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hello everyone and welcome to today's webinar understanding new drug applications presented by row I'm Joe Keenan contributing editor to fierce markets and I'll be moderating this webinar our speakers today are David shoemaker PhD and senior vice president of R&D at ro and dr. Megan spa halle assistant vice president of operations at row you can read their full BIOS on the right side of your window before we begin just a few technical notes this webcast is being streamed through your computer so there is no dial in number for the best audio quality please make sure your volume is up you can find additional answers to some common technical issues located in the Help button at the bottom of your screen this webinar is being recorded and will be available on demand within 24 hours after the event we will follow a presentation with a Q&A session please submit your questions using the Q&A button on the left side of your screen and you can do that throughout the presentation all right I think we're ready to begin David please go ahead thank you very much so by way of introduction this is just the topics that we're going to cover today I'm going to start with a you know pretty 30,000 foot view of an NDA and then Megan is going to come in and and give what I think is probably the most critical section of this presentation today because it's about the integrated summaries which I think received too short of shrift in most presentations of this type and then Megan will turn it back over to me and I'll roll through the different documents in addition to the integrated summaries the submission process and the review process and finally what happens in approval so to start off with an overview I think most of you are probably aware that critical thing about your product is that it is safe and effective for the use in the population is going to be receiving your medication benefit risk assessment is part of every application evaluation by FDA and that is something that you can use beyond drug evaluation you can actually use it in your day to day life as well and finally I'm also in addition to the integrated summaries that Meagan is going to talk about I'm going to emphasize that the manufacturing process while it's not forefront in everybody's mind is off often a stumbling-block and so I want to make sure that everyone's aware that that's a critical part of the process so looking at what a marketing application is it is FDA's license to you to say upsell and market your product and it it behooves you to give FDA an accurate representation of what your development program has shown so the application has to be written very clearly and it has to tell a story both clinical and manufacturing and non clinical such that FDA can easily review and come to conclusions without asking a whole lot of questions fewer questions that you have to answer from FDA the better in my book there are different types of marketing applications we're going to be talking about specifically the NDA today the abbreviated new drug application is also considered an NDA by generic manufacturers and there are other biologic license applications and there are obviously different applications of this type in other regions but today we're going to focus on the u.s. MDA and specifically we're going to focus on primarily the 505 b1 application which is an NDA for a new chemical entity or new molecular to tea and those are novel products that go through the development from discovery to marketing applications there are also 505 b2 s and as I said a NDA's which are also NDA's but we're not going to be speaking about them today so who's involved in mende a and I think this gets overlooked is the totality of the development team there are incredible number of disciplines that must be engaged all throughout the process and they generally have to participate in the marketing application as well there's some aspect where you're going to need their contribution and so if you don't have your team assembled right from the beginning you're going to waste time identifying these components of your application preparation team the format of the NBA and you hear a lot of people refer to when NBA as a CTD and it's not a CTD CTD is merely a format that was developed by IC H in I think the year 2000 are there abouts it's been revised recently in a in a guidance in 2016 but it basically is a reorganization of the way an NDA was done back in the day and it is harmonized between the US Europe and Japan and other countries have adopted IC H as well but it is a means for an an individual company to submit a marketing application to several regions historically that was thought to be done simultaneously in the different regions but in actual fact I mean aside from the big pharma companies a marketing application is is rarely submitted simultaneously to both Europe and the US it's done you know months in sequence oftentimes the content of an application is obviously the data that's what we're going to be talking about primarily today the data is rolled up into summaries that make it easier for the FDA reviewer and you also have to provide FDA with a history of your development process from the beginning so that they understand what agreements have been made prior to the submission of this NDA and you you all know that you're regulated by regulations as well as guidances and other regulatory publications so the key decisions that a reviewer at FDA is going to make is again whether it's safe and effective for its proposed use in the defined population whether benefits outweigh the risk and whether the proposed labeling is appropriate manufacturing again enters in as an important part of this everyone thinks about clinical being the most important part of the NDA and it does drive everything but it is not it is the data ultimately that is going to determine the approve ability of your application so one of the biggest mistakes that we see having done you know several dozen of these personally and we do two or three of these a year are the planning effort that's put into these applications typically you should start planning your NBA at proof of concept and most companies are loath to invest that much time but it is driven obviously by your clinical proof of concept but there are obviously support of non clinical studies that must be completed CMC and quality or CMC or quality issues that need to be conducted and evaluated and regulatory strategy that all need to be folded into a target product profile so that you can determine the roadmap for your development waiting longer than the proof concept of your therapeutic is definitely possible you just lose efficiency also as you start planning your NBA it's good to start documenting the decisions that you make so you don't revisit these decisions continually having a decisions log does not require you to follow the only decision that you've made but it creates somewhat of a higher energy of activation for you to revisit that decision again safety database needs to be constructed data standards is something that we spend a lot of time on in our shop because most companies don't give this the effort that it's needed to allow a smooth transition to an NDA preparation and then obviously you're going to have regional requirements that Megan will even talk to in her section of the talk today so success factors are a coherent registration strategy having no gaps when you altima Talisa MIT your application your document should be well written and it should be Q seed and QA so that there aren't obvious errors that the FDA picks up on and begins to dig deeper because they find inconsistencies and this is all made much easier by a competent program manager who keeps everyone on the team operating at maximum efficiency to their define timelines so that you're going to have bumps in the road regardless but the more transparent you are with the entire team on when everything is coming together the more efficient your process will be in the more likely you are to meet your timeline again this is the organization or the format that I talked about that was promulgated in 2000 the CTD module one is is different for Europe and Japan in the US module two through five are identical in the three regions with the exception of some special documents like the ISS and IOC that that Megan is going to talk about today in the u.s. the label whether it's a target product profile or it's an annotated package insert or it's the final package insert is the absolute distillation of your entire NDA the target product profile can be used very effectively in in development the annotated package insert you are required to annotate or footnote every statement that you make in your final label and so it's good to be thinking about what data you have that supports statements that you want to make in your label I am forever talking with companies that want to say something in a label when they have no data to support that statement and it just can't be done FDA won't let you do it and the package insert or prescribing information is the ultimate goal and this is just an example of a table that we use in our MBAs and you can see that this is the indications and usage section of the label the product is indicated and you define what the indication is in the draft text and then over here on the right-hand side the annotation module or reference listed drug P I if you're doing a 505 B 2 you have to reference where the facts are that justify your statement absence facts or any justification you are not allowed to make a statement and that's an important issue that's lost on many people so this is the organization of the CTD again module 1 contains the label but aside from that it's regional depending on what i CH region you're submitting your application to I will go through later the us components in module one and if you look at the CTD and moths the data resides in module three four and five four CMC not non clinical and clinical data and that's where the original reports CSRs for clinical the stability reports for quality and the toxicology reports for non clinical exists modules two point six and two point seven are distillation x' but it's still largely data so that's where the data resides and then FDA allows you the ability to create opinions surrounding this data in the summary it's not you know ad libitum your interpretation but you are allowed some leeway whereas in the data sections of the CTD it's just the facts mam this is your interpretation it's where you can begin to craft your story so if module one is regional and it DIF differs between Japan US and Europe modules 2 through 5 are the CTD proper and again if you write this once you can then use this section of the CTD in multiple regions around the world so if you look at the module 1 again the label again is the distillation of all of this that's working up to the summary in module 1 so now I'm going to turn it over to Megan and she is going to talk about what I think is too often overlooked and not done soon enough by many companies preparing their nd thanks David so just to recap the NBA includes all information about your product from its inception through clinical testing and the integrated summaries of safety and integrated summaries of efficacy are limited to just the clinical portion of your product development but they tell the story of the data across your whole clinical program so similar to how your clinical product project needs a statistical analysis plan your ISS and ISE also have statistical analysis plans that are needed to describe the integrations an analyses that you're going to perform now these statistical analysis plans are not just a regurgitation of what happened at the study level because it's a separate analysis with a separate purpose and we're going to talk about the ISS ISE and the purpose and goal for the next several minutes so your ISS as you know your phase 2 and phase 3 studies they are designed to establish efficacy or effectiveness for your product most aren't designed to test safety or to identify adverse events that are predefined with a level of specificity so really what your goal of your ISS is is to combine the safety data of your program to describe the safety profile of your product this can include analyses of safety related events estimates of risk over time you will need to look at different possible sub group differences in your safety and also it will help you identify risk factors associated with the events and enumerate them to the FDA so what we want to make sure is we there are things that we expect a reviewer will look at with regards to you or integrated summaries of safety and in 2005 the FDA put out there safety review guidance in 2010 cedar additionally put up a good review practice which provides a lot of insights into how the agency will review nba's um at a minimum you will expect that your reviewer will look at serious adverse events that could be related to the drug on common AES that could be related to the drug and then factors that would predict the occurrence of these adverse events as well as exposure so exposure looks at the duration the amount of time the population and how long you followed your subjects up in your clinical studies before we get into the meat of what you should be looking at and questions you should be asking about in your ISS um there are key considerations and three guiding principles that you should always keep in mind related to an analysis plan you're creating for your integrated summaries of safety first you want to produce reliable estimates of safety that describe your whole profile to do that you um we'll talk a little bit more about how to define your parameters of interest but once you have those you also want to include a ease of special interest and different populations of special interest a lot of these are going to be dependent on your indication or on the class of your um drug product additionally you have this all of the ISS is basically exploratory in nature when it comes down to the statistics that you use there's very little formal statistical testing ie testing in an adequate well controlled environment where the p-value has any more anything other than a descriptive meaning but you still need to look through all of these you need to test different things because what you want to do is show the agency that you have identified trends and issues and that will help with your risk benefit statements later on so when you start looking at your ISS as David said this really takes a village there are a lot of people involved in making sure that the messaging and that you have in your NDA are appropriate for the indication that you're trying to get approval for so there are three key questions that can really help your whole team move forward in what's best for the ISS so this is when you get your clinicians your statisticians your metal writers all in a group all in a meeting to talk about these three key questions and these questions should be asked in the order that is on your screen so first is what are the safety parameters of interest you'll have to look at the key safety messages you'll want to go in your label and define what parameters would then help you with that messaging once you know the parameters you want to ask how to present those key safety messages to define the overall safety profile and then once you have that you can talk about how to best characterize the information from the studies in the program that was really quick so let's get into each question individually to have a better idea of what your team should be discussing so there is going to be a lot there's a lot specified and agency guidance on what safety parameters you should look at there are also going to be on eight years of special interest based on your indication or based on the class of drugs or your compound and there are also going to be things that come up throughout the studies that allow you to want to look further based look further into it to make sure you're not seeing trends across studies on all of they're also as you to finalize your program and you're getting towards the end of your last phase 3 you're going to be reviewing the data to identify any safety parameters that have come up that were unexpected and at the start of the program so when you look at the different parameters um typically you'll see things about exposure and the agency is going to expect exposure data data on concomitant medications deaths and other adverse experiences laboratory measures and vital signs and then other investigations that are either specified in an agency guidance on your therapeutic area or otherwise or have been discussed through either your pre NDA meetings your your Ben disease 2 meetings you're going to want to look through all of that to make sure that you're investigating appropriately um although all of these are quite common the level of emphasis for each is really going to be very dependent on your specific compound and the class of drugs and the type of indication you're going for I can't stress enough how important it is for clinical and staff to come together to address if these parameters are going to be the most effective to develop your key messages once you've prioritized the measures and you have it in place we can start moving to question 2 so really this question is once you know what you're going to look at you need to define how to present the key safety messages and overall profile so when you're looking at this you need to think about what should the analysis and presentation approach accomplish and you're gearing all of this to how the reviewer is going to see this data so you want the reviewer to get a true value of the parameter of trust and you also want to make sure that there are meaningful comparisons this could either be between active groups and placebos or it could be between from any comparator group that you've had in your phase 2 and phase 3 trial so how do we do this so how can we with the parameters how do we make sure that we're characterizing them appropriately for the agency there are a lot of different choices here and um the methods listed to the right are common and epidemiologic analyses and they're also very common throughout an ISS but with what you choose is dependent on the parameter of interest so you might want to use a crude rate or just a proportion so if you want to know that 35 percent of the subjects on this in across the program had a certain adverse event um that might be worthwhile and then you could just use a proportion you might want to use an incidence rate if time is a factor for example if you have a vaccine trial you're going to get erythema but what you wouldn't want is erythema after two weeks after the vaccine so you might want to look at certain times of limited functions and then you would use an incidence rate or there might be an instance where you wanted to use on where a subject could get multiple events throughout time and if you want to take into account not only the number of subjects who have the events but the number of events that happened you'd want to look at a total incidence rate so once again as you're going through your parameters what you truly want to look at is the message you're trying to state what you want to look at and that and then your statistician can help you with what type of measure you'll look at to make the most impact in your messaging once you know how you're going to characterize the safety parameters you can also look at how you're going to compare the two treatment groups again one has many choices on there your statistician is going to be able to tell you what is best for your messaging based on what you've chosen um as your on characterization and I think that um here you have to remember that these comparisons differ from formal comparisons that would be in any efficacy setting so they are made for the purpose of assuring that no safety signal is missed they're not necessarily made to show that there is a treatment difference or a treatment effect you're wanting to give confidence that you've looked at your safety parameters and that you're not missing anything as far as a trend or a safety issue so with these key parameters that you want to look at you also need to ask about questions and special-interest we've come up with veces methods to characterize our parameters we're going to compare them across groups but based on your indication there could be questions um that you want to consider and that could be are there specific adverse experiences that are of clinical importance are there are there known adverse experiences with your drug or with drugs in your class that you should be highlighting for your risk benefit statement and also you don't want to give the agency everything you have to focus on what is important for your compound for your indication for your therapeutic area one of my colleagues routinely says don't send a mine and tell the agency to find the Diamonds you need to focus and you need to tell the agency about the Diamonds so there are going to be good things and there are going to be bad things on potentially bad things that come out of um your your integrated summary of safety the biggest thing is that you show the agency what you have and what you found be transparent and then any any of the things that could be deemed questionable can be addressed in your risk benefit statement you also when looking at the parameters to use and how to characterize them you need to consider some special challenges that can pop up across your program so these are things like the variable length of follow-up and exposure across the different drug trials there might be some studies that are uncontrolled there might be if all the others are controlled and have a placebo arm you might you could also have an unblinded study all of these are going to add in different levels of variability to your point estimates which then just need to be able to be described and thought through so the easiest for the earlier you discuss these special issues that can pop up the better you'll be in the better messaging and narrative you'll have in showing your data to the agency so now we have the parameters of interest we know how we're going to characterize them we know how we're going to show differences across treatment arms and now we have to go and paint the picture of our safety profile and the biggest thing is that we want this to be an objective look at the on safety profile as David said there are other modules of the NDA that can get into more building this story this is what the data is showing and only what the data is showing so you're under a regulatory obligation to present all of the safety data this could include all studies in the database um but you're under no regulatory obligation to pull all of the studies for all of the analyses that's really ultimately a sponsored decision however you have to keep in mind that the FDA and any Advisory Committee that you might go be part of our convinced divisibility of the strategy so really what this comes down to is how do you pool your data um you would pull your data because once again your individual trials are not really set up as far as the sample size is concerned to show safety trends especially for more rare incidents rare events and so the more data you have the more precise and reliable your estimates are going to be on that will allow you to better describe your overall safety profile also as you get an increase sample size you're allowed to explore where there are possible interactions this could be a drug demography interaction a drug disease interaction a drug drug interaction having a larger sample size can allow you to look into these subgroup analyses so you want to combine your data in the most valid way and your safety message should drive the pooling strategy so you don't want to pool just for pooling sake you want to make sure that you're taking the message into account you also want to make sure that you're pooling with an effect to have transparent results so this isn't the time if one of your on pivotal trials showed that there was a safety signal this what the agency isn't expecting is for you to pull everything to mask that one study's output you want to be transparent in what you've seen and in that particular case the agency will likely look at a individual study level anyway and see that the one trial had a different safety event status than the others so what are some factors to consider about pooling the biggest thing is that there is variability across your studies and so the more differences you see across your studies the more variation in your parameters it's going to to be imposed on so you have to look at the design similarity are your designs similar did they have similar on visits did they have similar visit windows where the dose is similar did they did you follow the subjects up for the same duration did you dose the subjects for the same duration and then the type of control you use whether it's placebo controlled active controlled or an uncontrolled trial the geographic region in which your studies are conducted and then your populations all can all need to be taken into account when you're developing your pooling strategy you want to make sure that it makes sense to show what is going on as far as a safety profile but also makes sense in regards to the population that you're trying to get on your label so to recap on the IFS we've provided some information that is useful in what you need to think of when creating your integrated summary of safety and we've talked about three questions that you should work through that can help provide a roadmap to creating a complete safety analysis of the product the ISC is um you can ask very similar questions to the IOC as the ISS and I would actually ask that you do because once again you want to focus on your parameters of interest how you're going to describe them and characterize them how you're going to show differences and then how you're going to pool but the ISEE is really focused on integrating summary of data demonstrating effectiveness rather than safety and you want to focus on your claims indication so you want the data to support your dosage and administration you also want to look at subgroups to make sure that there is um there is efficacy across different subgroups or if there's not you can discuss that further in um as it might be a difference in your label claim um so your primary objective for your IFC is to get precise estimates of your primary endpoint which is very similar to the safety if you are able to pool some of that data and pull some of the information your estimates of effectiveness will be more precise you also want to look at key secondary endpoints assuming they support evidence for your primary and then the agency is expecting to see subgroup investigations to examine the consistency of the effect so here you're going to rely on your adequate and well controlled trial these are typically your phase three studies however they don't necessarily need to be your phase three trials depending on your program phase two trials that are not adequate and well controlled typically don't control for your type one error rate on you tend to have a lot of multiplicity you're looking you're having multiple comparisons throughout your trial and so these weren't set up to be adequate and well controlled studies but throughout your ISC you want to focus on your primary endpoint or Co primary if that's how your program was set up and as I said you want to look at one or two secondary endpoints that have clear clinical relevance to show consistency of your product across multiple different endpoints um subgroups of interest are important because the agency does want to see that consistency in effect and once again with a larger population with the pooled data you have a you have a more precise estimates of if there is any response based to any subgroups the subgroups could be age gender or race or something else that is important to your particular indication and just like the ISS everything is not okay you don't want to throw in every endpoint secondary and exploratory that you've looked at across your program keep it simple stick to the primary as in one or two key secondaries and then finally the ISE is also where you're going to show your demographics and baseline characteristics to categorize the population because you want this to be your evidence to support your proposed labeling population as well and any differences that come out of the population based on the program that you have should be addressed and you need to talk about why you are or are not pulling your data I'm going to send it back to Davis to just give a quick overview of the rest of the NDA process thanks Megan so hopefully by now you have an idea of the criticality of the ISS and the IOC to the success of your NDA that is where FDA starts when they're determining the safety and effectiveness of your product there also is module two point five point six which is actually a high-level summary of benefit risks which incorporates the meaningful elements of the ISS and the IOC into an almost an abstract of why your products should be approved so those are the seminal NDA documents in addition to the label obviously so now I'm going to briefly go through the other technical module documents and hopefully leave time for questions at the end just to reorient you again there is CMC quality non clinical and clinical cascading up to your label in this organization of the CTD the clinical module 5 contains primarily of importance both the tabular listing of all clinical studies and FDA as a very standard format for this table that allows them to look at your entire clinical program and see what was done in significant detail and then your is s and ISC will typically be in module five point three along with your clinical study reports if you have a very abbreviated development program when rare disease many times you can get permission from your reviewing division to put the ISS and the ISE into two point seven three and two point seven four but there are page limitations on those sections which you will see so the ISS and ISE typically live in in five point three and then obviously literature references so module two point seven again now we're moving up in the triangle into those documents that are allowing some interpretation on the part of the applicant so you can begin to describe your data with what it means to you a little bit more than just giving blanket statements about what the data say and the biopharmaceutical itical methods is is primarily a CMC driven document with you know elements about manufacturing and development of your product clinical pharmacology is is really the clinical aspects of your product how it's handled in the body what are the pharmacokinetics the effect on the body with what time frame and then you have the 2.73 and 2.74 documents that I just referred to that if they're not the ISE and ISS proper in a rare disease program they are a distillation of the ISS and the ISE and again literature references synopsis of individual studies but this entire 2.7 module is recommend to be less than 400 pages in the ice eh guidance and so rarely does the ISS and the IOC make it into this because of the sheer volume of those documents but I encourage you to talk with your regulatory project manager at FDA because we just submitted module 273 that is probably 400 pages alone so they do bend the rules sometimes with different divisions but you've got to get clearance following module 2 non clinical documents you have the data and the interpretation in the module 2.6 as which is also contains a comprehensive tabulated summary of what studies were done and then the messaging or the opinion resides in the overview which is in module 2.4 2.6 again tabular summaries dealing with pharmacology and and there are recommended formats for these tables and I CH and the FDA has guidance on this as well but typically broken down into pharmacology pharmacokinetics and toxicology the pharmacology being those experiments that demonstrate your rationale for development in the in the first place and the pharmacokinetics being how your drug is handled in animals and toxicology I think people are aware of now this is the organization of module 2.4 again it's an overview so it allows some interpretation for these different disciplines whether it be pharmacology toxicology or clinical pharmacokinetics in animals this is all animal studies that are being described here and the mechanism of action is not a absolute that you must have a mechanism of action for your product but FDA wants to make sure that you at least did the due diligence necess very to examine what the mechanism of action is for your product and it also includes primary pharmacology secondary pharmacology and safety pharmacology so before you ever get to the toxicology studies in your program you should examine some of the safety parameters and the animals that you're testing in your pharmacology studies and then the pharmacokinetics how the drug is metabolized and ultimately the toxicology the quality module 3 is pretty straightforward but pretty detailed so they break it down traditionally into the drug substance which is your active farms farm assuit achill ingredient and the drug product which is the final material which is injected into humans this is just an idea of the outline of the table of contents for the drug substance none of these documents are that long but they're extremely technical and need to be reviewed and presented accurately to the FDA reviewer this is a very I'll say attention to detail part of the it's all attention to detail in the NBA but chemists tend to be over the top so these documents have to be pristine similarly with the drug product the final material that is injected or swallowed by humans is is described in in module 3 point 2 P best practices for preparation of the CMC or quality documents this is always occurring at the last minute it seems clinical is done and wrapped up and they're still CMC activities that are ongoing so whether it's a last lot of material or it's a some contaminant that is suddenly be prepared to make last-minute changes in your CMC section the document 2.3 is a summary of module 3 and this has to be written after all the work is done and all the data is prepared in order for it to be you know up to date this is the organization of module 2.3 in the overall summary again just breaking down those complex tables of contents that I showed you earlier into a brief narrative again module 2.2 and 2.1 2.1 is simply the table of contents and the CTD introduction is an abstract for the entire NDA the module two point five point six is a abstract of the benefit risk this is an abstract of everything that's in your NDA so it should be written last it should touch on all the critical messages or the label components that you want to point out to the FDA and this can be a leading document but if it gets too biased the FDA is going to stop reading so it needs to be a well-written document with some slant but not too forceful and then module one is a lot of information for the region that you are submitting your MBA and these are just some of the documents that are included in module one it's as I said not just forms but it varies from the history of the regulatory correspondence and meeting information that you've exchanged with FDA the patent information which is obviously important for generic manufacturers who are looking to follow your product into the market and you need to apply for your proposed proprietary name well in advance your submission date these are box checking exercises but they're not without a significant amount of work especially things like if you're developing a opioid with a anti-abuse component to it there's an entire set of studies that have to be done and included in the NDA a medication guide if your product is not inherently clear to the patient you need to give the patient some help the user fee waiver or the user fee fee has to go in before the NDA if you're not going to pay that fee you have to justify letters of authorization from people whose data you are accessing and if you do have a life-threatening disease you can include justification for a priority review so that your application is reviewed in eight rather than twelve months so that includes the documents I'll now quickly go through the submission this is just a routine electronic publishing and submission process it starts out with report level publishing it goes to submission level publishing that has to be approved by the sponsor of the drug who is going to submit it to FDA and then it's submitted to FDA via the electronic submissions gateway and a receipt and acknowledgement will be obtained within hours after submitting your NDA to give you an idea of what these NDA's comprise this is the total files ultimately down to this is just a recent example that we have the volumes are fairly significant if we were still doing it in paper and the hyperlinks is a job in and of itself making sure that all those hyperlinks go to the right places the fiscal year 2018 user fee is on the order of two and a half million dollars if it's an original NDA if it's a 505 B 2 and you don't require clinical data you can get away for a simple 1.2 million the review process has changed in the last five years and FDA on its website has a very good diagram that demonstrates when the submission is given to FDA if it's a priority review this whole process takes four months fewer than a standard review but that has to be for a life-threatening indication that you're typically going after otherwise you'll submit your NDA and typically within the first two months you will hear back from FDA that your application has been filed and is in review and the review takes obviously several months there is often a mid-cycle review meeting it's not mandatory but it happens on you know I would say on average 75% of the applications where FDA will ask you to come in to resolve some issues that they've termed up during the review and then finally if it is 8 months priority review will be finished and a review decision will be issued otherwise you will most likely undergo a Advisory Committee meaning and have another meeting with the agency the wrap-up meeting is one that allows you to begin talking about your final label and official action will be taken prior to your paducah date which will be for a standard review at the end of month 12 and there's a lot of activity here yay their team works on one MBA at a time it seems so as soon as they get you information it's behooves you to turn that information around by the deadline that they give you which is typically 24 or 48 hours the approval process is fairly straightforward at the end of those 12 months you will be told that you are approved and that is really the goal of your NDA and an FDA is doing a much better job at approving applications during the first cycle rather than issuing a complete response letter but if your MBA is deficient in any way shape or form you will receive a complete response letter with a list of deficiencies that you will be required to answer and resubmit that as a complete response to FDA at whatever date you finish all the work that they've given you to do so a first cycle approval is is what is the goal when you're submitting an NDA and with that I will turn it back to Joe and ask him to moderate the Q&A session okay David thanks so we'll go ahead and move on to the Q&A I think we have enough time for a couple questions so David Megan I'm just going to kind of throw them out there first question is what percentage of MBAs are approved following the initial cycle of review yeah that's what I made reference to I think it's up to around 75% now you know five years ago it was down in the 50 percent range so it was you know I think FDA is taking it seriously they're trying to give more information to development teams earlier on meeting with them more frequently certainly breakthrough designations have assisted in upping this with the communication on a you know and sometimes an almost monthly basis so but right now I would say that it's up around set five percent can you give a brief outline on the major differences if any between a BL a and an NDA yeah I think the differences really are not in the review period obviously Sieber and Seeta are not identical centers so they have their own inclinations I think the the CMC section is typically much more complicated on a BL a where you have a biologic that you're examining and and you just have a lot more I don't know biology to deal with whereas on the seedier side with the drugs it's typically a small molecule interacting with a receptor and the downstream biologic effects are generally can be less complicated than with a biologic there's also the immunology associated oftentimes with most biologics so I would say the CMC is probably the biggest difference that being said you know BL a sometimes can be very quick if it's a very specific monoclonal antibody targeting a very specific receptor so it's not a black-and-white but frankly I would I would bet on a nd a review being quicker alright this looks this might be our last question and it's a two-fold question does Roe have any experience helping companies prepare NDA's for live by our therapeutic products and if so can you comment on any ways the NDA preparation process or LTPS is distinct from the process for small molecule drugs yeah I think it's infinitely different we do not have any experience with live biologic products we we tend to work with dead biologic products if they're alive at all I mean we do work with gene transfer and gene therapy products which in some sense are alive in as much as they can be integrated throughout the body and that's a safety concern of FDA but live viruses or things of that nature we do some you know I would say we've done a fair amount of vaccine work but I don't know if that's what you're specifically talking about in terms of a live biological product but vac is Dave and I'm gonna that's Ryan's screen okay if you wanted to continue on I was just going to squeeze one more question and if we could sure what is the approximate cost of each FDA hearing pre well that made it easy there's no charge point it's just getting it's just getting a face-to-face meeting with FDA if you don't have the justification to meet with them face to face they will many times relegate you to a teleconference which in some cases is not bad because they're able to put you on mute and discuss things and change their decisions whereas in a face-to-face meeting they are extremely reluctant to change their minds on any thing that they decided before they walked to the room all right that finishes our Q&A session I'd like to thank everyone for attending this fierce markets webinar and submitting so many great questions I'd also like to thank our speakers for participating in row for presenting today's webinar the reminder the audience the webinar has been recorded and you will be able to access the recording within 24 hours using the same audience link that was sent to you earlier thank you again for joining and we look forward to seeing you at future events