the pre-submission process.

We think the pre-submission process is still a very important way to work through complicated trial design and other issues related to an IDE that's in development. And we think it's an important process for sponsors to use as they are working through various development stages of their device.

Finally, this process may not be right for every sponsor. We envision that there will be certain IDE sponsors that would find this helpful and others that don't think that the balance of time and input from FDA is really right for them.

So we are specifically seeking input on this proposed process from our stakeholders. Particularly industry but also other stakeholders whether they believe this is an important use of FDA resources to help improve the clinical trials that are conducted to support marketing applications.

We're interested in hearing from IDE sponsors whether they would use this process, if there are elements of it that would make it more attractive or certain elements that make it less attractive or less useful given your experience with the IDE program.

So we have mentioned today on slide 38 we've mentioned several sections where we're asking for your comments and we really do want comments from all of our stakeholders out there.

Specifically on how FDA should be communicating study design considerations, how we should be communicating future consideration and then the proposed pre-decisional IDE process that I just walked through.

So how do you find this guidance if you haven't had a chance to read it yet and how do I provide comments on slide 39 is the link to the guidance document on our Web site.

And to provide comments you go to the regulations.gov Web site do a search and search for IDE decisions and there's a nice big box that says comments now.

So please provide your comments by September 12, 2013 that's when the docket closes. We really appreciate those who take the time to provide those. So I've included contact information for Dr. Faris and myself here on slide 40.

And I believe at this time we can take some questions, thank you for your attention.

Coordinator: Thank you this concludes - if you would like to ask a question please press star 1 on your touchtone phone. You will be prompted to record your name, to withdraw your request you may press star 2.

Again to ask your question please press star 1 at this time, one moment please. (Amy Walters) you may ask your question.

(Amy Walters): Yes is the pre-decisional process is that active now or is that pending the issuance of the final guidance?

(Ashley Boam): Thank you for your question. At this time it's simply a proposed process and we are not actively accepting submissions. We are considering whether to announce a pilot program but it would be after the end of the comment period if we do that and there would be a formal announcement that we were accepting submissions as a pilot.

But that's still under consideration and maybe certainly impacted by the comments that we receive during the comment period.

(Amy Walters): Thank you.

Coordinator: (Rena Starks) you may ask your question, Ms. (Starks) your line is open please check our mute button.

(Rena Starks): Hello I am asking this question in accordance with emergency introduction of new drugs. If you are in the process of doing the emergency introduction of new drugs and you need an emergency device do you have that open for access also?

(Ashley Boam): I'm sorry I'm not familiar with the emergency access to new drugs provisions. We do have a number of provisions that allow access to investigational devices including emergency use as well as compassionate use and treatment use and there is information about those on our Web site.

(Rena Starks): Thank you.

(Ashley Boam): If you want to send me an email after this audio conference I can put you in touch with our IDE staff and some more specific documents to that affect?

(Rena Starks): Wonderful that's awesome I will.

Coordinator: (Clarie Damico) you may ask your question.

(Clarie Damico): Yes my question pertains to the ability to convert to a formal IDE specifically not for the pre-decisional IDE but for the pre-submission. Is that option available in the pre-submission and will that also result in a shortened response time?

(Ashley Boam): That is not an option for the pre-submission process primarily because the pre-submission process is intended to really be a focused review instead of feedback.

So for the pre-submission process we ask that you provide us focused questions upon what your feedback and so that would typically be for example a clinical protocol, which filters questions about the protocol.

Or it would be a proposed animal study protocol with focus questions about the protocol but the pre-submission would not include the data from that test protocol and we would not typically review data from a protocol where the testing is being conducted as part of a pre-submission.

So there's not really the ability to convert a pre-submission to an IDE because it would be incomplete.

(Clarie Damico): I see, thank you.

Coordinator: (Patricia Linton) you may ask your question.

(Patricia Linton): Yes my question pertains to the impact of these new regulations on the CMS IDE petition approval that is necessary (unintelligible) can bill for a category B investigational device.

How will the staged cohort IDE approval or the approval with conditions be it full or staged impact the IDE petition process? In other words will Medicare look at a staged approach and say that - and not approve the IDE petition effectively holding up the start of the study.

Owen Faris: So it's a good question we've certainly been in touch with Medicare and had a lot of conversations to make sure that they fully understand our letters and what we are conveying in them.

It's really a Medicare decision as to how to reimburse for those studies so I think that, you know, we can't really fully answer your question, you know, I think all that we can do is make sure that both that we are being very clear with Medicare so that it's full understanding in terms of how we are making our decisions and what those decisions mean.

(Patricia Linton): Okay it's just it's effectively even though you say the study may begin just so that obviously you're aware that you can't begin a study unless you can also bill for it.

So it's a catch 22 for the investigators so thank you and we'll be pursuing that as we get conditions with approval or IDE approval with condition rather letters and see how RFI responds.

Owen Faris: We certainly understand the importance of reimbursement and also frankly IRB approval and that frankly that's a great major part of why we modified some of the language in our letters to add clarity regarding what it means to be approved, what it means to receive approval with conditions, what it means to be disapproved.

We are trying to make sure that at the very least everyone is making their decisions with full understanding of how we got there.

(Patricia Linton): Thank you.

Coordinator: (Freda Missery) you may ask a question.

(Freda Missery): Sir, will you be clarifying the process for treatment determining - devices that are treatment determining that are for studies that are also being conducted under an IND?

Will you - is there a way to clarify how CDRH and CDER may interact?

(Stacy Beck): That's under a different process that's called a - I'm sorry this is (Stacy Beck) and I work in the office of vitro diagnostics and radiological health. And that would be done under the companion diagnostic process.

So we work with CDER regularly and as you probably know you can submit either an IND or IDE for a joint drug and device trial and we work together with CDER to help to make a determination on that submission.

I don't know that the pre-IDE kind of process here that (Ashley) has laid out would be the best way to do that but it's not necessarily precluded either. So I would definitely put that in the comment section of the draft guidance so that we can investigate that further.

(Freda Missery): Thank you.

Coordinator: (Erin Corday) you may ask your question.

(Erin Corday): I'd like to know if we should expect a follow up letter with the FDA determinations when we receive a letter in response to electronic submission that indicates the IDE study may begin in 30 days unless you have concerns? I'm paraphrasing because I don't have one of these letters in front of me.

Owen Faris: Right so I think you're referring to the acknowledgement letter that's received when you first submit an IDE is that correct?

(Erin Corday): Correct yes.
Owen Faris: So, yes that - so if we miss a 30-day review clock for an IDE what happens is they - there's quote "They are deemed approved." That's extremely, extremely, rare so almost

always you will receive a follow up letter with a decision within 30 days or receipt of the IDE.

(Erin Corday): Thank you.

Coordinator: (Leanne) you may ask your question.

(Leanne): The question has already been asked, this had to do with the interface between IDEs and INDs so OIR answered the question already thanks.

Coordinator: (Mike Shenekky) you may ask your question.

(Mike Shenekky): Sure, thank you. My question is with regard to if you get an IDE approval with let's say some design considerations and you, you know, take the feedback and you get your - you amend your protocol and you get your IRB approval does CDRH want a courtesy copy of the final protocol that was actually implemented in the field?

Owen Faris: So that's a great question I'm really glad you asked it because in fact it's more than a courtesy copy. We actually do need to receive a supplement from you modifying your protocol.

We will review it and make a determination. We do want to make sure that we are comfortable that the changes you are making aren't impacting the protection of subjects in the study.

So you do need to submit a supplement that we will review and render a decision on prior to you implementing those changes.

(Mike Shenekky): I guess my question was is you've already determined that you approved the IDE so you assessed that its safe but you - it not necessarily would it affect, you know, maybe support a marketing application but with these changes, you know, it might be closer to what you want.

Owen Faris: Right.

(Mike Shenekky): I'm just wondering, you know...

Owen Faris: So it is extreme - right so it is extremely likely that those changes that you would make would be approvable as well but you actually are required to submit a supplement to make those changes because many of those studies and considerations are suggesting changes to the protocol, some changes to protocol can impact the protection of study subjects.

We also need to have on record what is the approved protocol for the IDE. So you need to submit a supplement that describes those changes. We will in most cases approve those changes and render a decision and also give you feedback on whether we think you have now created a study, modified your study such that it does meet its goals.

If we send you a letter and approval letter, which study design considerations and you make modifications and submit that supplement to propose changes to address those study design considerations if we agree that they have in fact been addressed our letter will reflect that.

And say that we now believe your study is adequately designed to support its study goals.

(Mike Shenekky): Well thank you very much.

Coordinator: (Kathleen Chester) you may ask your question.

(Kathleen Chester): Yes while I agree that we need a more formal pre-submission process I'm really struggling to understand the benefit of the pre-decisional IDE because if you need to have your full submission complete at the time you do your pre-decisional there really doesn't seem to be any advantage other than I don’t get my feelings hurt that I get a disapproval letter.

And it seems that it would be more helpful to be able to do a pre-decisional IDE on the clinical aspects, have those fully done, submit that in parallel while you're pre-clinical testing is still ongoing and get some really solid feedback from FDA earlier in the process.

(Ashley Boam): So thank you for your comments. Certainly there's the ability to have a fairly in depth discussion about your clinical trial protocol as part of the pre-submission process while your pre-clinical testing is ongoing and that's still an important part of the pre-submission process.

I will note however that we have found that a fairly substantial proportion of original IDEs are disapproved on the first round not because of clinical trial issues but actually because of non-clinical testing issues.

And so one of the advantages, potential advantages of this process is that unlike the pre-submission process from a non-clinical testing perspective in this process you would actually get a full review and you would have this automatically set up meeting or teleconference within 15 days of getting that letter.

So right now if you send a formal IDE and we disapprove it it's unlikely that we would be able to accommodate a meeting request to meet with you within 15 days of having issued that letter.

And so in this process you would have that opportunity immediately to sit down and talk with a review team. We've also had some feedback from industry sponsors that where they've had an initial disapproval letter then worked through the issues sufficient to get to, you know, approval with conditions or full approval letter.

And they have submitted that to IRBs or to payers to get reimbursement. They've had requests from those payers or IRBs to see the original disapproval letter because FDA's, you know, follow up letter will say we've reviewed the response to our June the 1st, 2013 disapproval letter and you have answered a sufficient number of questions but now you are approved of conditions or you've answered all of our questions and now you are approved.

And that - those third-parties would say, well there was a prior letter we want to see it and that that was causing issues because the IRB or the payers were asking questions about deficiencies from the original disapproval letter and not really focusing on the letter that says that the sponsor could start this study.

And so where folks have had that concern this process allows for more informal process to get all of those issues on the table and get them resolved before the formal IDE comes in.

(Kathleen Chester): Thank you.

Coordinator: (Nina Moore) you may ask your question.

(Nina Moore): Hi, I was wondering if you could clarify if an IDE would be required when using an in vitro diagnostic in a phase one study?

(Stacy Beck): Yes it depends - sorry this is (Stacy Beck) again with the office of vitro diagnostics and radiological health. Basically it depends on what the IDE or the diagnostic device is being used for in that phase one study.

So as they - was kind of alluded to in the presentation it depends on whether it would be considered a significant risk device and that can have to do with whether you're using it to select patients for therapy that they would not get otherwise or they would not get the therapy that they would have gotten otherwise.

And that can push sometimes push it into what would be a significant risk device. So it really depends on the study design and what - how you're using the device.

So I would recommend coming and talking to our group the office of vitro diagnostics and radiological health to determine that beforehand so you can do that in a pre-submission process.

You can also submit as part of your IDE or I'm sorry your IND and (CDER) would meet with us and work with us on that.

(Nina Moore): Okay thank you.

Coordinator: (Evelyn Lopez) you may ask your question.

(Evelyn Lopez): Yes hi thank you. My question is a follow up on the significant risk study versus non-significant risk study. My understanding is this guidance document is really - is applicable only to significant risk studies or significant risk devices am I correct?

Owen Faris: Yes.

(Evelyn Lopez): Thank you.

Owen Faris: Yes, you are correct.

(Evelyn Lopez): Thank you, another question is - I'm sorry. The decision of the pre-decisional IDE at one point FDA has the decision agreement meetings. How do these decision agreement meetings relate to the pre-decisional IDE process?

(Ashley Boam): So the formal early collaboration meetings so determination meetings and agreement meetings are both - they were established in the statute and they are still in existence.

So a determination meeting is a request for FDA to make a determination about the type of clinical study needed to demonstrate effectiveness. And an agreement meeting is intended to provide an opportunity for FDA and the sponsor to reach agreement on specific elements of a clinical trial protocol.

Those are both formal processes and the decisions are binding on SEA unless there would be a public health concern should we follow them. And so both of those meeting types are still in existence and are not replaced by these less formal processes.

(Evelyn Lopez): Thank you.

Coordinator: (Ann Marie Hipley) you may ask your question.

(Ann Marie Hipley): Yes, my question is actually two-fold because another person brought up another thought but the first question is if you're doing human clinical studies internationally and you basically want to do the pre-decisional process to vet out your design and your non-clinical let's say testing issues if any exist because of this in depth look at the protocol.

Would this be an appropriate pathway to vet those out prior to determining your device, you know, changes and modifications rather than to get in, you know, go forward in the process and determine that there does need to be made a change?

Owen Faris: So my understanding that you are talking about the scenario where you would be conducting your clinical study outside the U.S. but you want to finalize your device design and want to know if FDA would have any concerns about the pre-clinical testing and the final - on the final device design before your proceed with that outside the U.S. clinical trial is that what you're saying?

(Ann Marie Hipley): Correct, yes.

Owen Faris: So the pre-decisional IDE process as the scope of it at this stage is strictly for studies that will be conducted under an IDE in this country.

((Crosstalk))

(Ann Marie Hipley): I mean that's obviously the plan...

Owen Faris: Right.

(Ann Marie Hipley): ...is to take the next step would be to take our data to do the process in the U.S. but is there benefit to vet out the protocol and the design changes now prior to, you know, submitting that pre-IDE?

Owen Faris: So we do under the pre-submission process we are very happy to look at pre-clinical testing that a sponsor has done for a device that will be tested outside the U.S.

We are also very happy to look at a proposed protocol that will be conducted outside the U.S. under the pre-submission process. It isn't this sort of complete entirely comprehensive review that we're describing for the pre-decisional IDE.

But we do consider that to be very important we recognize that a lot of devices are primarily tested in the clinical environment outside the U.S. and that it's most efficient for those studies to be conducted in a way that is consistent with what our expectations would be in the FDA.

Both in terms of the study itself and the pre-clinical testing that would go into support that future marketing application. So we're very happy to talk with you the pre-decisional IDE process isn't the mechanism to do that.

(Ann Marie Hipley): And how soon or how early do you recommend people to do that in the process of things, as soon as possible?

Owen Faris: Really as early as you have something that we can review and have an informed discussion on with a specific question or questions that you have in mind that you want feedback on. So that can be very early.

(Ann Marie Hipley): So that could be just simply vetting out the protocol even if we haven't started the human trials.

Owen Faris: Absolutely and would be advisable.

(Ann Marie Hipley): Okay and then the second question I have is the terminology. So you say that a large percentage or I think it was actually like I said are non-clinical testing issues, which create disapprovals. Define - could you define what that is, non-clinical testing?

(Ashley Boam): So that could range anything from about compatibility concerns to bench testing to inadequate software validation to sterility concerns, really anything in the non-clinical bucket.

(Ann Marie Hipley): Okay.

(Ashley Boam): Animal study concerns in terms of either how the study was conducted or the results, you know, we see, you know, testing that's done on, you know, bench testing that's done where to few samples are used or the samples aren't representative of the device that's going to be used in the trial, all sorts of those types of issues are very common.

Owen Faris: Anything basically for which we believe that the data provided on that particular test don't yet fully or adequately support the safety profile or the potential for the device to be effective.

(Ann Marie Hipley): Got it, thank you. I think this would be extremely valuable for people doing studies outside of the U.S. to start early I think it would be fantastic so there's my first comment for you.

(Ashley Boam): Thank you.

Coordinator: (Jose Cabrera) you may ask your question.

(Jose Cabrera): Hi thanks the question was essentially answered so the - regarding CMS interaction I think that's a very important aspect of this so thank you for answering that.

And earlier you also mentioned the reason for IDE deficiencies are the pre-clinical just like the lady spoke earlier. Is there data that the FDA is currently publishing that reflects reasons for IDE rejections or non-acceptance are those statistics available? That's all.

(Ashley Boam): At this point we don't have good statistics on that. We have done some sampling and internal reviews but it's been more of a manual process to go back and try to identify what are the types of reasons why IDEs don't get off the ground.

And so we don’t have anything that we are able to put out publicly but we are, you know, looking toward the future recognizing this is something we need to be able to track more closely and more accurately.

So hopefully going forward we will be able to share those types of statistics with you.

(Jose Cabrera): Okay last question, the CDRH form for the informal process do you foresee the form changing?

Owen Faris: I'm sorry could you repeat the question?

(Jose Cabrera): The CDRH form that's used for submissions, the informal process that's being promoted is that still through all correspondence still through or more informally not using the form?

(Ashley Boam): So are you referring to the CDRH cover sheet?

(Jose Cabrera): Correct yes.

(Ashley Boam): So at this point the CDRH cover sheet has been recently revised to reflect the addition and sort of terminology changes to the pre-submission process. If we go forward with the pre-decisional IDE process I imagine we will try to make some changes to the form to have an appropriate place for that to be checked as well but it's a little premature at this point since it's a proposed program.

(Jose Cabrera): Great thank you, that's all.

Coordinator: (Greg Kuhns) you may ask your question.

(Greg Kuhns): Thank you the question was answered concerning combination devices.

Coordinator: Once again if you would like to ask a question please press star 1 at this time, one moment please.

(Ashley Boam): If there are no more questions on behalf of Dr. Faris and all of here at CDRH we'd like to thank you very much for joining today. Again we very much...

Owen Faris: We've got more questions.

(Ashley Boam): ...I'm sorry.

Owen Faris: We just got some more questions.

Coordinator: We did have a few more come in, (Nathan Manzer) you may ask your question.

(Nathan Manzer): Hi I have a quick question for you. How does the recent deadline of June 30 for the (ANC) 60601-1 2005 edition safety testing guidelines affect existing and future clinical studies here in the U.S.?

(Ashley Boam): I'm sorry we don't have the technical experts in the room that could answer that question but if you would like to send it to me via email I'd be happy to put you in contact with the right folks after the audio conference.

(Nathan Manzer): Okay great.

Coordinator: (Unintelligible) (Rivera) you may ask your question.

(Rivera): Is there a fee associated with this pre-decisional program, an additional fee other than the IDE submission?

(Ashley Boam): There is no fee for the pre-decisional IDE process, there is no fee for an IDE and there is no fee for a pre-submission.

(Rivera): Great.

Coordinator: And our final question comes from (Sue Autey) your line is open.

(Sue Autey): My question here for the panel is that is - since this is a proposed program we are already getting a system in my last IDE letter I got from CDRH that it is already implemented.

Is this implemented are we bound by this new guidance document or are you following still the old guidance document?

Owen Faris: Right, so this is Owen so this is a little bit of an unusual guidance document because it is both proposing new elements but also reflecting what FDA had to implement to be consistent with legislative changes.

So our letters were changed shortly after FDASIA was passed. There have been subsequent minor modifications since but we had to be consistent with the law immediately and so this guidance reflects those changes and describes them.

And while we are still very open to comments there any modifications we make would have to be consistent with the law that was passed on July 9 of last year.

So those elements, you're right you've seen those in the letters and essentially the guidance is describing what you are already seeing. What is really new and out for comment in terms of that has not been implemented is the pre-decisional IDE process.

We have not implemented that, that is FDA's efforts to try to help get more studies to a state where not only are they approvable but are the right study that we all agree with in terms of supporting the goals of that study.

But you're right the letter's right now reflect our interpretation of the law and our efforts to be consistent with it. We have implemented study design considerations we have implemented staged approval.

We will certainly - we are certainly very interested in your comments on our approach and our method of implementation but we are under that policy now.

(Sue Autey): Okay, can I have a follow up question to that?

Owen Faris: Sure.

(Sue Autey): Is that in this design - study design consideration there are things in there that I - in the letter for example that it seems like the design study consideration creates a lot more risk to the company in the back end because FDA could later (unintelligible) doesn't affect the safety of the study but, you know, we would like you to do ABCD, which you didn't do.

And so because of that after running a 500 patient study we're not going to approve your study. How do you avoid that kind of...

Owen Faris: So our strong recommendation is that you come in with a supplement to make modifications to address those considerations. These are for the most part considerations that prior to July 9 of 2012 would have been some sort of deficiency either an approval with conditions letter or a disapproval letter.

Now they are not deficiencies and you may proceed with those studies but these are considerations that we think are important to be addressed in order for that study to meet its goals.

And we strongly urge you to make changes to address them, to come in and discuss with us if you have questions. Certainly it's very typical for a sponsor to come in with a pre-submission to discuss some of these issues.

And on our part we are going to great efforts to make sure that the issues that got identified as study design considerations such that the language in the letter says that we think you need to make these changes in order for your study to meet its goals that those issues are really important issues that rise to the level of supporting those kinds of statements in our letters.

And, you know, again our recommendation is that you address them and we'd like to talk with you about them.

(Sue Autey): Okay thank you.

Owen Faris: So I believe that we have gone through all of the questions and so now I'll do the sign out this time. And so now on behalf of (Ashley Boam) and the others who have piped in here (Stacy Beck), I'd like to thank you for your participation and for your great questions.

And again encourage you to offer any comments to the docket on the link on the last slide from this slide set or second to last slide prior to the end of the comment period.

Woman: The recording.

Owen Faris: And there will be a recording posted shortly after this call, thanks very much.

Coordinator: This concludes today's conference, thank you for your participation and you may disconnect at this time.

 

END

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