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antimicrobial antifungal and antiviral siddik IND NDA applications and she's also an active member on many agency committees and then we have Miss Judith Millstein she joined cedar as a consumer Safety Officer back in 1999 in the division of anaesthetic critical care and addiction drug products she then joined the division of anti-infective drug products in 2001 as a regulatory health project manager and she became a supervisor in the division of special pathogen and transplant products in 2005 which is currently called the division of transplant and ophthalmology products so welcome our speaker is pleased did it do and I have a long history work together probably over 18 years so we've got a little bit of a tandem presentation today I'm gonna be covering the content and format of your initial IND submission so what that would look like I know from Kevin's presentation earlier that a lot of you have actually already made an IND presentation or IND submission so probably a lot of this information won't be unfamiliar to you but hopefully you do learn something and then Jude it's gonna take the second half of the presentation and let you know once we get your IND what happens to it in those first 30 days so we're gonna try and get get through all of this so again my presentation is on the content and format of an initial IND submission and you can find information on this and the regulations at 21 CFR 312 point 23 I'm here it's my disclaimer so I thought let's start off with a little bit of an audience interactive so I know a lot of you again have submitted these IMD's before but really recently I think in April of this year we've updated the 1571 which is the form that comes in with every application for an IND so when I see how many people you know that have submitted since that time point know which fields in this form have recently been added so you know how many people think that it's field 6b how many people think it's 7d people think it's filled 12 okay guys we're all doing good okay so all above is actually is actually true and I'm gonna cover these as we move through the presentation today here's an idea of what show which fields those are my screens jumping all over so I do apologize so so again the requirements for content form out of an IND can be gonna be found in 312 point 23 you know in my presentation will be a little bit more of a regulatory to us because that's the area that I work in and what I would look for in your application on your application submitted to us over veal the presentation I've got a couple slides on that what we would expect to see for content and format cover letter regulatory forms table of contents introductory statement your investigational plan that's to get a brochure Monica protocols and then your chemistry Oh non clinical information human experience if you have any at that stage I'm in an additional information so we're gonna go through all of these this schematic is I think really helpful for people that may be a submitted IND is in the past it gives you an idea of moving to the common technical document where these pieces of information fit and I just put it up here because I think it's a really good schematic to show you where the pieces now fit in the five modules that are required in the CTD format we call this a CTD triangle and the triangle basically outlines for you were the middle pieces modules three four and five and two are your common technical document and then your first module module one can vary depending on where you submit your application I mean that's all of your administrative information another good example of the hierarchy where your pieces fit sometimes they get a lot of questions about where do I put my submission in my application we have a very good document on this and it will tell you as new things come up for us where they get added into the hierarchy for your submission so I have a link at the end and I you know do encourage you to look at that to figure out where your pieces go especially as you're into electronic submission so first modules your administrative information and then summary information is to quality three and then so on four and five for non clinical and clinical so let's take a little look at the administrative information so this is kind of an outline and as many index of what you're going to be including in your administrative section so first is your cover letter it's usually you know a couple pages long depending on you maybe patent pre-ind meeting what this there's some more information that you want to explain to us dressed our division director provides us with basic information on what we can expect to find in this submission or if there's anything unique you want to call out to us this would be the place to do that it's always hard when if there's information buried somewhere in the submission for us to find it later later on in our review so you know do tell us all of your information up front in your cover letter although the cover letters actually not required for an IND submission the 1571 is somewhat your cover letter for your submission and provides a lot of information to us but we do appreciate a cover letter with your submissions as well so we talked a little bit about the form 1571 it's electronic sized it's kind of a fill in the blank form now has a lot a lot of information in it every time you submit after your initial submission you're gonna be required to submit a 1571 to us so it's really good to become familiar with all the pieces of the 1571 your administrative information in the contents of your application provides us with your sponsor information contact information etc so we're gonna look at a couple of the screens next and they're gonna be pieces that I pulled out from the 1571 which I think are important to highlight so of course you know name a sponsor goes in number one and then name a drug in number five so for people you know put in the name of the drug if it's a code name you tell us as much information as you can about your your drug and also tell us what your dosage form is this is one thing that I find gets missed a lot I'm in the submission so it please if you you know oral can mean a lot of different things it could be a tablet or capsule suspension you know so be a little more specific for us it really helps us all this information on the 15 7471 form gets into our database so the more accurate information coming in the more accurate your file is field 6b this is one of the new fields and this some is a commercial and research witch coven actually talked a little bit about earlier today one of the main reasons for this is we've moved in an electronic format and if you're a commercial IND you're gonna be expected to be an electronic format they'll look trying to common technical document research can still be in paper although we highly encourage you to submit electronically on the document room if your commercial and you send it in paper we'll send your sent will notify you that your submission has not been accepted so they've been doing that quite quite regularly over the last two weeks so because they had announced that this was coming for a while so so again it's it's kind of a highlight of you know Kevin covered this earlier a commercial IND is a product that eventually is going to be commercialized and the reason you know usually just for research and it may be for publication or something else field seven this field is very new to all of this it's the sno-med CT terms code and about mine for you here where you can go to find this information and how you can get this onto your form this is very new to us so you know bear with us as we make this change and update our database and the idea behind this is so that we have more standardized terms in our database because you might get an indication that says you know for treatment of high blood pressure it's really hard to search a database when you have various terms in there so the idea is to get all the terms to be more consistent helps with the electronic medical records etc so there's a Barrett very new to us section 11 is the submission what your submission contains you know for your original IND it's gonna be the first box you're going to check but later on you may have a multiple of submissions and you may need to check a number of boxes so be diligent about doing that it really helps us get your submission to the right where viewers when it comes into the agency so we don't lose any time number 12 this is one of the other newer fields and this is for combination products again I've outlined for you the combination categories if your application is not a combination product then you're gonna select the box No and you're not going to fill it in but if you are please select the appropriate box and fill that in on the form contents of the application another really important piece especially for an initial IND submission check off all the boxes that are that are applicable to your submission this is one area that I highlight and this is your contact information and this is we get a lot of errors in this area and you know so make sure you put down for us who your authorized representative is and if that person does not reside in the United States and please list for us in number 24 who your regulatory contact will be and then make sure you both sign the form form 36 74 is your clinical trial certification form on an initial submission this is registration you notify us that you've registered clinical trials.gov for original submissions submit the form to us their appropriate boxes to check on that form that maybe this doesn't quite apply yet but you're aware of it and then as you move to your face two or phase three studies you're gonna want to resubmit an updated form that lets us know you've registered and you've got your NCT number with that the requirement is within 21 days of enrolling your first patient in your face to three studies that you get this form updated investigational plan general information on what do you plan to develop this drug for please provide us with some general information on that your investigator brochure everything you pretty much know about the product at the point you submit this application this is investigator brochure that will go to your investigators at the investigator sites and gives them a really great snapshot of everything that does known about the product madjoe penned a whole lot of time on this later on in your modules 3 4 & 5 or all your really detailed information and then so the summary information comes from that information and it's something that I as a regulatory person would review when this application comes in to make sure all the pieces of the application are there before sending out to our reviewers and the same for the introductory and summary information this is all really valuable information for us please be you know as comprehensive as you can again I'm just highlighting what goes into summary sections political overview clinical summary non clinical chemistry quality information another very big part of a new IND submission you know tell us about your drug substance where you getting it from how's it being manufactured your drug product provide us with your certificates of analysis if your study is going to use a placebo formulation you know please let us know how that's being made I've given you a link at the bottom provides a lot of additional information on this very large chemistry section of your application and you're also going to hear later on in the presentations very detailed information on both the chemistry and the non clinical and clinical sections section number four is non clinical this is all of your information on your animal studies could be drug disposition in your animals your pharmacokinetics pharmacodynamics your aadmi studies provide us with all the information that you have up to that point on your animal studies because this is really going to help us determine whether or not this product is ready to go into humans and whether or not any safety signals might have been identified many literature references that you may have you know please provide us with that information too moving into your clinical studies section you're gonna provide us with your 1572 s this is for your investigators they all need to to sign these forms you're going to tell us what protocol you're starting out what are you starting out with the phase one study a phase two study phase three study and any any clinical data that you have to do sometimes we have I Indies have not gone into man yet they have no clinical data if that's the case then you'll let us know that as well proponents for your clinical section again your phases of development and your qualifications for your investigators information on your facilities and your IRB s money and again any previous human experience and then again you know if you know that safety safety has been identified for a particular issue you know tell us how you plan to monitor for that risk you know tell us that upfront so we can take a look at that here's gives you an idea you know which which studies would qualify for Phase one which ones are gonna be phase two and which ones are gonna be phase three we see a lot of phase 2 studies coming in now and you know not so much in the face 3 but these are much larger studies more detailed give us a lot of information moving forward your form 1572 your investigator commitments so they need any investigator participating in the study needs to fill this out and sign it by signing this this is their agreement to conduct the protocol as as written to obtain informed consent on their subjects to assure us that they have institutional review board review and that they are willing to adhere to all the record-keeping requirements and to report the adverse drug reactions to us as required by our regulation so I know a little bit more on the safety in tomorrow's discussions previous human experience again anything that you have if you have any testing that has been done maybe overseas or you know you find in the literature on your on your product you know please provide that to us in any letters of authorization or rights of reference that you might have that would go in this section as well um if your IND happens to be a drug firaon drug dependence or abuse potential radioactive drugs or you're developing a pediatric a pediatric of formulation you know include this in this section as well and if you have foreign references for us please provide us with the English translation as a lot as well as the foreign reference that's very helpful and then a little bit I know it was covered earlier but just as a reminder that you know research on DS can still be submitted in paper electronic please use electronic common technical document you can also submit in on feet on physical media and it can come through our gateway submission which we'll talk about in the next slide or - there's your address how bad dress I'm not a real techy person so I suggested you if you have any questions on putting your application together how to get through our gateway formatting things like that I've provided a number of references our IT group is very helpful and can guide you in those areas but I do recommend very early on please get yourself even if you're not planning to submit an IND even if you have questions for us now please get secure email it's our only way to really communicate with you people want to get courtesy copies of things from us if you don't have secure email we cannot provide them so please please go and get that set up if you need to get a number assigned for your application you're gonna request it it's either up number provide that information and a new thing also with that is you know make sure that you let them know whether or not you're gonna be commercial or research otherwise you're gonna delay getting your number because they're gonna come back and ask you for that information so please please include that when you request a number general information on sponsor indication drug just needs to be provided to get that and they won't provide that to you without a secure email so please provide that I have provided a lot of references for you the agencies done a really nice job putting together a lot of information to help you guys so please take the time all these links I've checked they all work they're all live really a plethora of information for you I think you'll find that ant that they they're visiting these sites will answer a lot of your questions when you put together your IND again directions electronic directions for filling out your forms very very helpful please take a look at them and I guess I'm about out I'm actually exactly out of time so now that you put together your IND and your IND has been submitted to us I'm gonna let you two go over what happens to your IND as soon as we receive it so thank you I hope that I can do in timewise as good as Murray need because we needed to paratus another you have memoria introduce you to help to put together the IND submission and they elect elements that we require even the regulatory I'm gonna focus now on the black box and what's happening behind the walls when your submission gets to our place and what do we do with it you don't throw it away in the trash it's not disappearing and it's a time when we try to work on that Oh during with our team and it takes a lot of efforts because we have only 30 days to make a determination if they Andy is safe to proceed or if it's not and the emphasis is put on the safety of the patients that are going to be involved in the research so it's the most important time and for that let me emphasize it's really relevant to have all the information we need because it's very time-consuming and it's a lot of press that puts together with our reviewers if you have heard the communications and marine as of May the FIFO commercial I and these need to be submitted in electronic common technical document common technical document was presented in the previous slides it has to be an electronic they're here the limitation of the gigabytes I'm not a techie I'm just a paper and fax person I'm learning that our electronic submissions group will be able to explain you order the size of the gigabytes or not your forms that you need to feel and has to be filled out but if especially there 1571 that it needs to be completed and for research on these we still accept them in paper and however we we really recommend it would like you can submit it in electronic format what do I mean by electronic format you can submitted it in a CD or you can submit it in a pendrive comes to our document they'll upload it in the electronic document room and it's very helpful for the reviewers because a lot of the review work they do is cut and paste from the information you provided in their review this is to be able to substantiate the decision um the only thing is this is really nice if you can do that is if you can hyperlink or put bookmarks in a PDF format and that is uploaded and we get notification for that so arrives to cedar and I'm talking specifically to cedar because that's my area of expertise hey the first thing you anybody know so have her and what about darts well yes this is our tracking system tracking reporting regulatory tracking system for now is the system we have to track and work with a Indies and when it arrives it comes to the Chiefs and I don't like chief but that's the way they gave us the name chief project management's update we get a notification and it says okay this is a new IND what do we do with that does it belong to your division said oh yes this is an indication that the logs to my division but suddenly there is an indication that that's not and here is part of what I'm asking try to do sometimes the legwork before and communicate with us because the Division I work is the division of transplant and of technology products and we do transmit we do only solid organ transplantation you don't do stem cell transplant so that has to go to another division so if it comes to me and let's assume that we have 30 Cal in their day and they are they submitted and Friday afternoon we have Saturday and Sunday that we usually don't read the emails and Monday is a holiday as might happen and it comes to my division on Tuesday I can say okay maybe I tackle it use day because we look at it so it will go to the other division on Tuesday Wednesday so the review of lost almost a week so try to communicate with us give us a call pick up the phone I have a product for this and we'll try to connect you to the person that you need to go and make sure that you're submitted to the correct division when it so my division we need to on an initial submission we need to assign a review team this is all the clinical all the reviewers discipline-specific that will need to be involved clinical CMC clinger pharmacology all day and drugs that they look for antimicrobial on em antiviral activity we have some specific reviewers to do the clinical microbiology and if you submit the product that has to be sterile we need to consult to the people of micro sterility by the way all the products are of technological use has to be sterile by regulation so automatically we get a reviewer for micro sterility that is not clinical micro micro surreality and we have consults in many instances we need to consult another centre if the product is for a combination product we don't have the expertise in reviewing a device or howlite my work that needs to be radiate in the eye sometimes they the indication or the end point require us to consult with another division if you have a product that it's very typical that it's studying the antiviral properties people who do okay patient who undergo a kidney transplant and we have product who studies and antiviral properties for that that goes to the division of antivirals because the endpoint is the antiviral activity however if my division we receive an IND and if we say we're gonna study the graft survival in patients who have it's in buyers in their body so we don't have the expertise in antiviral we consulted the division of antivirals in their expertise but we have the expertise in the transplant and the graft survival there's a lot of backward that goes there but we more or less have it under control more or less if here comes a key within 30 days our review team we need to make a determination if the study is safe to proceed the IND goes into effect or if it's play some clinical halt and we're gonna look later in my next slice what happened with clinical hall just a pet peeve from the regulatory project management in Cedar high and these are not approved if anybody calls me and says he's my Island being approved I cringe we do not approve we deem them safe to proceed they become goes into effect that that's the regulatory term or is that the only one who approves research is the IRB and they approve research not just the protocol but all the other things that they're attached to your research advertising in so on so this is most important thing so we both of the division have a meeting by day 25 36 37 just to make sure that we are out of the same page and if you're IND is safe to proceed hey you're going in many division if you do not hear from us it's good to go and this is because the way it's written in the regs no news is good news there are some divisions who like in emphasize in writing the letters I work for the division of transform and of Technology the ophthalmology group doesn't issue safe to proceed letters we don't call you you're fine but the Division of transplant of Technology the transplant section and clinical team likes to get involved and because it's such a discipline that is really difficult to work we try to provide you comments we give you the letter safe to proceed so it's a different way both of them are right if you do not hear from us by day 30 pick up the phone to your project manager and talk to them and we will let you know if it's safe most of the time yes because if nothing would have called you before in case you have any question how do we manage all this IME here is a map and would try to provide you like more India than my previous colleagues as many Reece a opportunities for references so you can figure out where to find the information so in essence this is the best what do we do in the safety days we try to make sure that we provide for the safety of the patients this is the risk benefiting from this is the information you need to provide us are we covering the safety of the patients do you have all the information did you include in your study a creek area for individual stopping criteria after how many adverse events are you going to stop the research after how many patients demonstrating adverse events are you're going to have stopping research notice all information that needs to be included in the protocol if you don't write it we don't know about it so try to be exhaustive if you're going to leave a drive that can cause problems heart problems and you have a crash cart next to you to work write it in the protocol it's there a crash cart will be available in case we have an adverse event it's better to be over extensive than less because if not we're gonna call you and figure out where are you in that in essence the primary objective is to determine if the trial is conducted as is describing your protocol it can be conducted without unreasonable risk for the subjects or patient if you you identified four minutes I need area if you are identified that's good to have it there if you are identifying your protocol and your non clinical study some safety signals that doesn't mean that you cannot go in clinical trials it means that those safety signals will provide us a bet on how to monitor or to define the inclusion exclusion criteria if there are certain areas where there's higher standard but but you need to please we can always control for those element figure out what you have in that areas unfortunately your study is not safe to proceed and we put you in clinical Hall as much as you don't like an industry and sponsors don't like to be in clinic of all the agency doesn't want to put people in clinical Collider so there's going to be a lot of back-and-forth negotiation because we get to this point full clinical hold all research stops partial clinical hold it's part of it there's certain population there's some people who might not be able to do it we recently have a case of we discuss with the sponsor and we told them to enroll pediatric patients in the pre IND meeting come with the IND they provide a non clinical information and we see that they are they are also falling asleep and there is a lot of somnolence and you say well you know unfortunately we will not be able to go in kids it's not safety okay so your options are we put them on clinical horror oh we call the sponsor and tell them okay we've rescinding requests we made before you can conduct their study do not include pediatric patients for now and imagine that where are they happy about that yes of course there's less risk for that we ask them to do it they didn't want to do it in the beginning and we move forward they modify the protocol that I am the that protocol is safe to proceed protocols are safe in the IND so this is the grounds for imposing clinical ho for phase one trial let you read for that in essence is this safety of the patient let me tell you from all the elements that they're written in the regs in my almost twenty years of experience and I talked to marine most of the time very and these are placed on clinical Hall when there is insufficient information to assess the risks of the subjects all the other things I never put an eye on the on hold because of clinical investigation to qualified but it's written in the regs and this is part of the reason of all elements sometimes we need additional chemistry information to make sure that we're giving to the patient is really what you are proving in your ime I understand clinical whole when you have a clinical hold a potential Kaneko will talk to you will pick up the phone and that's why it's so important in your 1571 to add the name of an alternative contact if you submitted your IND and you said now I can go on vacation yes go on vacation it's not a problem but we need to have somebody to call in order to be able to resolve it the agency will try to call to you and figure out how we can resolve this issue the division director is the person who will call you and tell you you're in clinical hold if it is a commercial IND if it's an IND for research probably the project manager will call them will document that and in essence will explain the reasons and by day 30 you will receive notification on a letter stating that you are in clinical hold the reasons and how to resolve it work items or elements you need to provide or address or revise in order to be able to get off the clinical halt and you submit once again is somebody a complete response comes to us and at this moment another cycle of 30 days starts and we go again the only good thing about this is I don't need to request another T we have the team already in place so schedule the meeting figure out and in other 30 days will tell you if you are up hold or we can continue in clinic alcohol and this is what my reviewers do now you have the reason reason that you can appeal your decision if we told him cleaning a hole that you don't believe it's there the alternative to appeal it and there is the process that is coverage dispute resolution that you can go one step higher to try to resolve the clinical hall some of my best practice is two minutes I will borrow this practices require we love to have a cover letter tell us the history we like to read the 1570 why shoes have made everything but would love to see what are the elements in your program what are you gonna do especially contact phone number alternate phone number and if you have an email we really this dais communicates more than email that iPhone so if you can do it include that try to have it organized assure the safety of the subjects and that scientific information is there in for email communication you need to set up a secure email with the agency currently there is a pilot going on that we might be able to be able to fax you from our computer so they're gonna be secure but until that gets in place we need you to have a secure email not required but it's nice to have one protocol in your initial IND submission because if anything goes wrong we can address that you submit two protocols maybe the second one is not safe and the Hawaiian D goes on clinical so responsible submit only one I cannot emphasize more the second bullet we have a great group of people that are the project managers who really are your conduit to talk to the review division after then they will communicate with you you communicate with them and you will get all the information from them be available for discussion and consider a pre and D consultation as my former colleague said before few minutes where a we included here is here so most common five frequently asked questions come in she could come back on this slide then we need to move on I'm sorry dude it I'm not gonna do that okay thank you Thank You Jay