 So first I want to thank you for the organizer for inviting me to speak here today. My name is Jelena Berglund and in light of all discussion that we had today I feel that I didn't make a slide but I would like to say a few words about our office. And I'm looking at Dr. Berk here because he really voiced the need of having a regulatory group outside of IRB that will not be focused just on IRB applications although we work closely with IRB but really regulatory group that will support investigators in different ways when it comes to communication with the FDA. So our group is still mainly funded by CTSA grant which is one of the NIH grants and we got that and our group was formed in 2009 and actually Rob Caleb who is now commissioner of FDA at that time was PI at Duke and he had that idea that academic institution should have a regulatory group that should be able to help investigators in their FDA communication and to be free of charge. So we are free of charge and we so far worked with over 300 investigators, we did over 500 submissions and yes mainly they are drugs and biologics although in the last few years it's been a lot of devices. And as many of you mentioned today we work on a lot of devices but not a lot of them raise to the level that needs really an IDE and need to go to the FDA. So this is who we are and somewhere through our slides it will be linked to our website. We do work with investigators in other academic institutions so I would encourage any of you who are having any kind of regulatory questions and you are academics and not a company feel free to contact us and we might be able to help free of charge. So since we came to the point of so you determined the risk you had a discussion with the IRB or you knew up front that this would be significant risk study so now we are at the point where actually you need to submit an IDE and you also this is not the first slide outlining the content of IDE today so you heard from many speakers of what were the main topics and how you should put the idea together I really just try to so this will be pretty like organizational type of presentation what do you need to have and how you should be organized to send the application to the FDA. So the script itself is outlined in 21 CFR 312 so if you go to the FDA website you will see exactly those sections which we try to follow so we heard back from the FDA reviewer in reviewers in different offices that they like to know where to find your documents so they don't go through all like 700 pages in order to find risk assessment you should try to follow if possible this 14 outline sections if you're sending paper submission it looks slightly different if you're doing electronic obviously and I will go through some of those sections today in more details or less and here is a list link to our website that will take you to a lot of templates because through this slide last eight nine years of work we really okay every application is different and it will have a lot of specifics that you need to put in so it's not really simple you just open the template as I'm filling in but in general work is easier if you don't start from blank page open word document new so we created many templates including templates for how to have pre-submission meeting based on FDA guidance which is great guidance how to put ID together risk assessment templates and these were some other device things mainly drugs and biologics so first thing that we go through is a cover sheet which is also known as form 3514 we tend to sometimes use it sometimes not different from our drug submissions that always have 1571 and they have this form 3514 that is actually not obligatory to use so you don't have to use it if you don't want to and sometimes we do sometimes we don't the reason for not using it is that beside ID information it's a form that is used for 510 K PMA application scheduling the meetings reclassification request and stuff like that so they will you will see it's a five page long and there are sections that you really don't necessarily need where we find it very useful is when we are scheduling pre submission meeting and then we want to outline different standards that we use for our testing that's where we usually use this form not necessarily for ID submission but nothing wrong with using it actually I'm sure they might like it if you choose not to use it please outline in your cover letter that this is a original submission otherwise it could be a amendment report or supplement which kind of device what is the name of your device and some basic information about your device name intended use so to give reviewer just heads up what what is this application about who is the sponsor and manufacturers sometimes might not be the same entity or same people so you want contact information there and if you had any previous discussion with the FDA which we now strongly encourage our investigators to have so if you had a pre submission meetings and you have identity therefore you have this pre submission numbers so that we would like you are encouraged you to put in your cover letter so have the reviewer will receive your application and we'll could first of all know what this is about but also can go to the previous minutes and communications that had with the group and identified what where where did you where you are now with your device development second section is a name and address of the sponsor that's self-explanatory third would be a report of prior investigations and it really could be a very lengthy section or could be quite short we had it either way in situations in which you have investigator that is using at the approved device so there is a label obviously it's using a tough label because that's why you need an IDE you might just refer to a label and if someone was using a tough label similar to what you're gonna be doing you might want to list that previous publications and other or if there are some bench studies that you did or animal studies you want to outline but really we had it sometimes as short as just refer to order the FDA approved label because we were using it in a very similar manner but it was PMA device so we needed IDE sometimes and this majority of cases device in question is not have the approved device and this section then we can be quite lengthy because then we are listing all bench studies that you did where animal studies were done as a GLP or not and if not to what were the exemptions of GLP requirements if there are any clinical studies or pre-clinic other pre-clinical studies or clinical studies that someone else did then you would like to refer that to this would all go in a section three section four is investigational plan which is actually quite lengthy and has a couple of subsections here one is first purpose name and intended use and the purpose of your study what is the name of your device and intended use clinical protocol goes in this section risk analysis is something that we have quite lengthy discussion with investigators about there is a great guidance from the FDA how to make proper risk analysis because quite often risk analysis investigators take from protocol saying risk associated with these devices internal bleeding let's say which is true and that could be true and should be mentioned but general risk analysis is something that at least got we got as a feedback from the FDA that they see it is a very important and I'm looking forward for FDA people here in the room commenting do they feel that way but the guy if you look at the guidance itself and that we have template as well guidance is a self provided you with a quite nice description of how you should do risk analysis and you should start at risk analysis as soon as possible and even if you don't have a ID that you're gonna be submitting risk analysis something very useful for your device development so thinking it like mathematically kind of you would like to divide your whole risk into two parts one what is the risk associated with device itself what device breaks what if device bands what device give a wrong result so what is the risk associated device and then a separate part is what is the risk associated with the procedure that you need to utilize when using device and then what is the frequency of those risks some things can be very risky but chances of that happen can be one in million and the other things can be you know not so risky but they can be quite frequent and you don't want to have situation of death of thousand needles so once when you outline the risks you outline the frequency or what you think frequency will be or maybe experiments that you do to show the frequency of that needle banding let's say then you can outline the steps that you're gonna take to mitigate those risks in some way and some of course we realize cannot be completely eliminated but if you can mitigate them how you're gonna go about it so that would be risk analysis on our website to the link that was on a second slide we have a template for risk analysis with some guidance so you might find it helpful then we have description of device that would go all the figures drawings description of your device basically monitoring procedures that again working in academic institutions sometimes investigators identify as just safety risks but monitoring really procedure is monitoring not just for safety events but in general has the study being conducted according to the protocol are informed consents collected as it's supposed to be are they properly signed is the proper version of the protocol use and all the risk associated with the study itself not just safety risks any additional records or reports that you might have you want to outline here manufacturing information again section that can be sometimes small but most of the time is is actually quite a quite big one and and take some time to put everything together we see it I kind of try to divide into three parts they pan based on the complexity we will have investigators that are using FD approved device of label or they start with FD approved device and then they do some modifications so it's not anymore at the approved so that will be let's say the most simple case scenario sometimes we have investigators that are using non FD approved device but their contract in the company or they are collaborating with the company that is mating making that let's say IVD so they are not doing it they're not making the selves in the in the lab and they are not maybe even familiar with the way how is device manufactured that's medium complexity and the third one we have when device is non FD approved and that's something that you are building in house and we have diagnostic devices like that for different type of in vitro diagnostic actually so how do you go about it if device is approved you're using it off label you can just refer to a label FD review that manufacturing process when approving that device if you're not making any modification that should be just enough if you're making modification then you refer to the label and you describe which kind of changes you're making how did you make those changes what are the tests that you did to show that specifications are met or new specifications are met so that is add some complexity and the third scenario when someone else is making that device for you would lead to this letter of authorization which someone brought up as how do you refer to someone else proprietary information so if you are working with a company or another investigator that is making a device and he or she or company allows you to refer to their manufacturing information or their previous human experience or any kind of testing that they did in order for FD reviewer to be allowed to go and look at those proprietary information the company or a person need to send you letter of authorization that letter of authorization has to be sent to the FDA to their documentation as well as copy of letter needs to be sent to you so letter of authorization is what you need to have to be allowed to refer to someone else proprietary information and this is what it says it can it is from sponsor or company to their IDE it can be their IND and that we had sometimes for using the columns for cell therapy for example to their master file if they had master file just for device manufacturing thus the FDA reviewer will have a permission now to look someone else proprietary information in in relation to your study and of course copy of that letter as I said you need to include in your submission section 6 would be investigators agreement there is no form at the FDA site not yet developed form for investigators agreement so our group made based on what investigator agreement really is and I can open those things but based on what investigator agreement really is we made like a template similar to 1572 form that we give to investigators as them to sign and by signing that and checking box there and enclosing their CVs that basically complying with all those regulations so you what you want is as a sponsor you don't want to allow anyone to be part of your study or any investigators to be part of your study you don't want to ship your device or any results to another investigator that will be part of the trial before that investigator signs investigators agreement so you as a sponsor you are ultimately responsible what's going on in your study so someone else this morning defined the the sponsor so if you look back in those slides you will see who actually sponsored and who is investigator but basically is a sponsor what you want from investigator is CV as well as statement that investigator has a relevant experience that it was if it was involved in some type of investigation that was terminated by the FDA then it has to explain the circumstances financial disclosure information is not something that at this stage FDA needs to know but you as a sponsor would prefer to have financial disclosure from investigators participating in your study so there are known some negative surprises towards the end of your trial as well as investigator signing here the commitment basically that gonna conduct investigation according to agreement supervise all the testing ensure that informed consents are met and you will see if you go to those regulations there are a couple of more statements basically that investigator signs in order to be allowed to participate in a study once when you collected investigators agreement in your IDE you can just this is really just a sentence and it's present in our template already saying yes I will not allow anyone to start and be part of the investigation before signing investigators agreement so it's really just a statement you need to disclose RB information who will be the RBS that will be reviewing your protocol or your clinical study name and address of all investigators institutions or sites that will be participating financial claims which are different from financial disclosure in in some cases maybe even majority of cases when it come to device study we see situations when investigators are actually charging patients for participating in a study because insurance would not cover even FDA approved device to my knowledge if it's used as a part of clinical study so in this financial claim section what you really are explaining is that you are charging in order to recuperate the costs and cover the cost of device but you're not making any profit because you're not allowed to make a profit from clinical study obviously environmental assessment is a section that still exists in CFR but it's not really needed since last I think three four years so we just have a statement that it's not applicable but we kept the script according to CFR copies of all the labelings that you have and it will be put on a device including the statement that this is I know by heart but like prohibited by federal law for investigational use only because any device even FDA approved once when it's used in off-label manner obviously as a part of clinical study it's investigational device copies of informed consent they can be drafts in your initial submission you don't have to have them IRB approved and speaking of that you don't have to have your protocol IRB approved when you're submitting your ID initially you just have to have a draft of it and ultimately both IRB and FDA should have identical protocol and informed consent but at this stage you're basically getting feedback from AFDA and from IRB and any additional information if it's a pediatric population if it's involves any kind of radioactivity or any additional statements import information anything else or export anything else that you feel that FDA needs to know and you couldn't fit in any other area can go as a part of additional information here so we came back to the list that we started from again if you go to this website you will find actually couple of templates templates for IMD you will find templates for risk assessment template for investigators agreement template from protocol based on ICAG6 so a couple of things that you might find it helpful and ultimately we'll find our telephone numbers if you're coming from academia feel free to give us a call I know that David we speak a little bit more about how to to really do a submission so I kept this slide very abbreviated but basically this is current address of CDRH that's where you should send it since 2012 I think September in addition to paper copies actually you are required to send electronic copies which is different from ECTD submission this is just electronic copy that is on CD or it can be on flash drive or DVD and most of the times they're identical copy to your paper copy but it could be different and we had the situations which an investigator wanted to include movie clip of how device is really operating it was robotic so we wanted to have that as a part of e-copy in the in which case you have to acknowledge in your cover sheet or cover letter that paper copy is missing section so and so again very good guidance on how to prepare e-copy so you don't get on e-copy hold or anything like that which font you should use which adobe version how to how to name them because there is naming nomenclature that you need to follow this is a guidance that can very well that very well spells out what you need to do to don't end up in this like technicality issues and what i've been asked to because this was a very short overview of how to put ID together in look very simple and sometimes it really is sometimes it's much more involved as we heard today um what i wanted to say is that initially we had a training program basically or mainly for drugs and biologics but with the recent needed uke we developed last two years a medical device training program that is again free of charge for anyone and it can be attended remotely via webex we had people from an age we have even people from fda and people from company joining us and we would love you to join but also get the feedback if we can improve something and this is a link to our training program it goes over significant non-significant risk assessment what is abbreviated id how do you put id together what we have actually it's quite good because we have over 500 submissions with the fda our participants after signing confidentiality agreement are actually allowed to see real fda submissions as well as correspondence that we got from the fda which can be useful to see which kind of level of details they requested then what kind of feedback we got so if you're more interested in that it lasts six weeks you're joining via webex one hour per week and then you do your homework by seeing and reviewing those applications remotely and confidentially obviously so if you're interested more in that you can go to our website and contact the program coordinator and find out more about it and based on the time i'm happy to either take questions now or how would you advise or or wait for a panel discussion okay